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PHARMACOLOGY OF AUTONOMIC NERVOUS SYSTEM

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
		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 (NN) receptors	Nicotinic (NN) receptors	Nicotinic (NN) 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 (NM) 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 Gq-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 Gi-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	NM	Ligand (agonist) binding alters the three dimensional structure of receptor that opens the associated Na+ and K+ channels. Depolarization results from intracellular cation influx.
	NN

Classification and signaling mechanism of adrenergic receptors

Receptor type	Receptor subtype	Signaling mechanism
α (G-Protein coupled) receptors	α1	Ligand (agonist) binding stimulates Gq-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.
	α2	Ligand (agonist) binding stimulates Gi-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 Gs-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
			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
			β2	Relaxation of vascular smooth muscles causes vasodilaion
Uterus	Absent	Nil	α1	Myometrial contraction
			β2	Myometrial relaxation
Pancreas (Iselets of langerhans)	Absent	Nil	α2	Decreases insulin secretion and glycogenesis
			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)
			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	NM	Contraction of skeletal muscles	Absent	Nil
Autonomic ganglia	NN	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 M₃ receptors 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 α₁ receptors in blood vessels. But this rise in B. P is followed by reflex bradycardia (β₁ agonistic response) resulting from stimulation of vagus nerve. But Methoxamine lacks this adverse effect (undesirable cardiac aarythmia) by blocking β₁ receptors 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 α₁ receptors. Parentral administration of these agents can cause tissue necrosis and sloughing due to drug extravasation. This can be relieved through the use of α₁ antagonist. 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 α₂ receptors 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 and β₃ receptors. Stimulation of α₁ receptors causes vasoconstriction of splanchnic blood vessels whereas stimulation of β₂ receptors 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 β₁ receptors (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 (α₂ stimulation). 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 upon β₃ 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 β₂ receptors, 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 α receptors 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 α₁ receptor 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 α₁ receptor 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 β₂ receptors 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 β₂ receptors) and diabetic patients (as they cause hypoinsulinemia by blocking β₂ receptors in iselests of langerhans). Besides blocking β receptors (inhibiting their activation by endogenous catecholamines), Acebutalol and Pindolol also act as partial agonists of β receptors. 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 β₂ receptors 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.