Veterinarian of cvas

PHARMACOLOGY OF AUTONOMIC NERVOUS SYSTEM

2011-07-11T15:48:00.012+05:00

PHARMACOLOGY OF AUTONOMIC NERVOUS SYSTEM

Functional physiology of ANS: Nervous system (NS) is divided into central nervous system (CNS) and peripheral nervous system (PNS), depending upon the location. CNS consists of brain and spinal cord whereas PNS is formed by cranial nerves (originating from brain, 12 pairs in number) and spinal nerves (originating from spinal cord, 31 pairs in humans and 36 pairs in animals). To carry out its functions (such as co-ordination, communication and integration of body actions), nervous system is provided with neurons (basic structural as well functional unit of nervous system) and neurotransmitters (molecules that are meant for impulse transmission). Excitatory neurotransmitters (e.g. acetylcholine, serotonin, aspartate, norepinephrine and glutamate) and inhibitory neurotransmitters (e.g. GABA [gamma amino butyric acid], glycine and dopamine) are responsible to transmit excitatory and inhibitory nerve impulses respectively. Nervous system can be classified into two distinct functional units; sensory division (comprising of sensory/infow/afferent neurons) and motor division (consisting of motor/outflow/efferent neurons). Motor division is further divisible into somatic nervous system (which controls voluntary functions such as control of body posture, gait and movement of skeletal muscles) and autonomic nervous system (also called visceral, vegetative or involuntary nervous system as it controls involuntary body functions including heart beat, respiratory rate, peristalsis and secretion of exocrine glands). Autonomic nervous system has three subdivisions; sympathetic nervous system, parasympathetic nervous system and enteric nervous system.

Comparison of somatic nervous system and autonomic nervous system

Feature	Somatic nervous system	Autonomic nervous system
Feature	Somatic nervous system	Parasympathetic nervous system	Sympathetic nervous system	Adrenal medulla
Pre-ganglionic neurons	Only single type of cholinergic neurons are found which connect target cells to corresponding part of CNS.	Cholinergic (release acetylcholine at their nerve endings)	Cholinergic (release acetylcholine at their nerve endings)	There are no ganglia but cholinergic neurons transmit signals from CNS to adrenal medulla.
Ganglionic receptors	There are no ganglia hence no ganglionic receptors	Nicotinic (N_N) receptors	Nicotinic (N_N) receptors	Nicotinic (N_N) receptors are located on adrenal medulla
Post-ganglionic neurons	There is no pre-ganglionic and post-ganglionic classification of neurons	Cholinergic (release acetylcholine at their nerve endings)	Adrenergic (release norepinephrine at their nerve endings)	Epinephrine is released into the blood
Receptors on effector cells	Nicotinic (N_M) receptors	Muscarinic receptors	Adrenergic receptors	Adrenergic receptors

Enteric nervous system is also known as “Brain of Gut”. It consists of myenteric plexus (plexus of Auerbach, located between muscularis externa and interna) and Meissner’s plexus (submucosal plexus). It controls the motility, glandular secretions and microcirculation of Gut. It is not considered a true subdivision of ANS and its activity is influenced by sympathetic and parasympathetic nervous systems.

Difference between sympathetic and parasympathetic nervous system

Feature	Parasympathetic nervous system	Sympathetic nervous system
Origin	Crainio-sacral	Thoraco-lumber
Super ordinate control center (located in midbrain & medulla)	Serotonergic center	Ergotrophic center
Preganglionic neurons	Myeleinated and longer	Myeleinated and shorter
Post-ganglionic neurons	Non-myeleinated and shorter	Non-myeleinated and longer
Position of ganglia	Adjacent to target cells	Away from the target cells
Neuro-effector transmitter	Acetylcholine	Norepinephrine
Receptors	Cholinergic receptors	Adrenergic receptors
Significance for body	Vital for life	Not essential for life
Pattern of activity	Acts in diffused manner	Acts as a single functional unit
Functional dominance	Rest and digest conditions	Fight, fright and flight conditions

Autonomic neurotransmission: It involves the synthesis, storage, release, receptor occupancy and fate of neurotransmitter. It is divided into cholinergic and adrenergic transmission.

(1) Cholinergic neurotransmission: Choline is transported from extra-cellular space into the axoplasm of cholinergic neuron through a Na⁺ dependent symport (co-transport) system. This step can be blocked by Hemicholinium. Acetyl-coA is derived from Pyruvic acid or fatty acid metabolism. Choline acetyl transferase (CAT) enzyme catalyzes the combination of Acetyl-coA with Choline that results in the synthesis of Acetylcholine (ACh). Newly synthesized ACh molecules are transported into storage vesicles (granules) via counter-transport (anti-transport) mechanism that causes influx of ACh and efflux of protons. Packaging (storage) of ACh occurs to avoid its degradation. Calcium channels located on the outer surface of cholinergic neuron get opened (followed by intra-neuronal Ca⁺² influx that is required for the release of ACh from storage vesicle) through the action of action potential (an impulse from CNS) travelling across the length of that neuron. In this ACh is released from storage vesicle but this step can be influenced by Botulinum toxin (which inhibits this release and causes flaccid paralysis) and Black widow spider venom (which triggers the discharge of all ACh molecules leading to spastic paralysis). Free ACh molecules move into synaptic cleft (junctional gap) and specifically bind to post-synaptic cholinergic receptors to elicit the respective response (Anti-cholinergic agents can competitively block this step). This is followed by un-binding and then free ACh is metabolized by cholinesterase enzyme (present in synaptic cleft) into Choline (that is recycled) and acetate (that is excreted in urine). This step is blocked by cholinesterase inhibitors.

(2) Adrenergic neurotransmission: Tyrosine is found in the extracellular space (it is derived from diet and transported by blood) or it is prepared from phenylalanine and is into the axoplasm of cholinergic neuron through a Na⁺ dependent symport (co-transport) system. Hydro-oxylation of tyrosine (catalyzed by tyrosine hydro-oxylase), results in the synthesis of DOPA (dihydroxy phenylalanine) that is subsequently decarboxylated (by means of DOPA-decarboxylase) into dopamine. Dopamine is transported into storage vesicle via counter-transport (anti-transport) mechanism. This step can be blocked by Reserpine. Increased intracellular level leads to release of Dopamine (it can be inhibited by Bretylium and Guanithidine) that is hydro-oxylated (catalyzed by dopamine-β-hydro-oxylase) into norepinephrine. (Note: Contrary to adrenal medulla the adrenergic neurons are unable to convert into epinephrine due to lack of methyl transferase). Binding of norepinephrine to post-synaptic adrenergic receptors takes place to induce cellular response and then un-binding occurs. Free neurotransmitter is either broken down by catechol-o-methyl-transferase (COMT) or it is re-uptaken through any of the two mechanisms. COMT inhibitors (like Tolcapone) inhibit this step. Re-uptake 1 involves the entry of neurotransmitter into adrenergic neuron and its degradation by mono-amine-oxidase (MAO) that can be blocked by MAO inhibitors (like Tranylcypromine). While re-uptake 2 mechanism is used to recycle norepinephrine and it can be inhibited by re-uptake inhibitors (like Cocaine).

Classification and signaling mechanism of cholinergic receptors

Receptor type	Receptor subtype	Signaling mechanism
Muscarinic (G-Protein coupled) receptors	M₁	Ligand (agonist) binding stimulates G_q-protein that activates Phospholipase C (PLC) mediated conversion of phophotidyl inositol diphosphate (PIP₂) into inositol tri phosphate (IP₃) and diacyl glycerol (DAG). These second messengers increase intracellular calcium level to elicit cellular response.
	M₃
	M₅
	M₂	Ligand (agonist) binding stimulates G_i-protein which increases intracellular K⁺ level by opening K⁺ channel and decreases intracellular calcium level through inhibition of adenyl cyclase that converts ATP into cAMP. This second messenger is responsible for rising intracellular calcium level.
	M₄
Nicotinic (Ionotrophic) receptors	N_M	Ligand (agonist) binding alters the three dimensional structure of receptor that opens the associated Na⁺ and K⁺ channels. Depolarization results from intracellular cation influx.
	N_N

Classification and signaling mechanism of adrenergic receptors

Receptor type	Receptor subtype	Signaling mechanism
α (G-Protein coupled) receptors	α₁	Ligand (agonist) binding stimulates G_q-protein that activates Phospholipase C (PLC) mediated conversion of phophotidyl inositol diphosphate (PIP₂) into inositol tri phosphate (IP₃) and diacyl glycerol (DAG). These second messengers increase intracellular calcium level to elicit cellular response.
α (G-Protein coupled) receptors	α₂	Ligand (agonist) binding stimulates G_i-protein which increases intracellular K⁺ level by opening K⁺ channel and decreases intracellular calcium level through inhibition of adenyl cyclase that converts ATP into cAMP. This second messenger is responsible for rising intracellular calcium level.
β (G-Protein coupled) receptors	β₁	Ligand (agonist) binding stimulates G_s-protein which activates adenyl cyclase enzyme to carry out conversion of ATP into cAMP. Further this second messenger directs protein kinase A (PKA) enzyme for catalyzing phosphorylation of cellular proteins.
	β₂
	β₃

Location and functions of autonomic receptors

Organ	Cholinergic receptors	Result of stimulation	Adrenergic receptors	Result of stimulation
Exocrine glands	M₃	Increased secretion	α₁	Decreased secretion
Sphinctors	M₃	Relaxation of smooth muscles of sphinctor (to allow evacuation)	α₁	Contraction of smooth muscles of sphinctor (to inhibit evacuation)
Iris (eye)	M₃	Miosis (constriction of circular muscles leading to reduction of papillary diameter)	α₁	Mydriasis (constriction of radial muscles leading to increment of papillary diameter)
Blood vessels of skeletal muscles	Absent	Nil	α₁	Contraction of vascular smooth muscles causing vasoconstriction
Blood vessels of skeletal muscles	Absent	Nil	β₂ (Dominant)	Relaxation of vascular smooth muscles causing vasodilation
Male genitalia	M₃	Relaxation of corpus cavernosum, increases the inflow of blood and causes penile erection	α₁	Ejaculation which is the discharge of semen (sperms and secretion of accessory sex glands called semial plasma)
Detrusor muscles of urinary bladder	M₃	Contraction of Detrusor muscles leads to increase in urination	β₂	Relaxation of Detrusor muscles leads to decrease in urination
Bronchiolar smooth muscles	M₃	Contraction of bronchial smooth muscles causes bronchocontraction	β₂	Relaxation of bronchial smooth muscles causes bronchocodilation
Intestinal smooth muscles	M₃	Contraction of Intestinal smooth muscles increases peristalsis & intestinal evacuation	β₂	Relaxation of Intestinal smooth muscles decreases peristalsis & intestinal evacuation
Cilliary muscles of eye	M₃	Contraction of Cilliary smooth muscles accommodates the lens for near vision	β₂	Relaxation of Cilliary smooth muscles focuses the lens for far vision
Splanchnic blood vessels	Absent	Nil	α₁ (Dominant)	Contraction of vascular smooth muscles causes vasoconstriction
Splanchnic blood vessels	Absent	Nil	β₂	Relaxation of vascular smooth muscles causes vasodilaion
Uterus	Absent	Nil	α₁	Myometrial contraction
Uterus	Absent	Nil	β₂	Myometrial relaxation
Pancreas (Iselets of langerhans)	Absent	Nil	α₂	Decreases insulin secretion and glycogenesis
Pancreas (Iselets of langerhans)	Absent	Nil	β₂	Increases insulin secretion and glycogenesis
Heart	M₂	Bradycardia	β₁	Tachycardia
Adipose tissue	Absent	Nil	β₃	Lipolysis
Lacrimal glands	M₃	Increase tear production (lacrimation)	Absent	Nil
Liver	Absent	Nil	β₂	Glycogenolysis (enzymatic breakdown of stored glycogen into glucose and its entry into blood) and Gluconeogenesis (Synthesis of glucose from non-carbohydrate sources)
JG apparatus (Kidney)	Absent	Nil	α₁	Decreases Renin secretion and water retention (antidiuresis)
JG apparatus (Kidney)	Absent	Nil	β₁	Increases Renin secretion and water retention (antidiuresis)
Arrector pili muscles	Absent	Nil	α₁	Piloerection
Mast cells	Absent	Nil	β₂	Inhibition of degranulation
Parietal cells	M₁	Increases HCl secretion	Absent	Nil
Platelets	Absent	Nil	α₂	Increases platelet aggregation
Neuromuscular endplates	N_M	Contraction of skeletal muscles	Absent	Nil
Autonomic ganglia	N_N	Transmission of impulse to post-ganglionic neuron	Absent	Nil

Drugs acting on ANS:

(A) Cholinergic agonists or parasympathomimetics: These drugs have the ability to bind with cholinergic receptors and elicit respective response. Acetylcholine is the prototype drug (that drug of a class with which we compare the properties of other drugs belonging to that class) of this category. They are divided into two subgroups.

1. Directly acting cholinergic agonists:

(a) Natural drugs

Muscarine (obtained from Amanita muscaria): It possesses high affinity only for muscarinic receptors and lacks any clinical application.

Nicotine (obtained from Nicotiana tabacum): It possesses high affinity only for nicotinic receptors and being an addictive drug it lacks any clinical use. In low doses it stimulates autonomic ganglia whereas in high doses it acts as ganlionic blocker.

Areculine (obtained from Areca catecu or betal palm): It acts on muscarinic as well as nicotinic receptors. Previously it was used orally for causing purgation leading to the expulsion of tape-worms and round-worms in dogs. However it is no longer employed for any therapeutic purpose.

Pilocarpine (obtained from Pilocarpus microphyllus): It activates muscarinic as well as nicotinic receptors. It is used as miotic (in the form of eye drops or ophthalmic ointment) for activating M₃receptors located on circular muscles of iris followed by their contraction that is manifested as reduction in papillary diameter (miosis). Hence it is considered as drug of choice for emergency lowering of intra-ocular pressure in glaucoma (which occurs due to over production or inadequate drainage of aqueous humor) with subsequent damage to optic nerve and progressive vision impairment. Aqueous humor is produced in posterior chamber of eye and it is drained out by the trabecular meshwork through the canal of schlemm therefore its partial or complete hindrance can give rise to open-angle glaucoma and close-angle glaucoma respectively. Glaucoma is also termed as “silent thief of vision”.

(b) Synthetic drugs:

Acetylcholine: It is the cholinergic excitatory neurotransmitter (having affinity for both muscarinic as well as nicotinic receptors) that is synthesized by cholinergic neurons and can also be obtained from synthetic sources. Being highly susceptible to acetylcholinesterase-mediated enzymatic degradation it possesses a very short half life which limits its utilization as a therapeutic agent. However it is used to treat certain human cardiovascular disorders such as supraventricular tachycardia (A regular, abnormally fast heart beat that is originated above the ventricles and is caused by rapid firing of electrical impulses from a focus above the atrioventricular node (A-V node) in the heart) and Raynaud’s disease (A rare disorder that is marked by brief episodes of vasospasm (narrowing of the blood vessels) reducing blood flow to body extremities (such as fingers, toes and nails) thus causing ischemia, hypoxia and subsequent sloughing of gangrenous parts). In case of veterinary medicine it is used only for treating ergotism which is a mycotoxicosis, caused by Claviceps purpurea and involves vasoconstriction by direct action on the muscles of arterioles, initially reducing blood flow and eventually leading to complete stasis with terminal necrosis of the extremities due to thrombosis.

Carbachol: It acts on muscarinic as well as nicotinic receptors with high affinity for the former. It is used as neuromuscular purgative to increase intestinal motility in case of constipation. Myometrial contractions are stimulated through the ecbolic action of carbachol in dystocia (difficult birth/parturition). This therapeutic potential is mostly utilized during foaling (in mares) if pharmacological intervention is required. Carbachol can also stimulate the contraction of detrusor muscles (urinary bladder) to enhance urination in case of urine retention. However its administration is contraindicated in Volvulus, intussusception, torsion, urolithiasis, prostatic carcinoma and any other sort of blockage in urinary or intestinal tract to prevent muscle rupture.

Methacoline: The agonistic action of methacoline is largely restricted to muscarinic receptors with almost negligible affinity for nicotinic receptors. It is used to relieve atrial tachycardia in human patients.

Bethanecol: This cholinergic agonist activates only muscarinic receptors. Post-operative and postpartum urine retention associated with atony of urinary bladder are indications for the use of Bethanecol. Contraindications are similar to those as discussed for Carbachol.

2. Indirectly acting cholinergic agonists: These drugs do not directly interact with cholinergic receptors rather they increase the level of acetylcholine (cholinergic neurotransmitter and natural agonist of cholinergic receptors) by inhibiting its cholinesterase-mediated degradation. Therefore they are also known as anti-cholinesterase drugs.

(a) Reversible cholinesterase inhibitors: They utilize ionic bonding for reversibly binding with and blocking the action of cholinesterase enzyme. Following drugs are included in this group.

Edrophonium: It is used to differentiate myasthenia gravis from cholinergic crisis. Myasthenia gravis can be congenital (due to innate deficiency of nicotinic (N_M) receptors) or acquired (resulting from auto-immune related destruction and subsequent down regulation of nicotinic (N_M) receptors). Patients with this disease suffer from fluctuating muscle weakness and fatiguability. The muscle weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. So Edrophonium is helpful in the diagnosis of myasthenia gravis.

Physostigmine, Neostigmine and Pyridostigmine: These drugs have long half lives as compared to that of Edrophonium and therefore they are useful for the long-term management of patients suffering from myasthenia gravis. Physostigmine can cross blood-brain-barrier by virtue of its sufficient lipophilicity.

Overdosage of Atropine and other anticholinergic drugs is also an indication for the use of these agents. They can antagonize the effect of neuro-muscular blockers.

Rivastigmine, Tacrine, Galantamine and Donezepil: Theses are newer drugs which are applied to prevent the progression of cognitive loss in Alzeihmer’s disease. Alzheimer's disease is the progressive neurologic human disease of the brain leading to the irreversible loss of cholinergic neurons and the loss of intellectual abilities, including memory and reasoning, which become severe enough to impede social or occupational functioning. It first involves the parts of the brain that control thought, memory and language. Patients may have trouble remembering things that happened recently or names of people they know. Over time, symptoms get worse. People may not recognize family members or have trouble speaking, reading or writing. They may forget how to brush their teeth or comb their hair. Later on, they may become anxious or aggressive, or wander away from home.

Carbamtes (Methoxychlor, Lindane, Carbaryl): These reversible cholinesterase inhibitors are topically used for the treatment of ectoparasitic infestation in livestock. Inhibition of cholinesterase enzyme (of ectoparasites) is followed by hyperpolarization, paralysis and subsequent death.

(b) Irreversible cholinesterase inhibitors (Organophosphates): Their covalent binding to cholinesterase enzyme results in irreversible blockage of enzymatic function. Parathion, Malathion, Ethion, Trichlorfon (Neguvon), Dichlorvos, Coumaphos (Asuntol), Echothiopate, Tetraethyl pyrophosphate (TEPP) and Serine (Nerve gas) belong to this category and they are topically applied to kill or eradicate ectoparasites of domestic animals. Lack of precautionary measures (such as application of mouth muzzle and overdosage) can cause the accidental oral intake (as a result of licking by the animal) of these agents which can give rise to organophosphate intoxication (common in dogs), characterized by hypersalivation, lacrimation, frequent urination, diarrhea, miosis and ultimately death. Treatment must be anticipated as early as within 4-6 hours by the parentral administration of Atropine (cholinergic blocker) and enzyme re-activator (Pralidoxime (2-PAM) or Obidoxime). Co-administration of Phenothiazine-derivated tranquilizers potentiate organophosphate intoxication therefore concomitant administration of these agents should be avoided.

Adverse effects of cholinergic agonists: Overdosage of cholinergic agonists can give rise to cholinergic crisis that is manifested by miosis, profused salivation, diarrhea, bradycardia, broncoconstriction and frequent urination. Cholinergic antagonist preferably Atropine should be given to alleviate the condition. Contraindications: Diarrhea or dysentery, cardiac arrest, asthma, urinary incontinence and diseases associated with hypersalivation (e.g. rabies) are contraindications for cholinergic agonists.

Drug interactions: Laxatives, purgatives, diuretics, sialagogues (drugs which stimulate salivation) and tocolytics (drugs that decrease myometrial contractions) show interactions with cholinergic agonists.

(B) Anti-cholinergic drugs: These are also known as cholinergic blockers, cholinergic antagonists or parasympatholytics. They possess affinity for cholinergic receptors but lack intrinsic activity. Atropine is the prototype drug of this family. They can be divided into following subgroups.

(a) Natural alkaloids: These agents are derived from herbal sources and are known as alkaloids because they contain nitrogen.

Atropine: It can be obtained from Atropa belladonna (Deadly nightshade) and Datura stramonium (Jimson weed). It acts as competitive antagonist of Muscarinic receptors but in high doses it antagonizes nicotinic receptors as well. It is available in the form of Atropine sulphate (Atrosine) in the market. It is used as Pre-anesthetic (to avoid anti-peristalsis and profused salivation associated with anesthesia), Anti-spasmodic, Mydriatic and antidote of organophosphate poisoning.

Scopolamine (Hyoscine): Hyoscyamus niger (Henbane) is the source of this drug which is available with the brand name of Buscopan. It is commonly used as antispasmodic/spasmolytic for the treatment of abdominal pain (colic) resulting from smooth muscle spasm. The antagonistic action of Scopolamine on muscarinic receptors of vestibular nuclei is valuable for the prophylaxis of motion sickness (travelling related vomiting) in susceptible individuals.

Belladona extract: Plant extract of belladonna serves as substitute of Atropine. Despite its suspected purity it is equally effective as a therapeutic agent as Atropine itself.

(b) Semi-synthetic drugs (Atropine analogues): Molecular modification of Atropine has led to the development of certain drugs having same pharmacological properties but reduced adverse effects. These drugs include Homatropine, Methatropine, Eucatropine, Ipratropium and Methylscopolamine. Ipratropium is used as bronchodilator to treat asthma.

(c) Synthetic drugs: This class consists of Pirenzapine (antacid), Propenthaline (anti-diarrheal), Glycopyrrolate (pre-anesthetic in equines), Tropicamide (mydriatic), Oxybutynine (used to reverse hyperreflexia of detrusor muscles) and Cyclopentolate (mydriatic).

Adverse effects and contraindications: Inappropriate administration of Anti-cholinergics reveals signs opposite to those observed in organophosphate poisoning. These include xerostomia (dry mouth), mydriasis, tachycardia, constipation, bronchodilation and urine retention. Treatment involves the administration of reversible cholinesterase inhibitor like Physostigmine, Neostigmine or Pyridostigmine. Cholinergic blockers should not be used in glaucoma, hypertension, anuria and ruminal/intestinal stasis.

Adrenergic agonists: These are also known as sympathomimetics and are classified into following groups.

Selective Adrenergic agonists: They are divided into following subtypes depending upon the subtype of receptor for which the selectivity is possessed.

Selective α₁ agonists: They include Phenylephrine, Methoxamine, Naphazoline, Oxymetazoline and Xylomatazoline. Phenylephrine is used to increase B. P in hypotensive patients by activating α₁receptors in blood vessels. But this rise in B. P is followed by reflex bradycardia (β₁agonistic response) resulting from stimulation of vagus nerve. But Methoxamine lacks this adverse effect (undesirable cardiac aarythmia) by blocking β₁receptors if used in higher dose. They are also used as nasal decongestants to treat rhinitis (occurring due to peripheral vasodilation and subsequent blood stasis in nasal mucosa) and to induce mydriasis (without cycloplegia) by activating α₁receptors. Parentral administration of these agents can cause tissue necrosis and sloughing due to drug extravasation. This can be relieved through the use of α₁antagonist. Co-administration of MAO inhibitors or COMT inhibitors with α₁ agonists is contra-indicated to prevent extension of their half lives and associated toxic effects.

Selective α₂ agonists: These agents activate α₂ receptors and cause hyperpolarization through opening K⁺ channels. This hyperpolarization blocks the impulse transmission pathway. Therefore these drugs are having good sedative and analgesic properties which are benefited in terms of their use as pre-anesthetics. Xylazine (Xylaz), Clonidine, Detomidine, Medetomidine and Romifidine are important members of this class. Cocktails containing Xylazine and Ketamine are used for the induction of general anesthesia in small animals and birds. Most common adverse effects linked with the use of α₂ agonists include depression of thermoregulatory system (hyperthermia or hypothermia will occur depending upon the environmental temperature) and areophagia-induced bloat (in heavy breeds of dogs). Activation of α₂receptors in iselets of langerhans gives rise to decline in the release of insulin (hypoinsulinemia occurs) and the resultant hyperglycemia is manifested in terms of glucosuria and polyuria. Concommitant administration of catecholamines and α₂ agonists will cause cardiac arrhythmia.

Non-selective adrenergic agonists: These include catecholamines and non-catecholamines.

(a) Catecholamines: Epinephrine, Norepinephrine, Dopamine (these three are naturally found in the body) and Isoprenaline (it is also called Isoproterenol and is supplied from exogenous sources) are members of this family.

Epinephrine (Adrenaline): It is synthesized by the chromaffin cells of adrenal medulla, released into the blood stream and then stimulates α₁, α₂, β₁, β₂ andβ₃ receptors. Stimulation of α₁receptors causes vasoconstriction of splanchnic blood vessels whereas stimulation of β₂receptors causes vasodilation of blood vessels located in skeletal muscles. Epinephrine shows biphasic effect on blood pressure [initially blood pressure rises due activation of α₁ (located in blood vessels)and β₁receptors (located in the heart) and then blood pressure decreases as a result of reflex bradycardia (mediated by vagus nerve), β₂-mediated vasodilation of blood vessels] but the overall effect is reflected in the form of increased blood pressure. Other responses include mydriasis (α₁ stimulation), piloerection (α₁ stimulation), lipolysis (β₃ stimulation) and decreased insulin secretion (α₂stimulation). The action of on uterine myometrium involves significant inter-species variation.

Effect of Epinephrine on uterine myometrium of different species

Species	Effect of Epinephrine on pregnant uterus	Effect of Epinephrine on non-pregnant uterus
Rat (Rattus norvegicus)	Relaxation	Relaxation
Rabbit (Oryctolagus cuniculus)	Contraction	Contraction
Ewe (ovis aries)	Relaxation	Contraction
Woman ( Homo sapien)	Relaxation	Contraction
Queen (Felis domesticus)	Contraction	Relaxation

Epinephrine is used for relatively few clinical purposes due to its high susceptibility to enzymatic metabolism (induced by MAO and COMT) that shortens its half life. Epinephrine is administered (as life saving drug) through intravenous, intratracheal or intracardiac route for cardiao-pulmonary resuscitation (stimulation) in cardiac arrest and shock. Incorporation of Epinephrine in local anesthetics leads to slow and prolonged absorption at a subcutaneous or intradermal site. Anhydrosis (Non-sweating disease) of equines is also an indication for the intravenous/intramuscular injection of Epinephrine (although Thyroxin tablets are also effective in this condition). The most common adverse effect associated with Epinephrine-mediated vasoconstriction (leading to rise in B. P) is diminished blood flow (perfusion) towards peripheral organs (e.g. kidneys). And this inadequate renal perfusion can predispose the patients with pre-existing renal dysfunction to renal shut down (cessation of the excretory function). Concomitant administration of Halothane and other related gaseous anesthetics with Epinephrine is contraindicated as they increase the sensitivity of myocardium to Epinephrine (and other catecholamines). MAO inhibitors (e.g. Imipramine, used as anti-depressants) and COMT inhibitors (e.g. Tolcapone, used for the treatment of Parkison’s disease) interfere with the half life of Epinephrine and therefore their co-administration should be avoided.

Norepinephrine: Besides exerting stimulatory action on α₁, α₂ and β₁ receptors, it also activates β₂ receptors to some extent but no activity occurs uponβ₃ receptors. The pharmacological actions, clinical indications, contra-indications and adverse effects of Norepinephrine are similar to those of Epinephrine (except that Norepinephrine lacks the potential to cause lipolysis).

Dopamine: It usually acts as agonist of dopamine (D₁, D₂, D₃, D₄ and D₅) receptors which are located in brain (responsible for inhibitory neurotransmission), cardiovascular system (modification of B. P) and renal vascular beds (regulation of renal micro-perfusion). Dopamine as such is unable to cross blood brain barrier. It is the immediate precursor of Norepinephrine and is effective in several clinical conditions such as shock,

Parkinson’s disease and renal perfusion disturbances. Parkinson’s disease is a disorder that occurs due to deficiency of dopamine in CNS (resulting from congenital lack or destruction of dopaminergic neurons), begins around the age of sixty and is characterized by uncontrolled, uncoordinated muscle movements like trembling of hands, arms, legs, jaws and face. Adjunctive treatment consists of Levodopa (source of Dopamine and capable to cross BBB), Carbidopa (Dopa decarboxylase inhibitor, prevents the enzymatic metabolism of Levodopa) and Tolcapone (COMT-inhibitor that inhibits the break down of Dopamine/ Levodopa by COMT enzyme). Besides causing increase in B. P, Dopamine also improve renal micro-circulation therefore it lacks the adverse effect of renal shut down (in susceptible patients).

Isoprenaline (Isoproterenol): It stimulates only β₁ and β₂receptors, causing cardiac stimulation and vasodilation respectively. So it can be used to induce bronchodilation in asthma coupled with unwanted tachycardia.

(b) Non-catecholamines: This class includes drugs which indirectly enhance the level of endogenous catecholamines by inhibiting their re-uptake and MAO-mediated degradation.

Amphetamine and Methamphetamine: Besides increasing the concentration of catecholamines they also enhance the secretion of Serotonin [also known as 5-hydroxy tryptamine (5-HT)] and Dopamine in CNS leading to CNS stimulation (characterized by mental alertness and associated muscular activation). They are used for the treatment of narcolepsy (a sleep disorder that involves uncontrolled, irregular and unintended sleep bouts/episodes during day time) and hyperkinesis (inability to concentrate on any thing or any matter). Achievement of CNS stimulation in athletes and race-horses is another purpose for their administration. Insomnia (inability to sleep), fatigue (a state of excessive tiredness on physical or mental level), psychological dependence (addiction) and hallucination [a sensory perception experienced in the absence of an external stimulus that may occur in any sensory modality - visual, auditory, olfactory, gustatory, tactile, or proprioception (sense of balance and position in space)] are possible adverse effects linked with inappropriate use of these agents. Tranquilizers can be used to alleviate these symptoms.

Ephedrine and Pseudoephedrine: Ephedrine [an alkaloid derived from Chinese plant “Ma huang (Ephedra vulgaris)” has a vast history for being used as a bronchodilator throughout the world. Pseudoephedrine is the semi synthetic analogue of Ephedrine. The principal mechanism of its action relies on their indirect stimulation of adrenergic receptors. Action upon the central nervous system (CNS) is limited because they only cross the blood-brain barrier weakly and not very efficiently. In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries. Both ephedrine and pseudoephedrine act as bronchodilators, but pseudoephedrine is considerably less potent. Both also increase blood pressure, with again pseudoephedrine being considerably less effective.

Adrenergic antagonists: They are also known as adrenergic blockers or sympatholytics and are subdivided on the basis of adrenergic receptors that are blocked by them.

α-Blockers: These are subdivided into following subtypes.

Selective α₁ blockers: Prazosin, Terazosin, Doxazosin and Tamsulosin are important members of this category. Blockage of α₁ receptors gives rise to various responses including miosis, hypotension, sphincter relaxation, ejaculation failure and increased rennin secretion. They are primarily used to treat pulmonary hypertension (high blood pressure within pulmonary blood vessels) and systemic hypertension. Their first dose is always divided into multiple smaller doses (1/3^rd or 1/4^th) to avoid exaggerated hypotension (false decline in B. P of tremendous degree) which may lead to fainting of patient (called syncope). They are also used to ease urination (in older men) and defecation (in dogs) suffering from benign prostatic hyperplasia. Their prolonged and indiscriminate use can lead to tolerance (progressive decline in tissue response).

Selective α₂ blockers: Yohimbine (derived from Pausinystalia yohimbe) causes competitive short-term blockage of α₂ receptors (ANS) and partial stimulation of serotonin receptors (CNS). It is used as aphrodisiac (drug that can stimulate and enhance sexual desire) for treating erectile dysfunction and psychogenic impotence. Impotence is the inability of male to achieve or maintain an erection of sufficient rigidity to perform successful sexual intercourse that can result from psychological factors (performance anxiety or fear of unwanted pregnancy), sociocultural factors (negative sexual attitudes or religious beliefs), or physical causes (low testosterone levels, diabetes, arteriosclerosis, prostate cancer surgery) and neurological diseases such as Parkinson's disease. Yohimbine is also used as antidote of α₂ blockers/sedatives (e.g. Xylazine) and Amitraz (ectoparasitic drug). Higher doses of oral Yohimbine create numerous side effects such as rapid heart rate, high blood pressure, and overstimulation. It can also cause seizures (Uncontrolled electrical activity in the brain, which may produce a physical convulsion, minor physical signs, thought disturbances, or a combination of symptoms) through partial stimulation of serotonin receptors in the CNS.

Non-selective α blockers: Phenoxybenzamine is the most important member of this class which antagonizes α_1,α_2,muscarinic, histaminic and serotonin receptors. Other members of this class are Phentolamine, Ergotamine, Tolazoline, Azapetine and Piperoxane. Pro-administration of Phenoxybenzamine (or any other non-selective α blocker) followed by that of Epinephrine or co-administration of both agents modifies the impact of catecholamine on B. P. This is known as Epinephrine reversal phenomenon or vasoreversal phenomenon of Dale (pre-administration of Ergot followed by that of Norepinephrine in cat led to discovery of this phenomenon by Dale in 1906) and it involves the blockage of αreceptors by Phenoxybenzamine hence Epinephrine acts only on β receptors thereby causing vasodilation (hypotension) instead of vasoconstriction

(hypertension). Phenoxybenzamine is used during surgical manipulation of Pheocromocytoma (adrenal gland tumor) to inhibit excessive rise in B. P (which may prove fatal) attributed to high level of catecholamines that

are released into the blood. It also improves perfusion to laminae of hoof in horses by virtue of vasodilatory effect (through α₁receptor blockade) so it can be used to treat laminitis or founder (inflammation of hoof laminae that is manifested by fever, lameness, inability to transfer weight on affeceted foot and reluctance to stand or move). Reflex dissinergia (condition in which excessive contraction of urinary bladder musculature result in spasm and impair micturation) is also an indication for its administration. Adverse effects are relaxation of nictating membrane (3^rd eyelid), urinary incontinence (excessive relaxation of trigone muscles in sphinctor of urinary bladder causes the failure of holding urine in urinary bladder that is followed by unintended drop wise urination called dribbling) and failure of ejaculation (due to α₁receptor blockage). Ergotamine is the component released by Claviceps purpurea (a fungus that grows on rye and wheat and is known to cause ergotism) is sometimes used as post-partum uterine relaxant.

Selective β₁ blockers: Metoprolol, Esmolol and Atenolol decrease the force as well as rate of cardiac contraction (exert negative inotropic and negative chronotropic effect) by blocking β₁ receptors. They are known as cardio-selective blockers due to their exclusive β₁ receptors blockage. These drugs are used for the treatment of tachycardia, hypertension (decrease cardiac output will decrease B. P) and hypertrophic cardiomyopathy. They are safe for use in asthmatic patients as they don’t block β₂ receptors of bronchioles.

Selective β₂ blockers: Butoxamine is the only member belonging to this class and it lacks any clinical use because blockage of β₂receptors does not result in any significant clinical effect.

Non-selective β blockers: Propranolol (Indral), Timolol, Nadolol, Oxprenolol, Acebutalol, Pindolol, Carvedilol and Labetalol are included in this category. Propranolol is used for the treatment of many clinical conditions including hypertension [decrease cardiac output (through β₁ receptors blockage) decrease B. P], migraine headache (blockage of catecholamine-induced vasodilation in brain vasculaure relieves migraine headache), chronic glaucoma (blockage of β₂ receptors on ciliary body facilitates the flow of aqueous humor thereby decreasing intra-ocular pressure), chronic angina pectoris (decrease cardiac output decreases the cardiac oxygen demand and associated signs) and prophylaxis of 2^nd attack of myocardial infarction. Timolol and Nadolol are used to treat hypertension and chronic glaucoma. Propranolol, Timolol and Nadolol are contraindicated in asthmatic patients (as they cause bronchoconstriction by antagonizing β₂receptors) and diabetic patients (as they cause hypoinsulinemia by blocking β₂receptors in iselests of langerhans). Besides blocking βreceptors (inhibiting their activation by endogenous catecholamines), Acebutalol and Pindolol also act as partial agonists of βreceptors. Therefore they are said to have intrinsic sympathomimetic activity (ISA). This property enables them to be comparatively safe for use in asthmatic and diabetic patients. Carvedilol and Labetalol are blockers of α₁, β₁ and β₂receptors and these agents are used to treat pregnancy-induced hypertension.

Drugs acting on autonomic ganglia

Ganglionic stimulants: Nicotine (from Nicotiana tabacum; Tobbaco) and Lobeline (from Lobelia inflata; Indian tobacco) are natural substances which stimulate autonomic ganglia when administered in low doses. This ganglionic stimulation is reflected by increase in heart rate, blood pressure, peristalsis, urination, exocrine secretion, mental and muscular activity. Large doses of these agents cause the depression of autonomic ganglia. Nicotine is the component that imparts addictive potential (in the form of physical dependence) to Cigarette and other tobacco products. Nicotine is a drug of abuse therefore it lacks any therapeutic value. Research studies have postulated that Nicotine is a risk factor of vascular diseases (like coronary stenosis, myocardial infarction, stroke and atherosclerosis) and pulmonary disorders (like chronic obstructive pulmonary disease). Lobeline is sometimes used for smoking cessation. Tetramethyl ammonium is a synthetic agent that possesses the property of ganglionic stimulation.

Ganglionic blockers: Trimethaphan, Mecamylamine and Hexamethonium are drugs which cause the blockage of autonomic ganglia leading to inhibition of post-ganglionic impulse transmission (characterized by the depression of dependent responses). These drugs can be used as anti-hypertensive agents although superior agents are available now.

Skeletal muscle relaxants (Neuromuscular blockers)

Physiological aspects of normal muscle contraction: Normally the contraction and relaxation of skeletal muscles (that is controlled by somatic nervous system) is brought about by the activation and blockage of N_M receptors (nicotinic cholinergic receptors that are located on neuromuscular junctions and consist of five subunits; i.e. 2α, 1β, 1γ and 1δ) respectively. Chemically these receptors are pentameric proteins in nature while each subunit is a peptide. N_M receptors are a type of ionotropic receptors that are linked with Na⁺ channels. Each receptor consists of three domains; extracellular domain, transmembrane domain and intracellular domain. An action potential travels along a motor nerve to its endings on muscle fibers. At each ending, the nerve secretes a small amount of the neurotransmitter, Acetylcholine. There are two binding sites/pockets on extracellular domain with which two ACh molecules bind simultaneously and alter the three dimensional conformation of receptor ultimately leading to opening of associated Na⁺ channel. Influx of Na⁺ions modifies the intracellular cation concentration and depolarization occurs which causes the sarcoplasmic reticulum to release large quantities of stored calcium ions. The calcium ions initiate attractive forces between

actin and myosin filaments, causing them to slide alongside each other, which is the contractile process. After a fraction of a second, the calcium ions are pumped back into the sarcoplasmic reticulum by a Ca⁺² membrane

pump and they remain stored in the reticulum until a new muscle action potential comes along; this removal of calcium ions from the myofibrils causes the muscle contraction to cease.

Drugs affecting skeletal muscle contraction: They are used to cause relaxation of skeletal muscles for various clinical purposes like surgical operations, orthopedic procedures, tracheal intubation (placement of tube inside trachea during anesthesia to maintain patency of tracheal tract and ensure normal respiration) and for causing relaxation of bronchial muscles in asthma, pneumonia or chronic obstructive pulmonary disease. Some of these agents are used to capture wild and exotic animals. Co-administration of skeletal muscle relaxant with general anesthetic helps to reduce the dose of general anesthetic required for the induction of general anesthesia.

(1) Peripherally acting muscle relaxants: These are subdivided into depolarizers and non-depolarizers.

(a) Depolarizers: Succinylcholine and Decamethonium are partial agonists of N_M receptors and they are termed as depolarizers. Receptor occupancy is followed by partial but sustained stimulation of N_M receptors which leads to muscle twitching/fasciculation (due to subnormal muscle contraction). Consequently the receptors become resistant to bind with ACh and failure of muscle contraction (due to inhibition of depolarization) gives rise to flaccid paralysis. Succinylcholine and Decamethonium can be administered through oral or intravenous route. Their major disadvantage is that both of them are susceptible to enzymatic metabolism (by cholinesterase) which limits their half life in certain animal species like equine and canine (which are having sufficient enzyme concentration). Conversely inadequate enzyme level tends to extend the half life of depolarizers in bovine and ovine species. Prolonged half life of depolarizers in patients with congenital enzyme deficiency can cause diaphragmatic paralysis and death (due to apnea; inability to breath). Depolarizers are contraindicated in obesed patients as development of flaccid muscle paralysis increases the intragastric pressure that results in regurgitation and aspiration of gastro-intestinal contents. Overdosage of depolarizers causes severe muscular contraction of heavy muscles that is followed by recovery with myalgia (muscular pain). Cholinesterase inhibitors will prolong the duration of action of Succinylcholine and Decamethonium.

(b) Non-depolarizers: The historical perspectives for the use of non-depolarizers can be traced back to as early as 16^th century when arrow poison was used by the North Americans to paralyze their prey. Later in 1940, it was discovered that arrow poison contained a substance called Curare (d-tubocurarine) with muscle relaxant property. Other members of this category are Atracurium, Mivacurium, Dexacurium, Pancuronium, Vecuronium, Metocurine and Gallamine. Non-depolarizers are mostly given through intravenous route. Competitive antagonism of N_M receptors by non-depolarizers gives rise to muscle paralysis (muscle relaxation) in a specific pattern. Smaller muscles (facial, ocular and coccygeal muscles) are paralyzed first, followed by finger and limb muscles, then neck muscles, trunk muscles and finally intercostal muscles and diaphragmatic muscles. Recovery will occur in reverse pattern. Administration of non-depolarizers is contraindicated in asthmatic and comatosed patients as these agents cause the release of Histamine that can lead to severe bronchospasm, bronchoconstriction and hypotension. However pre-treatment with any antihistaminic drug [e.g. Chlorpheniramine (Avil) or Mepheniramine (Meprasone)] can help to prevent this adverse effect. Non-depolarizers should not be given to patients suffering from myasthenia gravis as such patients already have deficiency of N_M receptors so further antagonism of remaining N_M receptors can prove fatal for them. Patients suffering from glaucoma should also avoid these drugs as paralysis of ciliary muscles and circular muscles of iris can further aggravate intra-ocular pressure. Cholinesterase inhibitors will prolong the duration of action of non-depolarizers. Non-depolarizers show synergistic effect with Aminoglycoside antibiotics (like Gentamycin, Neomycin etc.) and Ca⁺² channel blockers (like Verapamil and Deltiazim; used as antiarrythmic drugs) as these drugs also lead to muscle paralysis by virtue of their Ca⁺² channel blocking ability. Diazepam and diuretics (by producing hypokalemia) enhance competitive blockage while high doses of corticosteroids (anti-inflammatory drugs) reduces it. Many drugs can be used as antidotes to treat toxic conditions caused by overdosage or synergistic action of Non-depolarizers. These include Cholinesterase inhibitors (reverse the competitive antagonism of N_M receptors by non-depolarizers), Aminopyridine (enhances the release of ACh in somatic nervous system) and Sugammadex (chelates non-depolarizers and thus facilitates their rapid excretion).

(2) Centrally acting muscle relaxants: These drugs reduce skeletal muscle tone by a selective action in cerebro-spinal axis without altering consciousness. They have no effect on neuromuscular transmission and muscle tone but they selectively depress spinal and supraspinal synaptic reflexes involved in the regulation of muscle tone. Meprobamate, Guaiphenesin, Mephenesin and Orphenadrine (Nuberol forte) are important agents of this category. Meprobamate is used as an antagonist to strychnine poisoning [strychnine is an alkaloid of Nux vomica, symptoms of intoxication is characterized by pronounced spasmodic contraction of the muscles of the limbs and trunk, and by a drawing back of the head and hollowing of the back (opisthotonus)] in animals. Guaiphenesin and Mephenesin are used for muscle relaxation in intravenous anesthesia, restraint of wild animals and treatment of tetanus. Guaiphenesin is also used as an oral expectorant (drug that reduces the viscosity of sputum and thereby enhances its removal), although definite proof of its efficacy is lacking. Overedosage may produce symptoms of nystagmus (involuntary, constant contractions of eye ball), apnea and hypotension and there is no specific antidote available to alleviate these signs.

(3) Miscellaneous agents: Certain anti-epileptic drugs like Diazepam (Valium) and Gabapentin also possess neuromuscular blocking potential that is particularly valuable in epilepsy, tetanus and general anesthesia.

Pharmacology of Respiratory System

2011-07-10T11:11:00.005+05:00

Pharmacology of Respiratory System

Functional anatomy and physiology: The respiratory system [divided into upper respiratory tract (including pharynx, trachea, and bronchi) and lower respiratory tract (including bronchioles, lungs and alveoli)], is responsible for a vital physiological process known as breathing (comprising of inspiration and expiration) that occurs for the sake of tissue oxygenation. The diaphragm also possesses a pivotal role as far as the process of inspiration (or inhalation) and expiration (exhalation) is concerned.

Respiratory defense mechanism: Although the presence of an effective blood-alveolar barrier restricts the entry of blood-born pathogens into respiratory tract, the direct interaction of upper respiratory tract with environmental air favors the inhalatory route to be employed for the introduction of harmful agents (like pollutants, allergens, infectious agents etc. that are expressed as noxious stimuli, invade the respiratory tract and subsequently bring about anatomical and/or physiological alterations). To overcome this problem nature has provided the respiratory system with an efficient defense mechanism in terms of muco-ciliary apparatus and mononuclear phagocytic system (MPS). The mucus secretion (released by goblet cells, located in external nostrils) forms a protective layer over the mucous lining of the nostrils and is capable to entrap foreign particles. The upper respiratory tract is lined by pseudostratified columnar streociliated epithelium (smoking leads to progressive loss of these streocilia and hence disturbs this protective barrier). These cilia oppose the access of any foreign invader by virtue of their synchronous movement. Mononuclear phagocytic system (MPS) comprises of alveolar macrophages and intravascular macrophages that are meant for the phagocytosis (enzymatic break down) of xenobiotics.

Nervous innervation of respiratory smooth muscles

Type of efferent pathway	Receptor	Neurotransmitter	Signaling mechanism	Response
Parasympathetic (Dominant pathway which provides baseline tone of mild bronchoconstriction)	M₃	Acetylcholine (ACh)	Phospholipase C -mediated conversion of PIP₂into IP₃ and DAG. These second messengers increase intracellular calcium level to elicit cellular response.	Broncho-constriction
Histaminergic	H₁	Histamine	Same as M₃	Broncho-constriction
Sympathetic	α₁	Norepinephrine	Same as M₃	Broncho-constriction
	α₂	Norepinephrine	Inhibition of adenyl cyclase-mediated cAMP synthesis	Reduction of parasympathetic Broncho-constriction
	β₂	Norepinephrine	Activation of adenyl cyclase-mediated cAMP synthesis	Broncho-dilation
Non-adrenergic non-cholinergic (NANC)	Irritant receptors (Nose)	Vaso-active intestinal peptide (VIP)	Stimulation of vagus nerve	Reflex Broncho-dilation

Bronchodilators: These drugs restore normal bronchial caliber to improve alveolar ventilation. They are also used to reverse broncho-constriction (caused by allergic/inflammatory reaction, COPD, bronchospasm or bronchial stenosis).These agents are preferably administered through inhalatory route (in the form of nasal sprays and inhalers) and are categorized into following types.

1. Sympathomimetics (β agonists): Selective β₂ agonists [Salbutamol (Ventolin), Terbutaline and Clenbuterol] as well as non-selective β agonists (Ephedrine, Pseudoephedrine and Isoproterenol) can be used to cause bronchodilation. But non-selective β agonists are linked with undesirable cardiac stimulation that can be life-threatening in animals with pre-existing tachycardia (like supraventricular tachycardia). The detailed pharmacology and toxicology of sympathomimetics has been described in chapter-1 (ANS).

2. Muscarinic antagonists (Anticholinergics): Ipratropium, Glycopyrrolate and Atropine are capable to block M₃-mediated broncho-constriction but they should be used cautiously to prevent unwanted adverse effects.

3. Methylxanthines: This group includes both natural substances like Caffeine (found in tea, coffee), Theobromine (derived from Cocoa plant, present in chocolate and candies) and Theophylline as well as synthetic agents like Aminophylline. They act as competitive inhibitors of phosphodiesterase (PDE) enzyme which causes the intracellular degradation of cAMP (this indirect increase in the level of 2^nd messenger leads to bronchodilation). Methylxanthines also stimulate CNS, cardiac contractility, diuresis, gastric acid secretion (therefore these are contraindicated in all conditions of hyperacidity) and skeletal muscle contraction. Methylxanthines also block adenosine receptors to display a bronchodilatory effect. Primarily, Caffeine and Theobromine are used to cause CNS (cerebral cortical) stimulation while Theophylline and Aminophylline are prescribed as expectorants. Dogs are unable to properly metabolize Theobromine and commonly suffer from chocolate poisoning (there is no specific antidote to treat this intoxication). Hyperacidity, tachycardia and seizures [uncontrolled electrical activity in the brain (resulting from CNS stimulation), which may produce a physical convulsion, minor physical signs, thought disturbances, or a combination of symptoms] are possible adverse effects of Methylxanthines.

4. Leukotriene receptor antagonists: Acolade is a high affinity competitive antagonist of Leukotriene (Leukotrienes are inflammatory mediators, released in response to the entry of allergens in respiratory tract, undergo receptor occupancy and trigger leukocytic infiltration via chemotaxis) that prevents antigen-induced bronchospasm.

Pathophysiology of asthma: Asthma is a common chronic inflammatory disease of airways characterized by variable and chronic symptoms [including wheezing (continuous, coarse, whistling sound), coughing, chest tightness (bronchoconstriction), and dyspnea (shortness of breath)], reversible airflow obstruction, and bronchospasm. The pathogenesis of asthma can be summarized in the following manner.

The entry of allergens (like pollens, dust particles and animal dander) into upper respiratory tract marks the initiation of this ailment by activating the first-line defense mechanism (muco-cilliary apparatus).

Soon after the degranulation of mast cells results in the release of histamine that binds with H₁ receptors.

Membrane damage also occurs during which membrane phospholipids are subjected to enzymatic degradation by phopholipase A₂ yielding arachidonic acid that is converted to prostaglandins and leukotreins.

Infiltration of mononuclear phagocytic cells mediates chemotaxis to provoke cells that are involved in defense mechanism (e.g. leukocytes).

Histamine, prostaglandins and leukotriens are all inflammatory mediators which cause vasodilation, bronchoconstriction and alteration of membrane permeability.

During later phase the infiltration of cytokine-releasing T-cells and eosinophils further aggravate the condition by causing edema, bronchospasm and epithelial damage that ultimately lead to obstruction and collapse of airways.

Anti-asthmatic drugs: These drugs are classified into following categories.

1. H₁ receptor antagonists (Antihistaminic drugs): Chlorpheniramine (Avil), Mepheneramine (Meprasone), Cetrizine (Zyrtec), Diphenylhydramine (Benadryl) and Dimenhydrinate (Gravinate) are common members of this category. They are also termed as anti-allergic agents as they are to relieve almost all sorts of allergic reactions. Diphenylhydramine and Dimenhydrinate are also applied as anti-emetics. Sedation is the most common side effect of antihistaminic drugs.

2. Mast cell stabilizers: Cromoglycate (also known as Cromolyn) stabilizes the mast cell membrane and thus inhibits their degranulation.

3. 5-HT₂ receptor antagonists: Cyproheptadiene (basically used as appetite stimulant to treat anorexia) has been reported to be effective in feline asthma.

4. Nonsteroidal anti-inflammatory drugs: Anti-prostaglandinic effect of NSAID_S can become advantageous to suppress inflammatory symptoms associated with asthma.

5. Corticosteroids: They inhibit the synthesis of leukotriens which carry out leukocytic infiltration and chemotaxis. The pharmacology and adverse effects of NSAID_S and Corticosteroids have been discussed in detail in chapter-2.

6. Adrenergic agonists: Selective β₂ agonists [Salbutamol (Ventolin), Terbutaline and Clenbuterol] as well as non-selective β agonists (Ephedrine, Pseudoephedrine and Isoproterenol) can be used to mitigate (reduce) bronchospasm.

7. Anticholinergic drugs: Ipratropium, Glycopyrrolate and Atropine can be used to induce bronchodilation and improve alveolar ventilation.

8. Methylxanthines: Theophylline and Aminophylline are used as bronchodilators and expectorants.

Allergic rhinitis (Hay fever or pollenosis): It is an allergic inflammation of the nasal mucosa and associated airways. It occurs when allergens such as pollens or dust particles are inhaled by an individual with a sensitized immune system, and trigger antibody production. The specific antibody is immunoglobulin E (IgE) which binds to mast cells and basophils containing histamine. IgE bound to mast cells are stimulated by pollen and dust, causing the release of inflammatory mediators such as histamine (and other chemicals). This causes itching, swelling and mucus production. Inflammatory mediators favor vasodilation that causes nasal congestion (passive hyperemia) and ultimately leads to rhinorhea (running nose). Fibrosis of nasal septum may also occur in chronic cases. The two categories of allergic rhinitis include: Seasonal (occurs particularly during pollen seasons) and Perennial (occurs throughout the year) rhinitis.

Treatment of allergic rhinitis: Any of the following drugs can be used for this purpose.

1. Nasal decongestants: Phenyleprine (selective α₁ agonist) can be administered to cause peripheral vasoconstriction that will lead to redistribution of accumulated blood (and will relieve rhinorrhea). However its use should be avoided in patients with pre-existing mydriasis and glaucoma.

2. Corticosteroids: They prevent the synthesis of leukotriens which perform leukocytic infiltration and chemotaxis. In this way the help to avoid further inflammatory response.

3. H₁ receptor antagonists (Antihistaminic drugs): Similar to other allergic conditions, allergic rhinitis is also responsive to the administration of antihistaminic drugs. But they should be used cautiously as their prolonged inhalatory application (via aerosol) can lead to rhinitis medicamentosa which is characterized by stiffness of the nose.

Pathophysiology of coughing reflex: Cough is a protective mechanism for the removal of foreign particles/allergens or excessive secretion from respiratory tract. It is divided into dry cough (mediated by irritation of upper respiratory tract resulting from the entry of allergens) and productive cough (that arises for the expulsion of sputum). Therefore productive cough is considered a beneficial mechanism, is not commonly treated and is nevertheless induced through the use of expectorants. Whereas dry cough is suppressed (through the use of anti-tussive drugs) as it can damage lungs. The upper respiratory tract (pharynx, larynx and tracheo-bronchial tree) consists of chemorecptors and mechanorecptors while lower respiratory tract (lungs) contains stretch receptors that are sensitive to noxious stimuli (like allergens and excessive secretion) and transmit impulses to cough centre (located in medulla) by means of afferent/sensory nerves (like vagus nerve and glossopharyngeal nerve). The cough centre (co-ordinated with respiratory centre and vomiting centre, which are also present in medulla) analyzes the impulses and then transmits signals (via efferent/motor nerves) to thoracic, abdominal and diaphragmatic muscles for causing forceful expulsion of air from the lungs that leads to coughing.

Anti-tussives: These are drugs which are used to suppress coughing (dry cough, commonly caused by severe bronchoconstriction) that can inflict damage to the lungs.

1. Centrally acting anti-tussive drugs: These drugs act by depressing cough centre and are subdivided into following groups;

(a) Opiod/Narcotic anti-tussives: Morphine, Codeine (Methyl Morphine), Hydrocodone and Hydromorphone are included in this class. They bind to opiod receptors (in CNS) and depress CNS (including cough centre located in medulla). These agents are also used to induce sedation and analgesia. They are linked with certain side effects like dependence/addiction and sedation.

(b) Non-narcotic anti-tussives: Dextromethorphan (free from addictive potential) increases the cough threshold set by cough centre and thus it depresses coughing.

2. Locally acting anti-tussives: These are further divided into following categories;

(a) Demulcents: They cause soothing effect on respiratory mucosa, reduce irritation and suppress coughing. Glycerine [C₃H₅(OH)₃], Honey and Liquorice (Mulaithi) are examples of such agents.

(b) Mucosal anesthetics: Benzotate desensitizes the pulmonary stretch receptors and blocks the sensory impulses of coughing.

Expectorants (Mucokinetics; muco = mucus, kinesis = movement): These drugs enhance the flow/fluidity of airway mucus (also known as sputum) either by increasing its volume or by decreasing its viscosity and thus facilitate its removal through coughing and ciliary action. Expectorants are used to induce productive cough in case of tracheobronchitis, bronchopneumonia and COPD. Expectorants are divided into following categories.

1. Stimulant/Secretory expectorants: These are further subdivided into following types.

(a) Direct acting stimulant expectorants: These directly stimulate the submucosal tracheobronchial glands to increase their secretion. Guaicol and Guaiphenesin (also used as skeletal muscle relaxant) are examples of such drugs.

(b) Indirect acting (reflex acting) stimulant expectorants: They indirectly stimulate tracheobronchial glands via vagal reflex. Ipecacuanha (obtained from Cephalis ipecacuanha) is included in this class. It is basically used as emetic/nauseant but it can cause expectpration when used in sub-therapeutic doses. Most common side effects are profused salivation and lacrymation.

(c) Mixed acting (or saline) stimulant expectorants: They utilize both mechanisms (direct and indirect) to induce mucokinesis. KI is orally given to treat chronic bronchitis but its overdosage can cause iodinism-induced goiter [excessive iodine inhibits its own active transport to thyroid follicle by saturating the transporter/carrier system. Therefore no iodination of thyroglobulin occurs inside the thyroid follicle (due to lack of iodine in the follicle) and deficient level of thyroid hormones in the blood triggers the release of thyroid stimulating hormone (TSH) from anterior pituitary gland (to stimulate thyroid glands) which facilitates the accumulation of more and more thyroglobulin in thyroid glands that leads to enlargement of thyroid glands (goiter)]. The use of KI is also contraindicated in lactating animals (as iodine will be released in milk) and pregnant animals (to avoid congenital goiter). NH₄Cl (ammonium chloride or Noshadar) and (NH₄)₂Co₃ (ammonium carbonate) are also expectorants with similar mode of action but their overdosage leads to hyperammonemia followed by dypnea and pulmonary edema.

2. Mucolytic expectorants: They cause depolymerization or hydrolysis of glycoprotein strands in mucus (called mucolysis) which leads to decline in mucus viscosity. Bromohexine and Acetylcysteine are such expectorants. Sulfhydral group of Acetylcysteine disintegrates disulfide bonds of mucus glycoproteins thus causing mucolysis. Acetylcysteine (also used as antidote of Paracetamol/Acetaminophen intoxication) is a precursor of Glutathione (anti-oxidant that arrests and inactivates reactive oxygen species (ROS) and prevents them from causing cellular damage).

3. Diluent expectorants: These agents dilute/hydrate the airway mucus and thus increase its fluidity. Steam can be used to liquefy viscous sputum but it is effective only in case of large airways (as the size of water molecules is about 10 μm which cannot penetrate inside smaller airways). Application of steam is not an easy procedure as far as animals are concerned.

4. Miscellaneous agents: 5% CO₂ is capable to cause bronchial hyperemia that is followed by expectoration. Antimony Potassium Tartrate is a nauseant expectorant that can also be used to induce productive cough. Additionally it has been found that dietary usage of chili (Capsicum annum) can cause expectoration (probably by acting as stimulant expectorant) and application of water over the head region (and even bathing) can liquefy/dilute the mucus to facilitate its removal. However the use of chili should be avoided in persons with pre-existing gastric ulcer, hyperacidity and digestive disturbances (as it can aggravate the conditions).

Pharmacology of Anti-inflammatory Drugs

2011-07-09T10:49:00.004+05:00

Pharmacology of Anti-inflammatory Drugs

Inflammation: (Latin, inflammare, to set on fire) is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The invasion of tissues by these noxious agents triggers the release of cytokines (IL-1, IL-6 and TNF_α). Moreover membrane phospholipids are broken down to yield arachidonic acid (through the catalytic action of phopholipase A₂) and then it is converted to eicosanides (PGE₂, PGI₂, PGF₂α and TXA₂) and leukotriens by cyclo-oxygenase (COX) and lipo-oxygenase respectively. Prostaglandins, leukotriens, thromboxanes, cytokines and histamine are called inflammatory mediators that are responsible for the manifestation of cardinal signs of inflammation; dolor (pain), calor (heat), rubor (redness), tumor (swelling) and functiolesa (loss of function). Although inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process, widespread and chronic inflammation may become detrimental and interrupt normal body functioning (can also lead to abscessation and fibrosis if left untreated) thereby requiring optimal intervention through the use of anti-inflammatory drugs.

Origin and functions of some inflammatory mediators

Mediator(s)	Source	Main Actions
PGE₂	Membrane phospholipids, mast cells	Inhibition of gastric acid secretion, broncho-constriction
PGI₂		Vasodilation, inhibition of platelet aggregation
PGF₂α		Improves uterine motility and renal perfusion
TXA₂	Membrane phospholipids, platelets	Stimulation of platelet aggregation, vasoconstriction
Leukotriens	Membrane phospholipids, leukocytes	Increase vascular permeability, broncho-constriction
Histamine	Mast cells	Vasodilation and stimulation of nociceptors
Cytokines	Macrophages, lymphocytes	Cartilage degeneration, necrosis

Anti-inflammatory drugs: These are broadly divided into two groups; Corticosteroids and Non-steroidal anti-inflammatory drugs (NSAIDs).

1. Corticosteroids: Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex to perform many significant physiological functions. Many synthetic steroids have been prepared that are used to achieve various therapeutic goals. Corticosteroids can strengthen the tolerance of organism to bacterial endotoxins, antagonize and relieve the reactions caused by bacterial endotoxins. However, they can’t neutralize bacterial endotoxins, and have no defensive effects on bacterial exotoxins. Large dose of Corticosteroids has the effect of antishock (by reducing peripheral vascular resistance, improving the blockage of microcirculation they incresase returned blood volume) and are widely used in various kinds of shock like toxic shock, septic shock, anaphylactic shock and hypovolumic shock.

Salient features of natural Corticosteroids (Adrenal steroids)

Portion	Functional zone	Secretion	Functions
Adrenal cortex	Zona Glomerulosa (outermost zone)	Mineralocorticoids (Aldosterone)	Regulate electrolyte and water levels, mainly by promoting sodium retention in the kidney
	Zona Fasiculata (middle zone)	Glucocorticoids (Cortisol)	Control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing leukotriene synthesis
	Zona Reticularis (inner zone)	Sex steroids (Androgens)	Affect the growth or function of reproductive organs, the development of secondary sex characteristics, and sexual behavioral of animals
Adrenal medulla	Chromaffin cells	Catecholamines (Epinephrine and Norepinephrine)	Catecholamines cause general physiological changes that prepare the body for physical activity (fight, flight or fright response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system

Classification of Corticosteroids

Mode of action	Category	Biological half life	Examples	Anti-inflammatory potency
Inhibition of leukotriene synthesis via blockage of lipo-oxygenase enzyme	Short acting corticosteroids	< 12 hours	Cortisone	0.7
	Short acting corticosteroids	< 12 hours	Hydrocortisone	1
	Intermediate acting corticosteroids	12-36 hours	Triamcinolone	3
			Prednisone	4
			Prednisolone	5
	Long acting corticosteroids	> 36 hours	Paramethasone	10
			Dexamethasone	25
			Betamethasone	25
			Flumethasone	30

Clinical uses: They are used in shock, allergic rhinitis, conjunctivitis, rheumatoid arthritis, bursitis, synovitis, tendinitis and otitis externa (inflammation of external ear). Corticosteroids can induce labor (inhibition of leukotriene synthesis favors the conversion of entire arachidonic acid reserves into prostaglandins, including PGF₂α that causes parturition by inducing uterine contraction) in cattle and has been used (as abortificient) to terminate pregnancy in bitches.

Adverse effects and contraindications: Corticosteroids should not be used in equines as they can cause laminitis or can worsen the already existing laminitis. These drugs suppress immune response and have many depressant effects on immunoreaction. They cause lymphocyte destruction, reduce the number of the lymphocyte by moving them outside the blood vessels, induce lymphocytic apoptosis and interrupt their division and proliferation. Therefore they should not be used in immuno-compromised patients. Animals receiving systemic corticosteroids may be more susceptible to bacterial or viral infections and the immune response to vaccination may be reduced when corticosteroids are given at the same time. Corticosteroids should be avoided during pregnancy and lactation unless the benefits outweigh the risks.

2. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs by virtue of inhibiting cyclooxygenases, are effective in suppressing inflammation, alleviating pain, and lowering fever. Cyclooxygenases (COX) (localized in endoplasmic reticulum) are responsible for the formation of a group of local hormones comprising the prostaglandins, prostacyclin, and thromboxanes (from arachidonic acid). These enzymes possess an elongated pore into which the substrate arachidonic acid is inserted and converted to an active product. NSAIDs penetrate into this pore and thus prevent access for arachidonic acid, leading to reversible blockade of the enzyme. Two principal types of COX can be distinguished: COX-1 is constitutive, that is, always present and active; it contributes to the physiological function of organs. Inhibition inevitably produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances of uterine function. COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed constitutively (kidney, vascular endothelium, uterus, and CNS).

Non-selective COX-inhibitors: These include Acetylsalicylic acid or Aspirin (Disprin), Paracetamol or Acetaminophen (Panadol), Ibuprofen (Brufen), Meclofenamic acid (Ponston), Diclofenac (Voren, Phlogen, Dyclo, Dicloron, Diclostar, Fenac), Metamizole (Dipyrone, Magnapyrol), Phenylbutazone (Butadin), Piroxicam (Feldene) and Naproxen (Neoprox).

Selective COX-inhibitors: Meloxicam and Celecoxib are included in this group.

Pharmacological actions of NSAIDs:

(a) Antipyretic effect: The hypothalamus that is responsible for thermo-regulation, is affected by exogenous pyrogens such as bacterial toxins and endogenous pyrogens (now considered to be IL -1). Pyrogens promote the synthesis and subsequent release of prostaglandin E (PGE). PGE can raise the set-point of body temperature, in order to increase heat production, dissipate heat production, and to raise the body temperature. NSAIDs being the inhibitors of prostaglandin synthesis are helpful to restore normal thermoregulatory control mechanism.

(b) Analgesic effect: Some inflammatory mediators like prostaglandins and bradykinins are also involved in pain sensation. Therefore the anti-prostaglandinic action of NSAIDs can provide good analgesia in many conditions such as neuralgia, myalgia, joint pain, muscle pain, and so on, but these agents are not effective for the suppression of acute pain and visceral pain.

(c) Anti-inflammatory effect: Prostaglandins are key mediators in inflammatory reaction, a large number of them exist in inflammation organizations. NSAIDs have the ability to subside inflammation by inhibiting the synthesis of prostaglandins.

Clinical uses: NSAIDs are generally indicated for the symptomatic relief of the many conditions like rheumatoid arthritis (auto-immune-mediated inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints), osteoarthritis, laminitis, dysmenorrhoea (menstrual pain), metastatic bone pain, headache and migraine, postoperative pain, pyrexia (fever), renal colic, myalgia and mild-to-moderate pain due to inflammation and tissue injury. Aspirin is used (for its inhibitory effect on platelet aggregation) in dissiminated intravascular coagulation (DIC), thrombo-embolic disorders and heartworm (Dirrofilaria immitis) infection in dogs.

Adverse effects: The following side effects are linked with improper administration of NSAIDs.

1. Some prostaglandins (like PGE) possess beneficial role in terms of suppression of gastric acid secretion and regulation of renal microperfusion. Thus prostaglandin inhibitors (NSAIDs) can cause (or aggravate) gastric hyperacidity and renal disturbances.

2. Inhibition of TXA₂ synthesis by NSAIDs results in profused bleeding and delayed clotting time (via inhibiting platelet aggregation). This property can be benefited to resolve intravascular thrombi (that can cause embolism and ischemia) in some cardiac disorders like myocardial infarction.

3. NSAIDs that are acidic in nature (like Aspirin and Paracetamol) undergo hepatic metabolism through glucoronide conjugation. Species that are inherently deficient in glucoronide conjugatory mechanism (such as glucoronyl transferase deficiency) are susceptible to serious toxicosis (the half life of these drugs is abnormally prolonged due to lack of sufficient biotransformation). Acetylcysteine (precursor of Glutathione and potent antioxidant) should be used to suppress free radical induced cellular damage that occurs during this idiosyncratic condition.

4. Large doses of Aspirin may cause hyperglycemia (by uncoupling phosphorylation during glycolysis) followed by glycosuria (release of glucose in urine) and deplete liver and muscle glycogen.

5. In humans the use of Aspirin has been implicated in the causation of salicylism (a syndrome that is characterized by dizziness, vertigo and reversible visual and auditory impairment) and Reye’s syndrome (occurs in infants suffering from viral infection and it is manifested by hepatic damage and encephalopathy).

6. Metamizole is known to cause agranulocytosis (decresed synthesis of agranuloctes; lymphocytes and monocytes).

Contraindications: NSAIDs are contraindicated in persons suffering from gastrointestinal ulceration, bleeding disorders and human infants (having viral infection). Aspirin therapy should be stopped one week before surgery (to avoid excessive bleeding), and it should be used cautiously in species with improper metabolizing potential (cats and fish).

Interactions: Aspirin enhances the action and toxicity of oral anticoagulants and Heparin by increasing risk of bleeding. The urinary excretion of acidic NSAIDs is increased and decreased by the concomitant administration of urinary alkalizers (like sodium bi carbonate) and urinary acidifiers (like ammonium chloride) respectively.

Pharmacology of Cardiovascular System

2011-07-08T11:16:00.004+05:00

Pharmacology of Cardiovascular System

Cardiac electrophysiology: Heart, blood, blood vessels and lungs constitute a significant physiological system that is responsible to supply nutrients and oxygen (via blood) to body tissues. Adequate tissue perfusion is ensured by the pumping action of the heart. This pumping activity demands for certain specialized and unique features (owned by cardiac muscles) in addition to conventional properties of muscular contraction and relaxation (that are possessed by skeletal, smooth and cardiac muscles). Like skeletal and smooth muscles, the cardiac muscles also respond to membrane depolarization (as a result of action potential) that is followed by repolarization and ultimately attain resting membrane potential. But the cardiac muscles possess their own intrinsic system for the generation (and perhaps propagation) of action potential in the form of pace maker cells located in sino-atrial (SA) node (in case of skeletal and smooth muscles contraction, the action potential is produced and transmitted by nerves). Unlike skeletal muscles which display a graded pattern of contraction (the degree of muscle contraction depends upon the number of excited/stimulated cells), the cardiac muscle cells respond to stimulus as a single functional unit (quantal response). The cardiac action potential is unusually long and can be divided into five distinct phases.

Phase- “0” (Fast upstroke): This initial phase is marked by fast inward current resulting from the opening of Sodium channels (elevating the intracellular cation concentration).

Phase-1 (Partial repolarization): Opening of Potassium channels leads to transient outward flow of current (reducing the intracellular cation concentration) during this phase.

Phase-2 (Plateau phase): This step involves the opening of calcium channels (to balance the Potassium leakage) that causes slow inward current resulting in depolarization.

Phase-3 (Repolarization phase): Once again the opening of Potassium channels leads to repolarization.

Phase-4 (Depolarization phase): Inward flow of current is caused by the opening of Sodium channels and myocardial cell once again tries to attain the threshold value required for the generation of action potential (depolarization). Depolarization causes myocardial contraction (systole) while repolarization results in myocardial relaxation (diastole).

Cardiac contraction: The fundamental contractile machinery of cardiac muscle cells resembles that of striated muscles. The force of contraction of cardiac muscles is directly related to the concentration of free (unbound) cytosolic calcium. Calcium comes from two sources; calcium channels (located on the cell membrane) and intracellular sources (sarcoplasmic reticulum and mitochondria). This calcium is utilized by actin and myosin filaments (contained in myofibrils) to execute contraction that is followed by relaxation [during which the intra-cellular calcium level is reduced through the calcium efflux (performed by Sodium/Calcium exchanger) and reabsorption of calcium by sarcoplasmic reticulum and mitochondria]. This cycle is repeated as long as the myocardial cells are stimulated by intrinsic action potential. Removal of free cytosolic calcium is also performed by two mechanisms; sodium-calcium exchanger (that exchanges calcium ions for sodium ions across the cell membrane) and calcium uptake by sarcoplasmic reticulum and mitochondria. Sodium balance is restored by Na⁺-K⁺-ATP_ase pump.

Heart failure/Congestive heart failure (CHF): It is a progressive disorder that involves insufficient cardiac pumping and is characterized by dyspnea, edema and fatigue. It is of two types. Left sided heart failure involves the inability of left atrium to receive oxygenated blood from the lungs thereby causing pulmonary congestion (congestion is passive hyperemia, the accumulation of venous blood) that is clinically manifested by dyspnea (difficult/labored respiration or shortness of breath). In case of right sided heart failure, right side of the heart (right atrium and right ventricle) fails to receive deoxygenated blood from major veins (like anterior and posterior vena cava). Thus blood is collected inside larger as well as smaller veins and intense pressure (exerted by the blood) enables the plasma to leak out of the capillaries into interstitial spaces which causes peripheral edema. To overcome the problem of impaired cardiac contractility and associated pumping defect, body has three compensatory mechanisms (baroreceptors-induced sympathetic stimulation (resulting in tachycardia), activation of rennin angiotensin aldosterone system and myocardial hypertrophy) but none of them is properly effective.

Myocardial stimulants: These drugs are used to stimulate myocardium (in case of CHF) and include the following classes.

1. Cardiac glycosides: These are derived from Foxglove plant and each agent consists of distinct moities; glycone and aglycone. The glycone portion is responsible for pharmacological action (myocardial stimulation) of glycosides. Aglycone (concerned with pharmacokinetic parameters of glycosides) comprises of basic steroid nucleus, cyclopentanoperhydropenanthrene that is having 1-3 sugar molecules attached at carbon number 3 (C-3), a large lactone ring at C-17 and one or multiple OH^- ions (that impart water solubility).

Plant source	Derived glycoside(s)
Digitalis purpurea	Digoxin, Digitalin
Digitalis lanata	Digitoxin
Strophanthus gratus	Strophanthidin

Cardiac glycosides bind to Na⁺-K⁺-ATP_ase pump (at K⁺ binding site) and inhibit its function (influx of K⁺ and efflux of Na⁺). This results in enhanced intracellular Na⁺level that favors the exchange of more and more Na⁺for Ca⁺² thus promoting cardiac contraction (displays positive inotrophic effect by indirectly increasing intracellular Ca⁺² level, positive chronotrophic effect is the increase in force of cardiac contraction). Extracardiac effects of these agents include diuresis (as a result of increased renal blood flow due to improved cardiac output) and nausea, vomiting (via activation of CTZ).

Cardiac arrhythmia (associated with reduced level of K⁺ in myocardial cells) is their common adverse effect (in case of toxicosis) that implies the administration of Potassium chloride. Cholestyramine (an adsorbant) is also used to treat digitalis poisoning. In addition to CHF, these drugs are also used to prevent anesthesia-induced cardiac arrest. Prophylactic digitalization is sometimes used to maintain optimal cardiac functionality during open heart surgery. Cardiogenic shock, renal failure and hepatic insufficiency are important contraindication for these drugs. Cats are highly susceptible to digitalis intoxication and therefore they should not be treated with these agents. Co-administration of calcium (potentiate cardiac stimulation), diuretics (intensify K⁺depletion) and β-agonists (chances of cardiac arrhythmia are increased) with cardiac glycosides should be avoided.

2. Phosphodiesterase (PDE) inhibitors: Phosphodiesterase enzyme is responsible for the break down of cAMP and cGMP. The intracellular Ca⁺² level can be elevated through inhibiting PDE-mediated degradation of cAMP.

(a) Methylxanthines: Methylxanthines inhibit PDE enzyme and block adenosine receptors. Synthetic methylxanthines like Aminophylline and Theophylline to cause myocardial stimulation. Methylxanthines are also used as CNS stimulants, expectorants and bronchodilators. Their detailed pharmacological and toxicological profile has been already described.

(b) Bipyridine derivatives: Amrinone and Milrinone are also PDE inhibitors that can be administered in CHF to facilitate myocardial stimulation.

3. Sympathomimetics: β-agonists like Adrenaline (α₁, α₂, β₁ and β₂ agonist), Dobutamine (selective β₁agonist) and Isoproterenol (β₁ and β₂ agonist) are also advantageous in heart failure as they cause tachycardia and thus improve cardiac output. However their frequent use is limited by their common and unavoidable side effects.

Hypertension and anti-hypertensive drugs

Blood pressure (B.P) can be defined as that force which propels vascular fluid (blood) throughout circulation. This pressure is exerted as a result of cardiac pumping activity and it executes a decline in intensity as the flow is progressed from aorta (98 mm of Hg) to peripheral blood vessels (about 3 mm of Hg in vena cava). The endothelial lining of blood vessels also offers a resistance towards the flow of blood. Although this vascular resistance is inversely proportional to the diameter of blood vascular lumen, maximum resistance is experienced by arterioles not the capillaries and veins (due to their weak and thin walls). Net resistance is known as total peripheral resistance (TPR) and it is calculated by the following formula

TPR (mm of Hg/L/min.) = Mean aortic pressure (mm of Hg) – Pressure in vena cava (mm of Hg)

Cardiac output (L/min.)

B.P = Cardiac output x TPR

Regulation of systemic blood pressure is carried out by two mechanisms.

1. Baroreceptors and sympathetic nervous system: Baroreceptors (located on arterioles) sense out hypotension and transmit signal to sympathetic nervous system which after stimulation releases norepinephrine. Norepinephrine occupies α₁ and β₁ adrenergic receptors to cause vasoconstriction (increases peripheral resistance) and tachycardia (enhances cardiac output) that ultimately lead to hypertension for normalizing blood pressure.

2. Renin-Angiotensin-Aldosterone system: Reduced renal blood flow, decreased volume and osmolarity of plasma result in the release of rennin from renal juxta-glomerular (JG) apparatus that converts angiotensinogen (synthesized by the liver and provided by the blood) into angiotensin-1. This angiotensin-1is further converted into angiotensin-2 by angiotensin converting enzyme (ACE). Angiotensin-2 can either itself act as a vasoconstrictor or it can facilitate the synthesis and liberation of aldosterone (a mineralocorticoid) from adrenal cortex that causes the retention of fluid and sodium ions by acting on its target cells (principal cells of collecting duct). This increases the volume as well as osmolarity of plasma and eventually increases blood pressure

Hypertension is defined as sustained elevated blood pressure that may be caused by chronic renal failure (improper glomerular filteration increasing the plasma volume and solute concentration), metabolic disturbances (abnormal solute concentration elevating plasma osmolarity) or endocrine disorders (inadequate aldosterone level). Hypertension can give rise to many serious outcomes like neurological disturbances (stroke-rupture of crainial vessels) and ocular defects (retinal edema, retinal detachment, retinal atrophy and glaucoma).

Treatment strategies for hypertension: Single agent or combination therapy must be used depending upon the requirement. Dietary salt restriction should be advised. Weight reduction (through exercise) is ideal to prevent obesity. Life-long treatment schedule must be followed if hypertension is due to chronic renal failure.

Antihypertensive drugs: These drugs are classified into following types.

1. Vasodilators: Hydroxyzine, Minoxidil (also used to treat androgenic alopecia [excessive hair loss due to enhanced androgen level) in men] and Nitroprusside are included in this category. Hydoxyzine overdosage results in hypotension. Co-administration of Hydoxyzine and sympathomimetics will result in additive tachycardia. After metabolized by red blood cells and endothelial cells, Nitroprusside forms nitric oxide that increases cGMP level (by stimulating guanyl cyclase enzyme) and finally vasodilation is caused. However it is not commonly used as it contains cyanide and can cause cyanide poisoning.

2. ACE inhibitors: Captopril, Enalapril and other ACE inhibitors display their antihypertensive action by blocking the synthesis of Angiotensin-2. Hypotension and hyperkalemia are their possible adverse effects.

3. Angiotensin receptor antagonists: Losartan and Valsartan can deprive angiotensin of its respective receptors and this action can be helpful to treat hypertension however these agents are used only in human medicine.

4. β-blockers: Cardioselective β-blockers (Atenolol, Metoprolol) or non-selective β-blockers (Propranolol) are also effective for hypertensive patients.

5. Diuretics: They reduce the volume as well osmolarity of plasma and thus decrease blood pressure.

It should be kept in mind that β-blockers and diuretics are always used only in adjunctive therapy (along with vasodilators, ACE-inhibitors or Angiotensin receptor antagonists) for hypertension as they cannot provide total relief when used alone.

Angina pectoris: It is a condition that is manifested by sudden, severe emergence of pain in chest (pectoral) muscles that can spread to arm, jaws, back and neck region. Atherosclerosis or vascular smooth muscles spasm reduces coronary perfusion that causes short-term ischemia (lasts for 15seconds to 15 minutes and is therefore unable to induce necrosis). There are three types of angina.

1. Stable or typical angina: It is caused by atherosclerosis and aggravated by high workload (physical or mental), exercise and emotional excitement. Appropriate rest or use of Nitroglycerine can relieve this problem.

2. Unstable or atypical angina: It occurs even during rest conditions and no relief is achieved with rest or Nitroglycerine administration. Some alternative method should be applied for therapy.

3. Prinzmetal or variant angina: It results from coronary artery spasm and shows good response to treatment with Nitoglycerine.

Treatment strategies for Angina pectoris:

1. Pharmacotherpy (use of drugs): Any of the following drugs can be used;

(a) Nitroglycerine: It is the drug of choice for angina pectoris and it enhances coronary perfusion by causing relaxation of coronary arterioles. It is usually administered through transdermal patches over the arm or chest region.

(b) β-blockers: Cardioselective β-blockers (Atenolol, Metoprolol) or non-selective β-blockers (Propranolol) are also effective for patients suffering from angina pectoris.

2. Smoking cessation is an integral part of medical counseling for angina patients.

3. Coronary angioplasty: It is a medical procedure that is conducted to remove stenosis or atheroma from coronary arteries.

4. Coronary artery bypass surgery: It is performed to provide an alternate way for blood (due to obstruction or stenosis of coronary artery) in-order to ensure adequate myocardial perfusion.

Cardiac arrhythmia/dysrrhythmia: It is defined as disorder of cardiac impulses characterized by abnormality in rate of origin of impulse generation or in conduction/propagation of impulse. Therefore it becomes clear that arrhythmogenesis involves either alteration in impulse generation (abnormal automatacity) or alteration in impulse propagation [abnormal conductivity; it may occur due to re-entry (recirculation of impulse) or atrio-ventricular block]. Classification of arrhythmias is based upon the nature of alteration in heart rate (whether increased or decreased) and site of origin of impulse abnormality.

Tachyarrhythmia: It is that arrhythmia which involves abnormally elevated heart rate. It is further subdivided into following subtypes.

(a) Atrial tachycardia (ectopic pacemaker activity in atria)

(b) Ventricular tachycardia (ectopic pacemaker activity in ventricles)

(d) Paroxysmal tachycardia (abnormality in any part of the heart causing rapid rhythmical discharge of impulse in all directions)

(e) Fibrillation (it may be atrial or ventricular depending upon the site of origin but it always involve random propagation of impulse)

Bradyarrhythmia: It is that arrhythmia which involves abnormally decreased heart rate. It is further subdivided into following subtypes.

(a) Sick sinus (slow depolarization/action potential generation at SA node)

(b) Sinus arrest (failure of SA node to generate impulse)

(d) Cardiac arrest (cessation/stoppage of all rhythmical impulses in the heart)

Classification of anti-arrhythmic drugs: Vaughan Williams and Singh (1969) classified anti-arrhythmic drugs into four classes while Harrison (1979) subdivided class-1 into three sub-classes.

Category	Mechanism of action	Examples	Comment
I-A	Na⁺ channel blockers	Quinidine, Procainamide	Slow down phase-0 depolarization. Due to decreased sodium influx, there is decreased potassium efflux which prolongs the duration of action potential.
I-B		Lidocaine, Mexilitine	Shorten phase-3 repolarization (decrease the duration of action potential)
I-C		Flecainide, Encainide	Markedly slow down phase-0 depolarization. Their action is similar to Quinidine and Procainamide but more pronounced than that.
II	β-blockers	Propranolol, Metoprolol	Suppress phase-4 depolarization (enhance the threshold value required for depolarization)
III	K⁺ channel blockers	Amiodarone, Bretylium	Prolong phase-3 repolarization (diminish outflow of potassium during replarization, therefore cells remain refractory even after full repolarization)
IV	Ca⁺² channel blockers	Verapamil, Deltiazem	Shorten action potential (decrease calcium influx in phase-2)

Pharmacology of Digestive System

2011-07-07T11:14:00.004+05:00

Pharmacology of Digestive System

Drugs affecting salivary secretion: Saliva (which contains a digestive enzyme called ptylin or amylase)

is continuously secreted into the oral cavity from salivary glands. The salivary nuclei located in the brainstem are excited by taste and tactile stimuli from the tongue and other areas of mouth. Parasympathetic stimulation causes profused watery salivation whereas sympathetic stimulation tends to

reduce the salivary secretion and enhances its viscosity.

Salivary stimulants/Sialics/Sialagogues: These agents increase the volume and fluidity of saliva and

thus stimulate appetite and even food digestibilty. Gentian, Nux vomica and cholinergic agonists (like

carbachol) can be used to stimulate salivation in hypoptylism (decreased salivary secretion) and xerostomia (dry mouth). Undesirable ptylism is also seen in organophosphate intoxication.

Salivary inhibitors/Anti-sialics/Anti-sialagogues: These drugs are salivary suppressants and have therapeutic significance in many conditions like oral surgery and inhalant general anesthesia (as pre- anesthetics). Anticholinergic drugs like Atropine, Hyoscine and Glycopyrrolate can be used for this purpose but they are not free from unwanted side effects.

Functional anatomy of gastric mucosa: Gastric mucosa is commonly glandular in all animals except horses in which both glandular and non-glandular mucosae are present in the stomach. The glandular mucosa undergoes frequent invaginations, called gastric pits that contain gastric glands at their basal position. On the basis of glandular activity, gastric mucosa is divided into three regions. Cardiac mucosa contains cardiac gastric glands which secrete thick alkaline mucus for providing protection to adjacent esophageal mucosa against gastric acid. Parietal region contains three types of cells; parietal/oxyntic cells which secrete HCl, mucus neck cells (responsible for the release of thin mucus) and chief cells that release pepsinogen (precursor of pepsin). Pyloric mucosa consists of gastrin-producing G cells.

Mechanism of gastric acid production: Acid secretion by parietal cells is a complex process that is made possible through the participation of various receptors and their respective ligands. Carbonic anhydrase (C.A) enzyme (present inside parietal cells) catalyzes the reversible reaction of H₂O and CO₂ giving rise to the synthesis of H₂CO₃ (carbonic acid). Further this carbonic acid is cleaved (by the same enzyme) into hydrogen and bicarbonate ions. The hydrogen ion is transported (via proton pump located on the luminal surface of parietal cell) into the gastric lumen to be used for HCl synthesis whereas the bicarbonate ion is moved out of the cell (by counter transport mechanism) in exchange for chloride ion. The potassium and chloride ions which are not so essential for cellular activities are transported into the lumen by another symport/co-transport system.

Four types of receptors (H₂, M, Gastrin and Prostaglandin receptors) are found on the apical/basal membrane of parietal cell and three different pathways (paracrine, neurocrine and endocrine) are involved in the regulation of gastric acid production.

Paracrine pathway: It is the most dominant pathway during which histamine is secreted by histaminocytes (its release is also mediated by gastrin and ACh) and it binds with H₂ receptors (that are linked with G_s protein). This binding stimulates G_s and then adenyl cyclase (A. C) which converts ATP into cAMP (that is utilized by proton pump (K⁺-H⁺-ATP_ase) to carry out the counter transport of H⁺ and K⁺; H⁺leaves the parietal cell while K⁺enters inside parietal cell. This paracrine pathway is blocked by prostaglandin E (exerts protective effect over gastric mucosa by inhibiting acid secretion) whose receptor are also located on apical membrane of parietal cell and are linked with G_i protein (that inhibits the activity of adenyl cyclase).

Neurocrine pathway: It involves the release of ACh followed by receptor occupancy and then synthesis of cAMP (2^nd messenger) which supports the function of proton pump. ACh also enhances the release of histamine (from histaminocytes) and gastrin (from G cells).

Endocrine pathway: Gastrin, released from G cells binds with its respective receptors and promotes proton pump-associated release of H⁺into the lumen for incorporation in HCl. Gastrin also enhances the release of histamine (from histaminocytes).

Phases of gastric acid secretion: Gastric acid secretion occurs in following four phases.

1. Cephalic phase: It occurs due to anticipation of food triggering the release of ACh which stimulates

parietal and G cells to secrete HCl and gastrin respectively.

2. Gastric phase: This phase is initiated by the entry of food into stomach; gastric distention is followed by the stimulation of stretch receptors and finally the release of ACh.

3. Intestinal phase: Entrance of acidic food in intestine causes intestinal P_H modification that further stimulates acid secretion in stomach.

4. Basal phase: This phase occurs in the absence of any external stimulus.

In case of humans, lowest acid secretion and peak acid secretion can be observed at 7:00 am and midnight respectively.

The following drugs will stimulate gastric acid secretion.

Pentagastrin (Gastrin analogue), Betazole (Histamine analogue), Histamine itself can also be used but it should be co-administered with H₁receptor antagonist to avoid broncho-constriction, hypotension and other signs of allergic reaction. Stomachics, (drugs which assist in digestion by improving gastro-intestinal motility and secretory activity) including Neostigmine and Carbachol can also be used for this purpose.

Acid neutralizing drugs: These are divided into two groups.

1. Systemic agents: Sodium bi carbonate and Sodium citrate are having sufficient water solubility which enables them to get absorbed into blood stream after oral administration and exert a systemic action. These drugs chemically react with HCl and form NaCl (a neutral salt), H₂O and CO₂. They are used for the symptomatic treatment of gastric hyperacidity and to achieve the alkalization of urine. Rebound acid secretion is the most commonly observed side effect that occurs as a result of excessive CO₂ production (as a product during chemical reaction) leading to gastric distension and triggering HCl production. Being alkaline in nature, both Sodium bi carbonate and Sodium citrate have the ability to accelerate the excretion of acidic drugs and to prolong the half life of alkaline drugs.

2. Non-systemic agents: They are unable to get absorbed into systemic circulation due to their hydrophobic nature and therefore they induce local action. Aluminium hydro-oxide acts as a demulcent (exerts soothing effect on mucus membrane) and smooth muscle relaxant activity (it can cause undesirable constipation). It also binds with phosphorus and decreases its absorption that can lead to hypophosphatemia and even osteomalacia. Magnesium hydro-oxide (Milk of magnesia), Magnesium carbonate and Magnesium trisilicate are also used (in the form of suspension). But they cause unwanted laxation due to enhanced release of cholecystokinin (CCK) and hypermagnesemia that can be fatal for patients with renal insufficiency. Chalk (Calcium carbonate) induces antacid and antidiarrheal action when given orally (topical application will provide antiseptic action). Its use is uncommon due to risk of hypercalcemia, hypercalciuria and urolithiasis (formation of stones in urinary tract). Acid neutralizing drugs are commonly used in combinations to minimize adverse effects and to improve efficacy.

Inhibitors of gastric acid secretion (Antacids): Overproduction of gastric HCl gives rise to several pathological conditions like gastritis, gastric ulcer, duodenal ulcer, gastrinoma (a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine), gastroesophageal reflux disease [GERD, a condition in which the stomach contents (food or liquid) leak backwards from the stomach into the esophagus. This action can irritate the esophagus, causing heartburn and other symptoms], peptic ulcer (erosion in the lining of the stomach or duodenum), Zollinger-Ellison syndrome (G cell tumor leads to excessive gastrin secretion which subsequently enhances acid secretion). Moreover Helicobacter pylori (gram negative bacteria) infection and inadequate use of NSAID_S also results in gastric hyperacidity. Antacids should be used for the treatment (and also prophylaxis in some cases) of above mentioned conditions.

Classification of Antacids: Antacids are classified into following categories.

1. H₂ receptor antagonists: Blockage of H₂ receptors will inhibit the paracrine pathway of gastric acid secretion. Cimetidine, Famotidine, Ranitidine and Nizatidine are important members of this category. Cimetidine has an apparent immuno-modulating effect by reversing suppressor T-cell mediated immune suppression. It also possesses weak anti-androgenic action which can cause loss of libido (sex drive), hypospermia (reduced sperm count), impotence (sexual dysfunction) and gynecomastia (abnormal enlargement of mammary glands in males due to enhanced plasma prolactin level) in males. Abrupt withdrawl of Cimitidine therapy can lead to rebound acid hypersecretion. It is a potent microsomal enzyme inhibitor and hence it decreases the hepatic metabolism of many drugs. Other are considered as comparatively safe (due to minimum or no side effects).

2. Proton pump inhibitors (PPI_S): Omeprazole, Esomeprazole, Pantoprazole (Zopent) and Lansoprazole have the potential to inhibit the action of proton pump. They are more potent than all other antacids. They are formulated in enteric-coated tablets to prevent them from degradation by gastric acid. Prolonged administration of high doses of these agents has been reported to cause hyperplasia of parietal cells. These agents also interfere with the hepatic processing of many drugs by inhibiting the function of microsomal enzymes.

3. Prostaglandin analogues: Misoprostol and othe PGE analogues can be used to block histamine-mediated gastric acid secretion. But they are effective only in the prophylaxis of hyperacidity and should not be used for the treatment of pre-existing hyperacidity.

4. Anticholinergics: Selective M₁ receptor blockers like Pirenzepine and Propantheline can reduce gasto-intestinal motility and gastric acid secretion. But they are linked with many side effects like mydriasis, constipation, tachycardia, xerostomia and urine retention.

5. Cytoprotective drugs: Sucralfate (it contains sucrose, Aluminium and Sulphate) is the most common member of this family. In acidic environment of stomach, Sucralfate is broken down into sucrose and sulphate. Sucrose protects the gastric mucosa by assuming a sticky gel like consistency while negatively charged sulphate groups electrostatically bind to positively charged proteins (in ulcerated and necrotic tissue) and inhibit their exudation. It has no direct acid neutralizing action and it is considered the safest drug for hyperacidity due to its minimum side effects.

Mediators of gastric motility: Gastric motility is responsible for the passage of gastric contents into small intestine (called gastric emptying). Gastric motility is regulated by local as well as central mediators. Parasympathetic stimulation increases gastric emptying through the agonistic effect of ACh on muscarinic receptors while sympathetic stimulation delays gastric emptying via adrenergic response (involving norepinephrine). ENS releases dopamine (that acts on D₂ receptors) and serotonin (binds with 5HT₄ receptors) which cause inhibition and stimulation (by increasing the release of ACh from myenteric plexus) of gastric contraction respectively. Motilin (released from duodenum) also promotes gastric contraction by binding to motilin receptors located in antrum and duodenum. Any interruption in above mentioned regulatory mechanisms can lead to gastric motility disorder that is characterized by chronic vomiting, anorexia, post-prandial discomfort (uneasiness after taking food) and gastro-esophageal reflux (the passage of acidic gastric contents into esophagus that can cause esophagitis).

Prokinetics are drugs that are used to restore gastric contractions in gastric motility disorder. They are divided into following classes.

1. D₂ receptor antagonists: Metoclopramide and Domperidone are prokinetics as well as anti-emetics. They increase the force and frequency of gastric contraction, relax the pyloris and have no effect on gastric, pancreatic or biliary secretions. Blockage of D₂ receptors in CNS can cause sedation, anti-emesis, behavioral modification and even Parkinsonism (in case of overdosage). Therefore these agents are contraindicated in patients suffering from Parkinsonism.

2. Serotonin (5HT₄) receptor antagonists: Cisapride stimulates the motility of stomach, small intestine and colon (colonic stimulation can cause diarrhea that is undesirable). Tegaserod is also a colonic prokinetic. These agents are used to treat delayed gastric emptying, colonic hypomotility, post-operative gastroparesis (gastric paralysis) and grass sickness (in horses).

3. Motilin like drugs: Erythromycin (basically a macrolide antimicrobial drug that is used to treat gram positive bacterial infection) stimulates antral motilin receptors when used in sub-antibacterial dose.

4. H₂receptor antagonists: Ranitidine and Nizatidine (basically used as antacids) decrease parasympathetic stimulation by increasing cholinesterase-mediated degradation of ACh.

5. Misoprostol: This synthetic prostaglandin E₁ (also used as antacid) increases the propulsive activity of colon and leads to prokinesis.

Constipation: It is the condition of infrequent defecation or lack of defecation characterized by straining to defecate and retention of hard, dry fecal mass (called scybala) in colon and rectum as a result of excessive water absorption and reduced intestinal motility. Treatment is anticipated by the use of laxatives or purgatives to restore intestinal motility.

Laxatives (Aperients): These agents increase intestinal motility in a mild/moderate manner, leading to excretion of soft fecal material. Laxatives consist of the following types.

(a) Lubricant laxatives: Their mode of action involves the lubrication of dry fecal material as well as intestinal mucosa to facilitate defecation. Liquid paraffin (a residue of petroleum distillation) is an example of such drugs. It can be given orally or as enema (administration of drug through intra-rectal route). Adverse effects include aspiratory pneumonia (due to accidental entry of drug into respiratory tract) and anal leakage/seepage of liquid feces (commonly seen in pets) that can lead to dirtiness of bedding and furniture etc.

(b) Surfactant laxatives (stool softeners): Docusate sodium, Docusate potassium and Docusate calcium are wetting and emulsifying agents which decrease surface tension and allow fats and water to penetrate in fecal mass.

Purgatives (Cathartics): They enhance intestinal motility resulting in watery feces (and may be diarrhea). They are subdivided into following groups;

1. Bulk purgatives: Bran (the outer covering of cereals), Agar (a polysaccharide obtained from algae) and Ispaghul/Psyllium seed (derived from Plantago psyllium) are hydrophilic substances which absorb water and swell up. This action increases the bulk of intestinal contents and exerts pressure on intestinal musculature to stimulate peristalsis.

2. Osmotic purgatives: Being hypertonic in nature, these drugs attract water and retain it in intestinal lumen which removes the hardness of fecal contents. Glycerine [C₃H₅(OH)₃] suppositories can be used for this purpose. Sorbitol and Mannitol (alcohols that are achieved after the reduction of glucose and mannose respectively) are mixed with activated charcoal to facilitate the excretion of some poisons. Excessive use of osmotic purgatives can lead to water deprivation which can be harmful particularly for patients with pre-existing dehydration.

3. Irritant/stimulant purgatives: These are further subdivided into two classes;

Direct acting irritant/stimulant purgatives: Bisacodyl (Dulcolex) is capable to directly stimulate intestinal mucosa and myenteric plexus (which leads to release of ACh) thereby causing increased peristaltic contractions as a result of parasympathetic stimulation.

Indirect acting irritant/stimulant purgatives: Vegetable oils require activation through digestive enzymes in order to be able to induce peristalsis. The hydrolysis of vegetable oils (in small intestine) by pancreatic lipase results in the synthesis of fatty acids that are subjected to saponification by reacting them with sodium and potassium salts. This process also yields glycerine as a by product. Castor oil (obtained from Ricinis communis, Arind) and Linseed oil can be used for this purpose. The active ingredients of Castor oil and Linseed oil are ricinoleic acid and linoleate respectively. Castor oil is contraindicated in pregnant animals as it can stimulate uterine contractions as well.

4. Drastic purgatives: Croton oil or Jamal ghota is a product of Croton tiglium plant. It contains crotinoleic acid as an active constituent. It drastically/harshly increases the intestinal motility and is not commonly used due to its narrow margin of safety.

5. Neuromuscular purgatives: Carbachol and other cholinergic agonists can cause purgation by activating muscarinic receptors located on intestinal smooth muscles. Miosis, bradycardia, frequent urination, salivation and broncho-constriction are their possible side effects. They are contraindicated in all conditions that involve gastrointestinal obstruction.

Diarrhea: Abnormal increase in the frequency, volume and fluidity of fecal contents is termed as diarrhea. Neoplasia, stress, toxins, dietary disturbance, poisoning and enteritis are most common causes of diarrhea. Symptomatic therapy (use of antidiarrheal drugs) combined with etiological treatment (removal of the cause) must be attempted for complete recovery.

Antidiarrheal drugs: These are divided into following categories;

(A) Non-specific drugs: They provide only symptomatic treatment and are further subdivided into following groups.

1. Gastrointestinal protectants and adsorbents: They protect the mucus membrane and reduce irritation by forming protective covering over mucus membrane and adsorbing toxins. Kaolin (Aluminium silicate), Pectin (a carbohydrate polymer), Activated charcoal and Activated attapulgite (Aluminium trisilicate) are examples of such agents. These are used either alone or in combination (e.g. Kao-pectate).

2. Anti-motility agents: Natural opiods (like Codeine, Morphine) and synthetic opiods (like Loperamide and Diphenoxylate) exert anti-motility action by decreasing the release of ACh. Side effects include sedation (stimulation in cats) and dependence.

3. Antispasmodics: Anticholinergic drugs like Atropine, Hyoscine and Propantheline are also used to treat diarrhea by decreasing intestinal motility. Xerostomia, mydriasis, tachycardia, constipation and urine retention are their possible adverse effects.

(B) Specific drugs: They help to specifically eliminate the pathogen involved in the causation of diarrhea. Neomycin (effective against gram negative bacteria), Penicillin (effective against gram positive and gram negative bacteria), Metronidazole (effective against anaerobic bacteria and protozoa like ameoba), Sulphadimidine (anticoccidial and antibacterial) and Furazolidone (anti-giardial) are commonly used to treat infectious diarrhea.

Emesis/Vomiting: Emesis can be defined as the expulsion of gastric contents through mouth as a result of anti-peristalsis. It can be caused by drugs, radiation, infections, motion sickness, metabolic disturbance, emotional disorders and neoplasms. Hyperemesis gravidarum (Morning sickness) is a severe type of vomiting that occurs during first trimester of pregnancy. It exerts deleterious effects on the health of the mother and debilitates her in day to day activities. Although exact cause is unknown however this condition can be attributed to altered level of human chorionic gonadotrophin (HCG) as a result of conception (and associated physiological modifications like absence of menstruation). Nausea is defined as the state of uneasy feelings that precedes emesis. The phenomenon of vomiting is observed only in carnivores and omnivores whereas rabbits, rodents, ruminants and horses are unable to vomit. Emesis is sometimes induced through the application of emetogenic agents (like CuSO₄, Na₂CO₃, Apomorphine) to facilitate the elimination of non-corrosive poisons. Sustained emesis can lead to dehydration, acid-base imbalance, electrolyte disturbance, physical exhaustion and even gastric rupture. Appropriate treatment approach must include the use of anti-emetics, fluid and electrolyte therapy, as well as dietary management. Vomiting is initiated by the stimulation and co-ordination of various organs and body regions (involving different receptors and their associated neurotransmitters) both at peripheral and central level. Different external and internal stimuli can provoke the vomiting pathway.

1. Visual stimuli (e.g. repulsive sight) and olfactory stimuli (e.g. pungent smell) are transmitted to cerebral cortex while head trauma (due to accident etc.) and increased intracranial pressure stimulate limbic system. Cerebral cortex and limbic system are higher centers of the CNS that are having H₁ and M receptors and they further transmit these signals to vomiting centre (located in medulla oblongata and provided with H₁ and M receptors).

2. Certain stimuli like motion sickness, labyrinthitis and exposure to ototoxic drugs are transmitted to vestibular nuclei (having H₁ and M receptors) of CNS by 8^th cranial nerve. From there the impulse is transferred to cerebellum which stimulates vomiting centre.

3. Localized pharyngeal irritation is a stimulus for nucleus tractus solitarius (NTS) which comprises of H₁, M, D₂ and 5HT₃ receptors and leads to emesis via stimulating vomiting centre.

4. Toxins and drugs contained in the blood act on chemoreceptor trigger zone (CTZ) that is located outside the blood brain barrier (in the 3^rd ventricle) and is supplied with H₁, M, D₂, 5HT₃and μ (a subtype of opiod receptors) receptors. CTZ can stimulate NTS as well as vomiting centre.

5. M, D₂ and 5HT₃ receptors located in gastric and intestinal mucosa respond to inflammation, radiation and exposure to cytotoxic drugs (used as anticancer agents) by activating CTZ and NTS.

Various efferent/motor pathways (like vagus, phrenic and spinal nerves) are stimulated by vomiting centre which carry out the relaxation of esophagus, esophageal sphincter and fundus coupled with pyloric and duodenal contraction. Ultimately strong rhythmic contractions of abdominal and diaphragmatic muscles take place which cause the expulsion of gastric contents through mouth (that is known as emesis).

Anti-emetics: These are divided into following categories;

1. Locally acting anti-emetics: They lack the ability to cross blood brain barrier so they cannot act on vomiting centre.

(a) Anti-cholinergic drugs: Scopolamine is commonly used to avoid motion sickness. It is effective only when used for prophylactic purpose. It should not be used for more than three days as it can delay gastric emptying that can cause vomiting.

(b) Prokinetics: Domperidone and Cisapride enhance peristalsis (by increasing the gastric emptying) and thus reverse anti-peristalsis which leads to vomiting.

2. Centrally acting anti-emetics: They induce their anti-emetic effect by acting on vomiting centre and are divided into following groups;

(a) H₁-receptor antagonists (Anti-histaminics): Cyclizine, Meclizine, Dimenhydrinate (Gravinate) and Diphenylhydramine (Benadryl) are included in this group. Most common side effect associated with their administration is sedation.

(b) D₂-receptor antagonists: These are further subdivided into many classes;

· Phenothiazine derivatives: They include Acepromazine and Chlorpromazine (Largectil) which are used as tranquilizers and anti-emetics.

· Butyrophenone derivatives: Droperidol and Haloperidol are examples of such agents and these are used as anti-emetics and antipsychotics (drugs that are used to treat mental disorders like schizophrenia and mania etc.).

· Benzamides: Metoclopramide (Maxolon, Metoclon) is a member of this class that is exerts prokinetic as well as anti-emetic action.

5HT₃-receptor antagonists: Ondansetron and Granisetron are well known members of this group and they are considered safest anti-emetics due to their minimum adverse effects

Pharmacology of Renal System

2011-07-06T11:18:00.004+05:00

Pharmacology of Renal System

The renal system is responsible to carry out certain significant physiological functions including; excretion of waste products (urea in mammals and uric acid in reptiles and birds), maintenance of acid-base balance (through retention and liberation of HCO^-₃and H⁺ respectively) and regulation of systemic blood pressure (via rennin angiotensin aldosterone system). The basic structural and functional unit of renal system is called nepheron that is broadly divided into two segments; renal corpuscle (including the cup shaped structure called Bowman’s capsule and associated capillary meshwork known as glomerulus) and renal tubule (subdivided into proximal convoluted tubule (PCT), Loop of Henle (U-shaped structure that consists of thin descending and thick ascending portions), distal convoluted tubule (DCT) and terminal collecting duct (CD). The kidneys receive approximately 25% of cardiac output that is subjected to glomerular filtration (it is driven by plasma hydrostatic/osmotic pressure and normally filters almost all plasma constituents except proteins, lipids and protein-bound substances). However about 99% of this filtrate is reabsorbed by renal tubule to avoid the loss of essential components like water and nutrients. Each segment of renal tubule is provided with unique structural as well functional adaptability to ensure optimum reabsorption.

PCT: The tubular fluid (present inside tubular lumen) contains sodium, water, carbon dioxide and other filtered substances. Excess of water and carbon dioxide are reversibly converted into carbonic acid (through the catalytic action of luminal carbonic anhydrase (CA) enzyme) for the sake of excretion. Alternatively carbonic acid can give rise to water and carbon dioxide which can passively diffuse into intracellular environment where once again the same enzyme is utilized to form carbonic acid and then it is splitted to yield hydrogen and bi carbonate ions. There are two transport systems (located on basolateral membrane) for the movement of bicarbonate ions into interstitial space; Na⁺- HCO^-₃symport system and HCO^-₃-Cl^- antiport system. Reabsorption of sodium is induced by three systems (located on luminal/apical membrane); sodium channels, Na⁺- H⁺counter transport system (which also serves to expel H⁺into tubular lumen) and system for the co-transport of Na⁺with glucose/amino acids. To compensate the increased level of intracellular sodium, Na⁺/K⁺/ATP_ase pump (located on basolateral membrane) drives sodium to interstitial space whereas potassium is made to enter inside intracellular environment. PCT is the site of action of carbonic anhydrase inhibitors (like Acetazolamide), which inhibit both luminal as well as intracellular carbonic anhydrase enzymes thereby preventing the reabsorption of water, carbon dioxide and HCO^-₃and partial inhibition of sodium reabsorption_.This results in enhanced flow of urine that is alkaline in nature. Reduced level of HCO^-₃in plasma leads to systemic acidosis that is undesirable. CA inhibitors are primarily used to treat hydrocephalus (cerebral edema) and glaucoma. CA enzyme is present in CNS (CA inhibition causes reduction of intracranial pressure, anticonvusant effect), ciliary body (CA inhibition enhances the drainage of aqueous humor thus reducing intra-ocular pressure), kidney (CA inhibition causes diuresis) and gastric mucosa (although CA inhibition reduces gastric acid secretion however it lacks any therapeutic significance).

Descending (thin) loop of Henle: This portion (located in renal medulla) is characterized by high permeability for water and absence of solute reabsorption. Transcellular and paracellular passive transport of water takes place at this point that can be prevented through the use of osmotic diuretics (Glycerol and Mannitol). Osmotic diuretics increase the osmolarity (and associated osmotic pressure) of tubular fluid that helps to draw more water from intracellular and interstitial environments causing enhanced flow of urine. Glycerol can be given orally however sometimes it can cause vomiting. Mannitol is unable to get absorbed after oral administration therefore it should be given parentrally. Activation of rennin angiotensin aldosterone system terminates the diuresis induced by osmotic diuretics.

Ascending (thick) loop of Henle: This portion is completely impermeable to water but it is responsible to conduct 25-30% of total sodium reabsorption. Calcium and Mgnesium use transcellular and paracellular modes of transportation to get entry inside cellular and interstitial space. Na⁺/K⁺/2Cl symport system (located on apical membrane) drives the concerned ions into cellular environment. Remining task is performed by Na⁺/K⁺ antiport and K⁺/Cl^- co-transport systems, located on basolateral membrane. Loop diuretics (like Frusemide/Furosemide (Lasix) and Ethacrynic acid) have the potential to cause diuresis, natriuresis and kaliuresis by blocking the action Na⁺/K⁺/2Cl symport system. Although these are considered as most potent diuretics but they can cause some side effects like ototoxicity and nephrotoxicity. Therefore they should not be co-administered with other ototoxic and nephrotoxic drugs (Aminoglycosides and Cisplatin).The hypokalemia associated with loop diuretics can predispose patients to Digitalis toxicosis. Mercurial diuretics (like Marsalyl) also possess similar mode of action but they are effective only in acidic urine (therefore they cause short-term diuresis). Furthermore their excessive administration can cause mercury toxicosis (Plumbism).

DCT: Parathyroid hormone facilitates the reabsorption of calcium through calcium channels located on apical membrane. Na⁺/ Cl^- symport system is also there to conduct solute reabsorption (only 5% of total sodium reabsorption occurs here). Chloride channels (located on basolateral membrane) transport excess of Cl^- into interstitial space while sodium is removed via Na⁺/K⁺ antiport system (located on basolateral membrane). DCT and ascending loop of Henle are known as diluting segments because they are impermeable to water and execute only solute reabsorption. Thiazide diuretics (like Chlorthiazide and Hydrochlorothiazide) act here by inhibiting sodium reabsorption (through blocking Na⁺/Cl^- symport system) and improving calcium reabsorption. These drugs can cause hyperglycemia and hyperuricemia therefore they are contraindicated in gout [Fixation (ankylosis) of joints due to uric acid accumulation, patient becomes temporarily immobilized] and diabetes mellitus (insulin deficiency or insulin resistance leads to hyperglycemia and glycosuria). Udder edema in dairy calves is a common indication for the used of these diuretics.

CD: This segment of nepheron comprises of two distinct cell types; Principal cells and Intercalated cells. Principal cells are having water channels that are meant for passive reabsorption of water under the influence of vasopressin/antidiuretic hormone (ADH; released by supra-optic nuclei of posterior pituitary gland). Aldosterone-mediated influx of sodium and efflux of potassium (across the luminal membrane) is made possible by the presence of sodium and potassium channels respectively (normally excretion of potassium and reabsorption of sodium takes place). Na⁺/K⁺ antiport system is responsible for ionic transport across the basolateral membrane. Intercalated cells contain H⁺/K⁺ antiport system (at the apical membrane) that supply hydrogen ion (derived from carbonic acid) into the lumen and remove potassium ions. This site is used by potassium-sparing diuretics (cause potassium retention) to elicit their pharmacological response. Triamterone and Amiloride induce diuresis via blocking Na⁺/K⁺ antiport system (leading to natriuresis and potassium retention). These agents can be used to inhibit the loss of potassium (leading to hypokalemia) that occurs with the administration of loop diuretics and thiazide diuretics. The ability of these drugs to cause hyperkalemia indicates their contraindication in patients taking potassium supplements and ACE inhibitors. Triamterone can cause megaloblastic anemia (oversized RBC production followed by their prompt degradation by reticuloendothelial system) by inhibiting the activity of folic acid (vitamin C). Triamterone and Amiloride are primarily used to treat cerebral edema.

Aldosterone receptor antagonists: Whenever there is a need for solute reabsorption (to enhance plasma osmolarity) the hypothalamus releases corticotrophin releasing hormone (CRH) that stimulates anterior pituitary gland to liberate adrenocorticotrophic hormone (ACTH). ACTH stimulates adrenal cortex for the synthesis and subsequent release of corticosteroids (glucocorticoids and mineralocorticoids). Aldosterone is a mineralocorticoid that undergoes receptor occupancy and then enters into the nucleus of target cell. There the hormone-receptor complex attaches to specific DNA sequence and promote transcription (synthesis of mRNA synthesis. Messenger RNA diffuses into the cytoplasm (where ribosomes are present) to initiate translation (protein synthesis). As a result aldosterone-induced proteins (AIP_S) are synthesized which carry out retention of sodium and excretion of potassium in CD of nepheron. Administration of aldosterone receptor antagonists (like Spironolactone) will block this pathway and diuresis will be caused. Same steroid receptors are shared by and other steroids (that are either naturally present in the body or they are given from exogenous sources) so always there will be a competition for receptor occupancy among steroid hormones. Overdosage of Aldosterone receptor antagonists can deprive testosterone and Dihydroprogesterone (Progesterone analogue) of their receptor occupancy (disturbing the level/activity of sexual steroids) that can lead to many unwanted effects in male (like impotence (sexual dysfunction), gynecomastia) and female (estrus/menstrual irregularities) patients. Spironolactone is used for the treatment of hyperaldosteronism.

Diuretic Tolerance: There are two forms of diuretic tolerance. Short-term tolerance, so-called braking, refers to a decrease in the response to a diuretic after the first dose has been administered. This can be prevented by restoring diuretic-induced loss of volume. The mechanism by which short-term tolerance occurs is unclear. It may be mediated by activation of angiotensin II or the sympathetic nervous system, but neither the inhibition of angiotensin-converting enzyme nor adrenergic blockade, separately or together, consistently prevents it. With long-term administration of a diuretic, the solute that escapes from the loop of Henle floods more distal regions of the nephron. By unknown mechanisms, increased exposure to solute causes hypertrophy of distal nephron segments, with concomitant increases in the reabsorption of sodium. Sodium that escapes from the loop of Henle is therefore reabsorbed at more distal sites, decreasing overall diuresis. The result is long-term tolerance of the loop diuretic.

Clinical indications for the use of diuretics

1. Edematous conditions:

Hepatic ascities: Hepatic necrosis (Cirrhosis) causes obstruction of portal blood flow, intense pressure is exerted (by accumulated blood) on walls of portal vasculature that favors the leakage of plasma followed by its accumulation in pericardial sac (hydropericardium occurs). Insufficient steroid (Aldosterone) metabolism as a result of cirrhosis can also promote edema by prolonging the duration of action of aldosterone.

CHF: Left-sided heart failure causes pulmonary edema while right-sided heart failure leads to peripheral edema. Diuretics (Frusemide, Acetazolamide or Thiazides) can be administered to resolve the edema.

Nephrotic syndrome: Altered glomerular filteration causes protein loss and reduced level of plasma proteins leads to hypotention that results in the activatioin of rennin angiotensin aldosterone system to induce solute and fluid reabsorption leading to edematous state. Aldosterone receptor anatagonists can be helpful to solve this problem.

Pre-menstrual edema: Hormonal imbalance (excess of estrogen) promotes the loss of fluid into extracellular space thus giving rise to edema.

Hydrocephalus (cerebral edema): Decreased osmotic pressure of CSF impairs its drainage (via crainial ventricles) and edema is developed. Osmotic diuretics and Carbonic anhydrase inhibitors are commonly used for this purpose.

Glaucoma: Overproduction or improper drainage of aqueous humor enhances the intraocular pressure and use of Carbonic anhydrase inhibitor is a good treatment option.

Udder edema: Swelling of udder that can be easily confused with mastitis (inflammation of udder).

Hydrothorax: Accumulation of fluid in thoracic cavity that can disturb normal breathing.

2. Non-edematous conditions:

Hypertension: Diuretics reduce the plasma volume and thus decrease blood pressure. Carbonic anhydrase inhibitors are commonly used for this purpose.

Hypercalcemia: Loop diuretics and others can be helpful to promote the excretion of excessive blood calcium however thiazides should not be used in this case as they facilitate calcium absorption in DCT.

Nephrogenic diabetes insipidus: This is characterized by non-responsiveness of principal cells (found in CD) to the action of ADH. The result is flow of large volume of diluted urine. Thiazide diuretics have the unique ability to undilute urine (by prmoting solute excretion) and can be used for this purpose. The 2^nd type of diabetes insipidus is known as central diabetes insipidus that occurs due to congenital or acquired deficiency of ADH.

Epistaxis: It is defined as nasal bleeding (common in race horses) due to peripheral vasodilation and accumulation of blood in nasal sinuses. Diuretics facilitate the removal of excessive fluid and relieve this problem. Application of cold water on the head region is an alternate option of therapy.

Hyperaldosteronism: It is an endocrine disorder that results in excessive release of aldosterone leading to overretention of fliud and solutes thereby causing edema. Spironolactone can be used to treat this condition.

ANTICONVULSANT DRUGS

2011-07-05T12:25:00.004+05:00

Anti-convulsant drugs

Anti-convulsants or anti-epileptic drugs are used to depress CNS in case of convulsive and seizure disorders (convulsion and seizure are pathological signs that are triggered by excessive inappropriate stimulation of spinal cord and brain respectively). Epilepsy is a complex syndrome of sudden and recurrent seizures that arise as a result of synchronous discharge of cerebral neurons in particular region of CNS which is referred to as primary focus (that may or may not be characterized by anatomical defect). The nature of resultant signs depend upon the cortical portion involved in the course of action. Involvement of motor cortex leads to convulsions (un-controlled, irregular movements) whereas visual (related to vision), auditory (concerned with hearing) or olfactory (smell related) hallucinations reflect the stimulation of parietal or occipital cortex. Normal CNS activity is maintained through the coordinated execution of excitation (performed by the release and receptor occupancy of excitatory neurotransmitters like ACh, Norepinephrine, Serotonin, Aspartate and Glutamate) and inhibition (involving inhibitory neurotransmitters like GABA, Glycine and Dopamine). Domination of inhibitory or excitatory mechanism (caused by pharmacological or pathological intervention) is manifested as CNS depression (including sedation, hypnosis. narcosis, anesthesia) and CNS stimulation (characterized by convulsions, seizures) respectively.

Pathophysiology of Epileptic disorders: Any of the following mechanisms can be implicated in the occurrence of Epilepsy.

1. Enhanced availability of excitatory neurotransmitters (due to overproduction, increased release or improper metabolism/uptake)

2. Diminished accessibility of inhibitory neurotransmitters (due to underproduction, lesser release or enhanced metabolism/uptake)

3. Altered function of neuronal membrane due to impaired activity of Na⁺-K⁺-ATP_ase pump or distorted permeability (resulting from hypoxia, inflammation, trauma)

4. Change in extra-cellular K⁺ and Ca⁺² concentration (seizure is associated with rise in K⁺ level and decline in Ca⁺²concentration)

Types of Epilepsy: Epilepsy is divided into following types on the basis of etiology.

Primary Epilepsy: It is caused by inherited anatomical defects of CNS and requires life-long therapy with anti-convulsant drugs.

Secondary Epilepsy: The underlying cause in this type of Epilepsy may be neoplasia (brain tumor), head injury, hypoglycemia, meningeal infection or abrupt alcohol withdrawl.

Classification of Epilepsy on the basis of signs and symptoms

1. Generalized seizures: It is characterized by the loss of consciousness and involvement of both cerebral hemispheres (there is no specific primary focus) and is further subdivided into following categories.

(a) Tonic-clonic seizures (Grand-mal Epilepsy): It is the common type of Epilepsy seen in humans and dogs. It is manifested by the rigidity of extremities followed by jerky movements for several minutes.

(b) Absence seizures (Petit-mal Epilepsy): It results in momentary loss of consciousness associated with staring, jerking of eyelids and lack of abnormal motor activity.

(c) Myoclonic seizures: It is a brief shock like condition that involves the muscles of limbs/extremities or entire body and no treatment is anticipated for dogs suffering from this type of seizures.

(d) Febrile seizures: This type of Epilepsy is caused by intense fever in children (most common during 3 months to 5 years of age) and is rarely treated as it never leads to neurological damage, cognitive impairment (loss of memory and learning ability) or death.

(e) Status epilepticus: It is a state of frequent or prolonged seizures that involves the appearance of subsequent seizure prior to recovery from the previous one. This can lead to extreme exhaustion, hyperpyrexia and even death.

2. Partial seizures: Consciousness is preserved/retained during this type of seizures. It consists of the following subtypes.

(a) Simple partial seizures: It gives rise to localized sensory or motor disturbances.

(b) Complex partial seizures (Temporal lobe Epilepsy): Consciousness is altered in this case and primary focus is present in temporal lobe. Patient exhibits confused behavior and purposeless movements.

Anti-epileptic drugs are divided into two categories.

1. Primary anti-epileptic drugs: These are the main agents which are specific for the condition.

Phenytoin: It selectively blocks Na⁺ channels and thus interferes with the improper generation and propagation of action potential. Gingival hyperplasia (hyperplasia of gums that can disturb the normal pattern of dental growth) and fetal hydantoin syndrome (characterized by cleft-lip, cleft-palate and congenital heart defets) are common adverse effects reported with the inadequate administration of Phenytoin.

Carbamazepine: Its mode of action is similar to that of Phenytoin. It has the property of auto-induction/self-induction (it stimulates the activity of microsomal enzymes responsible for its own metabolism).

Valproic acid: It is considered to be a broad-spectrum anti-convulsant drug (can be used to treat all types of seizures). In addition to the blockage of Na⁺ channels, it also enhances GABA-mediated inhibitory neurotransmission. Being a hepatotoxic agent, it can lead to inhibition of microsomal enzymes concerned with the biotransformation of most drugs.

2. Adjunct anti-epileptic drugs: These are meant for add-on therapy (combined with primary anti-epileptic drugs to provide better relief).

Felbamate: It blocks Na⁺ channels and NMDA (N-methyl D-aspartate) receptors.

Gabapentin: Although it is an analogue of GABA but it has no action over GABA receptors. It is responsible for the blockage of Ca⁺ channels.

Lamotrigine: It blocks both Na⁺ as well as Ca⁺ channels. It has the potential to cause life-threatening rashes (dermatitis) that are particularly harmful for patients less than 16 years of age.

Drugs modifying abnormal behavior

Veterinary ethology (branch of veterinary sciences that deals with the study of animal behavior in their natural habitat) is relatively a new field of study and the use of drugs to treat behavioral disorders of animals is still uncommon. Behavior is considered as abnormal if it affects owner, other animals or humans in a negative manner. However all behaviors are not physically harmful to other animals or humans.

Classification and treatment of behavioral disorders

1. Genetic-based behavioral problems: These include physiological malfunctions attributed to congenital or inherited defects. For example polydipsia (increased thirst) and polyuria (increased urination) associated with primary (congenital) diabetes insipidus (it results from congenital deficiency of ADH).

2. Developmental and age-related behavioral problems: Senility (old age) predispose the animals to uncontrolled urination/defecation while infantality (young age) deprive them of proper congnitive ability.

3. Instinctive (specie specific) behavioral problems: Coprophagia in rabbits is a common example of this category.

4. Disease-related behavioral problems: Hydrophobia, drooling of saliva from the mouth, self-mutilation (biting) and excessive barking are commonly observed in dogs suffering from rabies.

5. Adaptation-related behavioral problems: Newly acquired pets may exhibit destructive behavior (damaging the property and attempting to escape through the holes of fences), excessive vocalization (such as barking), panic reactions (acting wildly and damaging themselves) or elimination behavior (urinating and defecating at unacceptable sites).

6. Fear and phobias: Some animals get scared/frightened from thunderstorm, gun shots and loud noise such as that produced by auto-mobiles.

7. Displaced/redirected behaviors: It is the appearance of normal reaction on wrong stimulus/object. For instance a dog chases vehicles or bicycle if prey is not found and a male animal displays couplatory attitude towards inanimate objects if a female is not available nearby.

Many of the above mentioned behavioral disorders (except congenital, developmental and instinctive behavioral disorders) can be non-specifically treated with sedatives or tranquilizers to provide transient symptomatic relief.

8. Schizophrenia: The term schizophrenia is Greek in origin, and in the Greek meant"split mind". It is a psychotic (mental) disorder that arises as a result of inherent brain dysfunction and is characterized by delusions, hallucinations, anhedonia (inability to feel pleasure at normally pleasurable things/occasions), apathy, impaired attention and thinking or speech disturbances. It affects men and women with equal frequency. People suffering from schizophrenia may have the following symptoms:

Delusions, false personal beliefs held with conviction in spite of reason or evidence to the contrary, not explained by that person's cultural context.
Hallucinations, perceptions (can be sound, sight, touch, smell, or taste) that occur in the absence of an actual external stimulus (Auditory hallucinations, those of voice or other sounds, are the most common type of hallucinations in schizophrenia.)
Disorganized thoughts, behaviors and speech.
Catatonic behavior, in which the affected person's body may be rigid and the person may become unresponsive.

Neuroleptics or Antipsychotics are drugs that are used to treat patients suffering from schizophrenia or other psychotic (mental) disorders.

(a) Typical Neuroleptics (D₂ receptor antagonists): These are subdivided into following two classes.

· Phenothiazine derivatives (basically used as tranquilizers and anti-emetics) like Chlorpromazine (Largectil) and Acepromazine (Sedastress).

· Butyrophenone derivatives (also used as anti-emetics) like Droperidol and Haloperidol.

(b) Atypical Neuroleptics (D₂ as well as 5HT₂ receptor antagonists): Resperidone and Clozapine are common agents belonging to this category. Tardive dyskinesia [an involuntary movement disorder involving tongue (fly catching stance) and lateral movement of the jaws] is a frequent side effect associated with Resperidone.

9. Depression: It is a mood disorder that is manifested by intense sadness, hoplessness, frustration/desperation/disappointment, variation in sleep and appetite pattern and suicidal tendencies. Separation or death of a partner or owner, disease or surgical procedures can cause depression in pet animals.

Biogenic amine theory: It states that depression is caused by the deficiency of mono-amines (particularly Serotonin and Norepinephrine) at certain key sites in the brain whereas mania occurs as a result of overproduction of these substances.

Antidepressants are unable to cause CNS stimulation if used in normal/healthy individuals.

Antidepressant drugs are classified into following five groups.

I. Selective Serotonin re-uptake inhibitors (SSRI_S): As indicated by their name these agents selectively block the re-uptake of Serotonin and hence indirectly enhance its availability for repeated receptor occupancy. These drugs constitute the mainstay of treatment for patients suffering from depression. Paroxetine (Paraxyl) and Sertraline are common members of this class. In addition to depression these drugs are also administered to relieve Obsessive compulsive disorder (OCD), panic disorder, pre-menstrual dysphoric disorder (a condition marked by severe depression symptoms, irritability, fatigue, sadness or hopelessness, sleep disturbances, disinterest in daily activities and relationships and tension before menstruation) and bulimia nervosa (also called hyperphagia or binge-purge syndrome, a habitual disturbance in eating behavior mostly affecting young women of normal weight, characterized by frequent episodes of grossly excessive food intake followed by self-induced vomiting to avert weight gain). Frequently reported adverse effects linked with the inadequate use of SSRI_S include sedation (sleep disorder) and sexual dysfunction [impotence and delayed ejaculation in males while anorgasmia (absence of orgasm; inability to attain sexual climax/peak despite sufficient stimulation that can lead to sexual frustration) in females]. These drugs are contraindicated in children and teenagers due to the risk of aggravating suicidal thoughts.

II. Serotonin-Norepinephrine re-uptake inhibitors: These agents block the re-uptake of Serotonin as well as Norepinephrine and thus improve their availability at respective receptor sites. Venlafaxine and Duloxetine are important members of this category. Nausea, dizziness and sexual dysfunction are probable undesirable effects caused by these agents.

III. Atypical Antidepressants: These agents are devoid of a well-defined mode of action and sexual dysfunction (a common adverse effect of almost all Antidepressants). Bupropion (also used for smoking cessation/stoppage) and Mirtazapine are common drugs of this group.

IV. Tricyclic Antidepressants (TCA_S): In addition to the blockage of Serotonin and Norepinephrine re-uptake, these agents also antagonize Muscarinic, Histaminic and Adrenergic receptors. Imipramine and Clomipramine are important drugs included in this class. Imipramine can cause the contraction of internal sphincter of urinary bladder and therefore it is also used to treat enuresis (uncontrolled nocturnal urination also known as bed wetting) in children less than 6 years of age. Besides depression TCA_S are also utilized to alleviate narcolepsy (uncontrolled episodes of sleepiness during day time), cataplexy (loss of muscle tone as a result of narcolepsy), urinary incontinence [inability to retain urine in urinary bladder (probably caused by injury to sacral spinal nerves that are concerned with the regulation of inhibitory action over detrusor muscles of urinary bladder) leading to frequent drop wise flow of urine that is referred to as dribbling] and pruritis (due to presence of antihistaminic activity) in livestock. Antimuscarinic effects (xerostomia, blurred vision, mydriasis, tachycardia, urine retention etc.), antiadrenergic signs (such as orthostatic/postural hypotenstion), antihistaminic responses (like drowsiness and sedation) and sexual dysfunction are possible adverse effects associated with these drugs.

V. Mono-amine oxidase (MAO) inhibitors: Tranylcypromine and Selegiline (Deprenyl) are inhibitors of MAO enzyme (which is responsible to carry out the metabolism/break down of biogenic amines) and thus lead to extension of their duration of action at receptor sites. However their administration is subjected to complicated dietary restrictions such as avoidance of food items that are rich in tyramine amino acid (like cheese, chicken liver, beer and wine etc.). MAO inhibition prolongs the duration of action of tyramine (due to failure of metabolism) and excessive accumulation of tyramine leads to the release of high amount of stored catecholamines from nerve terminals which can result in hypertension, tachycardia and headache. In pituitary dependent hyper-adrenocorticism (PDH, also known as Cushing disease or old dog dementia), Selegiline maintains the levels of dopamine and corticotrophin releasing hormone (CRH) to be in balance inside hypothalamus, thereby reducing the amount of adreno-corticotrophic hormone (ACTH). Normally in the hypothalamus, CRH acts to stimulate the production of ACTH in the pituitary, and dopamine acts to inhibit the release of ACTH. But as dogs get older, there is progressive decline in dopamine synthesis that contributes to the development of PDH and associated cognitive dysfunction (known as “old dog dementia”).

10. Mania: It is a completely opposite behavior to depression and involves enthusiasm, rapid thought and speech pattern, extreme self-confidence and impaired judgment.

11. Bipolar disorder: It is a state of mental disturbance that is characterized by alternate episodes of both depression as well as mania. Bipolar disorder was called manic depression in the past, and that term is still used by some people. It is a psychiatric illness that causes major disruptions in lifestyle and health. Everyone has occasional highs and lows in their moods. But people with bipolar disorder have extreme mood swings. They can go from feeling very sad, despairing, helpless, worthless, and hopeless (depression) to feeling as if they are on top of the world, hyperactive, creative, and grandiose (mania). This disease is called bipolar disorder because the mood of a person with bipolar disorder can alternate between two completely opposite poles, euphoric happiness (happiness without any reason) and extreme sadness. Lithium [it inhibits the recycling of phosphotidyl inositol di phosphate (PIP₂) 2^nd messenger system] salts are orally given to treat mania and bipolar disorder but these are highly toxic and can cause polydipsia, polyuria and even diabetes insipidus.

12. Anxiety: It is a state of chronic depression, uneasiness, tension and fear from unknown sources. It leads to frequent tachycardia, diaphoresis (profused sweating) and trembling. Mild anxiety is not an alarming situation and requires no medical treatment but if the problem persists continuously then anxiolytic (anti-anxiety) drugs should be prescribed.

Anxiolytic drugs are classified into following groups.

(a) Benzodiazepines like Diazepam, Lorazepam and Clonazepam etc.

(b) Barbiturates like Phenobarbital, Pentobarbital and Amobarbital etc.

(c) Other drugs like Zaleplon and Zolpidem [it binds with benzodiazepine₁ (BZ₁) receptors but unlike other Benzodiazepines it lacks the property of muscle relaxation, anti-convulsion, serious withdrawal effects and appearance of tolerance (after excessive administration).

13. Obsessive compulsive disorder (OCD): Obsession means recurrent unwanted thoughts and compulsion means purposeless behavior/activities frequently performed in an attempt to get rid of obsessive thoughts (to achieve mental satisfaction). Obsessions are recurrent and persistent thoughts, impulses, or images that are intrusive and inappropriate. The thoughts cause severe anxiety or distress. The person tries to ignore or suppress the thoughts, impulses, or images, or to neutralize them with some other thought or action. The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind and are not based in reality. Compulsions are repetitive behaviors or mental acts that the person feels they must perform in response to an obsession, or according to rigid rules. Excessive skin picking (i.e., dermatillomania) or hair plucking (i.e., trichotillomania), nail biting (i.e., onychophagia) and unnecessarily collection of huge number of books (i.e., bibliomania) are all on the Obsessive-Compulsive Spectrum. Individuals with OCD are aware that their thoughts and behavior are not rational but they feel bound to comply with them to fend off feelings of panic. People might repeatedly wash their hands or clear their throats, making sure certain items are in a straight line, repeatedly check that their parked cars have been locked before leaving them, constantly organizing in a certain way, turn lights on and off, keep doors closed at all times. In addition to the anxiety and fear that typically accompanies OCD, some people may spend hours performing such tasks (i.e., compulsions) every day. In such situations it can be hard for the person to fulfill their work, family, or social roles. In some cases, these behaviors can also cause adverse physical symptoms. For example, people who obsessively wash their hands with antibacterial soap and hot water to remove what they consider to be contamination can make their skin red and raw with dermatitis. English footballer, David Beckham has been outspoken regarding his struggle with OCD. He has told media that he has to count all of his clothes, and his magazines have to lie in a straight line. It is hypothesized that the serotonin receptors of OCD sufferers may be relatively understimulated. This suggestion is consistent with the observation that many OCD patients benefit from the use of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications that allow for more serotonin to be readily available to other nerve cells. Behavioral therapy or cognitive behavioral therapy and medications should be regarded as first-line treatments for OCD. The specific technique used in behavioral therapy/cognitive behavioral therapy (BT/CBT) is called exposure and ritual prevention (also known as "exposure and response prevention") or ERP; this involves gradually learning to tolerate the anxiety associated with not performing the ritual behavior. At first, for example, someone might touch something only very mildly "contaminated" (such as a tissue that has been touched by another tissue that has been touched by the end of a toothpick that has touched a book that came from a "contaminated" location, such as a school.) That is the "exposure". The "ritual prevention" is not washing. Another example might be leaving the house and checking the lock only once (exposure) without going back and checking again (ritual prevention). The person fairly quickly habituates to the anxiety-producing situation and discovers that their anxiety level has dropped considerably; they can then progress to touching something more "contaminated" or not checking the lock at all—again, without performing the ritual behavior of washing or checking. Medications as treatment include selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline and the tricyclic antidepressants, in particular clomipramine. SSRIs prevent excess serotonin from being pumped back into the original neuron that released it. Instead, serotonin can then bind to the receptor sites of nearby neurons and send chemical messages or signals that can help to regulate the excessive anxiety and obsessive thoughts.

Chemotherapy

Chemotherapy is the branch of Pharmacology which deals with the use of chemicals/drugs (called chemotherapeutic agents like anti-bacterials, anti-fungals, anti-neoplastic and anti-virals etc.) that are selectively toxic to the foreign cells (pathogens) with minimal or no impact over the normal host cells.

Antimicrobials: These are substances having natural, semi-synthetic or synthetic origin and are effective against a wide range of micro-organisms (like bacteria, protozoa etc.). Antibacterials, antivirals and antiprotozoals are examples of antimicrobial drugs.

Antibacterials: Their origin may be natural, semi-synthetic or synthetic but their activity is only against bacteria.

Antibiotics: Their origin is always natural (from bacteria or fungi) or semi-synthetic but their activity may be against a wide range of micro-organisms (like bacteria, protozoa etc.).

Bacteriostatic: It is that antibacterial agent which inhibits the growth of susceptible bacteria e.g. Amphenicols, Macrolides and Lincosamides.

Bactericidal: It is that antibacterial agent which causes destruction/lysis of susceptible bacteria e.g. Penicillins, Cephalosporins and Quinolones.

Antimicrobial spectrum: It is the range of micro-organisms covered by a particular chemotherapeutic agent. It is of three types.

1. Narrow spectrum: It is used for those antibacterial agents that are effective only against gram positive or gram negative bacteria. For example Erythromycin is effective against gram positive while Streptomycin covers only gram negative bacteria.

2. Broad spectrum: Broad spectrum indicates the activity of concerned antibacterial against a wide range of bacteria, covering gram positive as well as gram negative, e.g. Oxytetracycline and Chloramphenicol.

3. Extended spectrum: It is subdivided into two types. Extended gram positive spectrum indicates that respective agent is originally active against gram positive bacteria but it also covers sufficient number of gram negative bacteria (but not all) e.g. Amoxycillin. Extended gram negative spectrum shows that concerned drug is basically effective against gram negative but it also covers sufficient number of gram positive bacteria e.g. Nalidixic acid.

Sulphonamides

Sulphonamides are antimicrobial drugs of synthetic origin which are extensively used to treat human and veterinary infections. In 1935, a scientist named, Domagk found that Prontosil dye inhibited the growth of streptococcal bacteria in mice. Later on it was found that Prontosil contained Sulphanilamide and Domagk was awarded with Noble prize for his discovery. The basic structure of Sulphonamides resembles to that of Para amino benzoic acid (PABA) that is used by certain micro-organisms to synthesize Folic acid (an integral component of vitamin B complex). Utilization of Sulphonamide (instead of PABA) depletes the micro-organisms of Folic acid (hence Sulphonamides are said to inhibit the metabolic pathway of micro-organisms especially bacteria). Metabolism of Sulphonamides occurs through acetylation. But this acetylation prolongs their half life as their solubility is diminished (and they get precipitated in tissues). Therefore Sulpha drugs are comparatively safe in slow acetylators and carry a risk of toxicity in fast acetylator species.

Mechanism of action of Sulphonamides

PABA + Pteridine

Dihydropteroate synthase

(inhibited by Sulpha drugs)

Dihydropteroic acid

Dihydro folate reductase Glutamic acid

(inhibited by Diaminopyrimidines)

Dihydro folic acid

Tetra hydro folate reductase

Tetrahydro folic acid

Thymine Purines Methionine Glycine

DNA, RNA DNA Proteins

Classification of Sulphonamides

1. Locally acting Sulphonamides: These are further classified into two categories.

(a) Topically acting Sulphonamides (e.g. Sulphacetamide is used for eye infections): These are topically administered to treat dermal infections caused by susceptible micro-organisms.

(b) Gut active Sulphonamides (e.g. Sulphaguinidine): They are poorly absorbed from GIT and thus they are effective for the treatment of enteritis and diarrhea associated with bacterial or protozoal infection (like coccidiosis, colibacilosis etc.).

2. Systemically acting Sulphonamides: They are meant for systemic action and are classified on the basis of their duration of action.

Category	Duration of action	Example
Short acting Sulphonamides	< 12 hours	Sulphanilamide Sulphadiazine
Intermediate acting Sulphonamides	12-24 hours	Sulphadimidine Sulphamethoxazole
Long acting Sulphonamides	24-48 hours	Sulphaethoxypyridazine Sulphamethoxypyridazine
Ultra long acting Sulphonamides	> 48 hours	Sulphadoxine

3. Potentiated Sulpha drugs: Di-aminopyrimidines and Sulphonamides block consecutive steps that are crucial for the metabolism of bacteria and if used in combination they show potentiated action.

Brand names of commonly used Potentiated Sulphonamides

Combination	Trade name (s)
Trimethoprim + Sulphamethoxazole = (Co-trimoxazole)	Septran
Trimethoprim + Sulphadiazine = (Co-trimazine)	Tribrissin, Triben
Pyrimethamine + Sulphadoxine	Fansidar (Anti-malarial)

Antimicrobial spectrum of Sulpha drugs: All Sulphonamides are bacteriostatic with broad spectrum antimicrobial activity (only against rapidly multiplying bacteria, those in lag phase are comparatively resistant to Sulphonamides).

Micro-organisms susceptible to Sulphonamides
Gram positive bacteria	Streptococcus, Hemophilus, Bacillus, Actinobacillus
Gram negative bacteria	Enterobacteracae family
Protozoa	Toxoplasma, Eimeria, Plasmodium
Micro-organisms resistant to Sulphonamides
Leptospira, Mycoplasma, Acid fast bacteria (e.g. Mycobacterium), Pseudomonas, Rickettsiae and Spirocheates

Antagonists of Sulpha drugs: Availability of PABA, Folic acid, thymine, purine or glycine will inhibit the utilization of Sulphonamides by bacteria therefore their concomitant administration should be avoided. Pus and tissue debris also contains these substances (especially PABA) thus Sulpha drugs may prove ineffective if used topically for pyogenic infections. Co-administration of Procaine (precursor of PABA that is used as a local anesthetic) with Sulpha drugs is also contraindicated.

Adverse effects: The toxicity profile of Sulphonamides is manifested in terms of acute or chronic toxicity.

Acute toxicity:

Crystalluria: Acidic urine causes the precipitation of Sulphonamides in renal tubules of glomerulus (resulting in obstruction of renal tubules) leading to crystalluria that is characterized by hematuria. Carnivores (having acidic P_H of urine) are more vulnerable than omnivores and herbivores. Administration of urinary alkalizer (like sodium bi carbonate), improving the hydration status of patient or using a combination of two or more Sulpha drugs (in this case each Sulphonamide will provide its individual solubility and the overall solubility of the mixture will be enhanced, chances of precipitation will be abolished) can help to avoid this problem.

Idiosyncratic hemolytic anemia: Individuals with congenital deficiency of glucose-6 phosphate dehydrogenase are unable to produce sufficient level of glutathion (anti-oxidant in RBC_S) therefore they are subjected to hemolytic anemia caused by reactive oxygen species (generated by oxidizing drugs like Sulphonamides, Paracetamol and Primaquin etc.). This may occur within 2-7 days of therapy.

Hypersensitivity reactions: Allergic skin reactions (such as expoliative dermatitis or cutaneous eruption) are frequent complications of Sulpha therapy. Sulphadiazine containing preparations may promote a reversible immune-mediated polyarthritis in Doberman breed of dogs.

Chronic toxicity:

Hypoprothrombinemia: Prolonged administration of certain Sulphonamides (like Sulphaquinoxaline) may lead to vitamin K deficiency due to inhibition of vitamin K epoxide reductase enzyme (this commonly occurs in poultry). This results in hypoprothrombinemia and deficiency of vitamin K dependent clotting factors leading to prolongation of bleeding and clotting times.
Keratoconjuctivitis sicca (KCS): Some Sulpha drugs possess nitrogen-containing pyridine ring (instead of benzene ring) that is responsible for lacrymotoxic effect (which causes hypolacrimation/dryness of eyes) on lachrymal acinar cells of eyes.

AMINOGLYCOSIDES

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AMINOGLYCOSIDES

Aminoglycosides (Aminocylitols) are a group of natural and semi-synthetic antibiotics having amino sugars linked to an aminocyclitol ring by glycosidic bond.

History:

Streptomycin was the first member of amino glycoside antibiotics discovered in 1944 by Walks man and co-workers from a strain of Streptomyces griseus.

Chemistry and source.

The aminoglycosides consist of two or more amino sugars joined in glycosidec linkages to a hexose (aminogyclitol) nucleus.The presence of amino group on the glycosides and the hydroxyl group on the sugars provide high water solubility ( or poor lipid solubility) to the drugs. Aminogly- cosides prepared from Streptomyces carry the suffix-mycin, where those derived from Micromonospora have name ending with –micin.

Properties

a) They are water soluble and polar compounds and generally ionize in solution.

b) They are not absorbed orally,

c) They are bactericidal in action and are more active against gram – negative.

d) They are more active in alkaline pH.

e) They show synergistic antibacterial effect with beta – lactam antibiotics,

Classification

On the basis of antibacterial spectrum, amino glycosides may be classified into following groups:

I. Narrow-spectrum aminnoglycosides

e.g., streptomycin and dihydrostreptomycin.

II. Broad-spectrum amino glycosides.

E.g., neomycin, framycetin,kanamycin and paromomycin.

Mechanism of action

The amino glycosides are bactericidal drugs that act by inhibiting protein synthesis in susceptible bacteria, mainly gram – negative organisms.

2. Binding of amino glycosides to bacterial ribosomes.

Amino glycosides can bind with both 30 S and 50 S ribosomal subunits, although their binding with 30 S subunit is stronger.

b) Distortion of m-RNA Condon resulting in misreading of the codon. This causes incorporation of one or more incorrect amino acid (s) into peptide chain and synthesis of abnormal proteins.

c) Promotion of premature termination of translation with detachment of the ribosomal complex. Binding of aminoglycosides to 30 S- 50 S juncture is probably responsible for their bactericidal effect,

iii) Aminoglycosides show long and concentration dependent post – antibiotic effect. There fore , despite their short half – lives a single injection of the total daily dose of aminoglycosides may be effective.

Antibacterial Spectrum

Antibacterial spectrum of aminoglycosides varies with the type of antibiotic streptomycin and dihydrostreptomycin have relatively narrow spectra mainly gram-negative species. The broad-spectrum aminoglycosides(e.g. neomycin and kanamycin) are active against many gram-negative and gram-positive organisms,

But not pseudomonas. The extended-spectrum aminoglycosides posses antibacterial spectra similar to broad-spectrum antibiotics and are also active against pseudomonas aeroginosa and a verity of aerobic bacteria. Anaerobic bacteria are only moderately sensitive to aminoglycosides .

Side effects /Adverse effects

All aminoglycosides have potential to produce toxic effects, but the relative propensity differs . Nephrotoxicity, ototoxicity, and neuromuscular blockade are important adverse effects observed with aminoglycosides.

1. Nephrotoxicity: Nephrotoxicity with aminoglycosides occurs as a result of excessive accumulation of antibiotics by the proximal tubular cells in kidneys. As aminoglycosides are positively charged agents , they get attracted to negatively charged phospholipids of the renal membrane followed by their transport onside the tubular cells via pinocytosis. This transport is directly related to the membrane content of phosphatidly inositol, which is high in renal cortex and cochlear tissues.

Manifestations of nephrotoxicity include presence of enzymes of brush border urine, proteinurea, presecnces of casts, and low GFR.Aminoglycosides , neomycin is most nephrotoxic.

Nephrotoxicity of aminoglycosides can be prevented or minimized by following some simple steps like avoiding use of potentially nephorotoxic aminoglycosides , ensuring adequate hydration status of patient, and avoiding concurrent use of other nephrotoxic drugs.

2. Ototoxivity: Aminoglycosides get accumulated into perilymph and endolymph of the inner ear in dose and time dependent manner.Ototoxicity is greater when the plasma concentration of drug is persistently high. Ototoxicity once occur is usually irreversible and result from progressive destruction of vestibular or cochlear sensory cells. Vestibular injury leads to nystagmus, in coordination, vertigo, head tilt,ataxia,and loss of righting reflex in animal. Hearing impairment or deafness may be produced by permanent damage and loss of hair cells in the organ of Corti .Aminoglycosides should not be instilled into ear unless the tympanic membrane is intact because direct administration of aminoglycosides into the inner ear could cause potential damage.

3. Neuromuscular blockade: All amino-glycosides have potential to produce neuromuscular blockade with curare-like action. The effect is produced mainly by interference with acetylcholine release from motor nerve endings, probably by antagonism of Ca ++ that is normally required for exocytosis.However, concomitant administration of neuromuscular blocking agents and general anesthetics with aminoglycosides may substantially increase the risk of neuromuscular blockade .

Contraindications and precautions

Pre-existing renal disease. Aminoglycosides may impair neuromuscular transmission and so are not given to animals with myasthenia gravis. They cause adverse effects on fetus, so their use during pregnancy is not recommended unless considered mandatory.

Drug interactions

Aminoglycosides show interaction with drugs that cause ototxicity , nephrotoxicity and neurotoxicity , Concurrent use of aminoglycosides with loop diuretics ( e.g.,, frusemide and osmotic diuretics (e.g., mannitol ) may aggravate the nephrototoxic or ototoxic effects of aminoglycosides. Risk of neuromuscular blockade and respiratory paralysis increases when aminoglysosides are used with inhalant anesthetics or neuromuscular blocking drugs .

Clinical uses

Septicamemia, osteoarthritis, and mastits.endometritis.

Side effect/Adverse effects

Adverse effects of streptomycin are similar to other aminoglycosides antibiotics, but it is less nephrotoxic than many aminoglycosides .Hypersensitivity reaction are rare.

TETRACYCLINES AND AMPHENICOLS

TETRACYCLINES

Tetracyclines are a group of broad – spectrum antibiotics having a nucleus of four cyclic rings.

History

The first member of the group was chlortetracycline derived from soil actinomycete Streptomyces aureofaciens introduced in 1948.

Chemistry and properties

As a group, tetracyclines are acidic and hygroscopoic compounds. They chatacteristically fluorescence when exposed to ultraviolet light. Physical and chemical properties of tetracyclines permit them to be formulated as infection, boluses capsules, powders, feed additives, and ointments for veterinary use.

Classification

Tetracyclines are classified according to their duration of action.

I. Short-acting tetracyclines(t1/2=<8houres)

Oxytetracycline, tetracycline and chlortetracycline.

II Intermediate acting tetracycline’s(t1/2=8-16houres)

Demeclocycline and methacycline.

III Long-acting tetracyclines (t1/2=<16houres)

Doxycycline and minocycline.

Mechanism of action

Tetracyclines inhibit bacterial protein synthesis and are primarily bacteriostatic.

Antimicrobial spectrum

The tetracyclines are broad – spectrum antibiotics. They ate active against a wide range of aerobic and anaerobic gram- positive and gram-negative bacteria. They are also active against Mycoplasma Rickettsia, Chlamydia, and some protozoa like anplasma, haemobartonella, and amoebae, Presently strains of pseudomonas aeruginosa, Proteus, Serratia, Klebsilla, Salmonella , staphylococcus, and

corynaebacterium species appear to have become resistant to tetracyclines. Tetracyclines are infective against fungi and viruses.

Effect on bones /teeth: Tetracyclines are deposited in growing teeth and bones due to their chelating properties with calcium .They from tetracycline – calcium orthophosphate complex, which inhibits calcification e.g. hypoplastic dental enamel and results in permanent discoloration (first yellowish) then brownish of the teeth. The stained and hypoplastic teeth are more prone to various degeneration. Delay fracture healing. Pregnancy in neonates.Tetracyclin may cause temporary suppression.

Hepatotoxicity: Tetracyclines in excessive doses can produce fatty in flirtation of liver.Hepatotoxicity with jaundice due to large doses of tetracyclines has been reported in pregnant woman and in some animals

Contraindication and precautions

Tetracyclines are contraindicated in hepatic insufficiency,

Drug interaction

Antacids decrease the absorption of tetracycline’s from GI tract.

Clinical uses: Used for treating mycoplasma , chlamydiae and rickettsiae, anaplasma, hemobratonella, ehrlichia, and borrelia, In birds, they are used in the treatment of psittacosis. For treating bronchopneumonia, metritis, mastitis, pyodermatitis.

Administration

Tetracyclines may be administered by oral, parenteral , topical, or intramammary route, The choice of route of administration depends on the species involved , type of action desired and compound to be used,

veterinarian,Palace

2010-11-07T10:58:00.001+05:00

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