Pharmacology of the autonomic nervous system

The nervous system is divided in to two; -CNS (brain and spinal cord) -Peripheral nervous system The peripheral NS is functionally divided in to two: - The autonomic NS/ANS/ and the somatic/voluntary/ system. The somatic division controls the activities of skeletal muscles. While the ANS controls the activities of visceral organs, blood vessels and cardiac muscles and glands. The ANS is again further subdivided in to three as-sympathetic NS/SNS/, parasympathetic/PNS/ and the enteric nervous system (where it consists of the intrinsic nerve plexuses of the GIT called as little brain). Both divisions of ANS /PNS and SNS/ are activated and integrated by centers in the brain, spinal cord or brain stem, hypothalamus while the enteric nervous system is of independent of these centers. PNS and SNS are anatomic divisions in reference to exit site of the pre ganglionic neurons in CNS. PNS originates from cranial nerves and sacral regions of the spinal cord hence called as the craniosacral out flow. While the SNS originates from the thoracic and lumbar regions of the spinal cord and hence called as the thoracolumbar outflow. N.B. The difference b/n the autonomic and somatic nervous system is incases of the ANS it consists of the two neurons that are arranged in series- i.e. the preganglionic and postganglionic neurons. But in somatic only one neuron arrangement. PNS: - the postganglionic neurons are found in target organs/ effector cells/ while the ganglia is found in the head and neck region. It produces more localized response and discrete function in the conservation and storage of body resources i.e. Rest and digest. The preganglionic are long and release acetylcholine while the post ganglionic are short and as well release acetylcholine. SNS: - ganglia is found outside the CNS and contain the nerve endings of the preganglionic fibers and cell bodies of the postganglionic fibers. It is organized to produce response of many organ system, i.e. preparation for the fight /flight. Preganglionic neurons are short and release acetylcholine while postganglionic neurons are long and release usually noradrenalin as neurotransmitter. 1

N.B. Internal organs have dual innervations by both PNS and SNS but have opposite body effects.
S p in a l Cord a PNS e1 SNS e1 S o m a tic e a s k e le ta l m u s c l e a e2 N e u r o m u s c u la r j u n c t io n e2 E ff e c to r C e ll ( h e a r t, s m o o t h m u s c le , g la n d s , et c .)

Figure 1. Somatic and autonomic (PNS and SNS) components of the peripheral nervous system showing afferent nerves (a) and efferent nerves (e) to and from the spinal cord. Both preganglionic (e1) and postganglionic (e2) efferent neurons are shown for the PNS and the SNS.

Drugs acting on the ANS: - are of two major groups 1.Drugs acting on the PNS:- are of two groups of drugs a.Parasympathomimetics/ Cholinomimetics b.Parasympatholytics/ Anticholinergics CHOLINOMIMETICS/PARASYMPATHOLYTICS/ -Acetylcholine/Ach/ is a neurotransmitter released up on activation of PNS to act on effector organs to bring response. Ach is synthesized inside the cytoplasm of nerve fiber from choline and acetyl CoA enzyme catalyzed by the enzyme the choline acetyl transferase enzyme. Once it is synthesized it will be transported in to the neuronal vesicle to be stored. Up on the impulse .Ach will be released in to the synaptic cleft and after release; it binds and activate cholinergic receptors in the postsynaptic tissue/0rgan. 2 2.Drugs acting on the SNS :- are of two groups a. Sympathomimetics/ Adrenergic drugs b. sympatholytics/ antiadrenergics drugs

Finally it is metabolized in to choline and acetate by enzyme acetylcholine estrae/AchE/ and then action of Ach will be terminated.

(diffusion)

8. (a) EPSP (b) IPSP 7. Ions Flow Na+, K+, Cl6. Permeability change

synaptic vesicle 1. Action Potential 2. Synthesis of neurotransmitter 3. Storage

9a

9b

4. Release by action potential 9a 9a Enzyme 9c

5. Combine @ receptor

9. Inactivation of neurotransmitter by: (a) reuptake [active] (b) diffusion (c) enzymatic change

PRESYNAPTIC NEURON cholinergic neu ron

Acetyl-CoA + Choline

SYNAPTIC CLEFT adrenergic neuron

Dopa

POSTSYNAPTIC NEURON or EFFECTOR CELL

Tyrosine

Dopam ine ACh

M AO
ACh

NE Choline

Deam inated derivaties NE

reuptake

ACh X X X AChE X

NE X X COM T N orm etanephrine

P ostsynaptic tissue

Postsynaptic t issue

Figure 2. Schematic diagram of a synapse

Figure 3. Neurotransmitter mechanisms in cholinergic neurons (which have acetylcholine

[ACh] as the neurotransmitter) and in adrenergic neurons (which have norepinephrine [NE] as the neurotransmitter

Cholinergic receptors:Mainly there are two types of receptor for Ach: - muscarinic/M/ receptor and nicotinic/nAch/ receptor. The muscarinic receptors are widely distributed and are subdivided as M1/ found in
stomach cells/, M2/ in cardiac cells/, M3/ glandular cells/, etc.While nicotinic receptors are

located in autonomic ganglia, adrenal medulla and neuromuscular junction. Effect of Ach receptors activation: - eye: - meiosis. I.e. constriction of the sphincter of muscle of iris. Heart: - decrease heart rate: Lung: - bronchoconstriction GIT; - incr. GI motility: Urinary bladder: - contraction, etc. DRUGS: - drugs can influence cholinergic transmission either by influencing postsynaptic Ach receptors as agonist or antagonists. Or by affecting the release or destruction of endogenous Ach. E.g. 1. On muscarinic receptors- agonists and antagonists 2. Ganglia- ganglion blocking drugs 3. Drugs blocking NMJ: non-depolarizing and depolarizing drugs. 4. Drugs that inhibit the enzyme AchE function. Cholinergic Agonists/cholinomimetics/ Direct-acting (receptor agonists) Indirect-acting

Choline esters [acetylcholine] Methacholine Carbachol Bethanechol -

Alkaloids pilocarpine

Reversible physostigmine neostigmine

Irreversible [organophosphates] Malathion, Nerve gas

Clinical indication of choline esters:t/t of Glaucoma t/t of postoperative urinary retention Paralytic ileus

PILOCARPINE: - is a partial agonist to muscarinic receptors and directly stimulates M receptors to bring PNS stimulation. USE: - used only as eye drop/ 0.5-4%/ in the t/t of glaucoma as miotic agent in the t/t of open angle glaucoma. What is Glaucoma: Glaucoma is a group of disease characterized by a progressive form of optic nerve damage associated with an increased intraocular pressure/> 21 mmHg, IOP/, sometimes referred as ocular hypertension. Treatment targets two options: - 1. Reducing the secretion of aqueous humour which can be achieved by using topical B-adrenergic blocker drugs, e.g. Timolol eye drop, Betaxolol eye drop, ETC. 2. By promoting the drainage of the aqueous humour achieved by using cholinergic drugs like pilocarpine eye drop and neostigmine. There are two types of glaucoma: - Open angle glaucoma/ wide angle, chronic simple glaucoma/:- can effectively be controlled by using drugs like Timolol, Betaxolol, pilocarpine, etc. While in Angle closure glaucoma/ narrow angle, acute congestive glaucoma/:- involves narrow iridocorneal angle. This is an emergency glaucoma and requires vigorous t/t and failure to reduce IOP brings loss of sight. The t/t can be helped by Topical beta blockers, miotics acetazolamide and these drugs only reduce the symptom, no more help in altering the path physiologic condition of the disease. Hence the definitive t/t is surgery/ laser therapy. Anticholiesterase enzyme inhibitors/AchEIs/:Drugs: - 1. Reversible AchEIs- Neostigmine. Physostigmine 2. Irreversible AchEIs- organophosphates, e.g. Malathion, insecticides, nerve gas Are agents that inhibit the enzyme AchE function and protect acetyl choline/Ach/ from being metabolized. PROTOTYPE DRUG: - NEOSTIGMINE:Kinetics: - Poorly absorbed, poorly distributed and can not cross the blood brain barrier

Mechanism of action: - It inactivates the enzyme AchE reversibly and builds up prolonged a contact of Ach with its receptor. Use: - 1. Used in the t/t and diagnosis of myasthenia gravis- which is an autoimmune disorder which brings structural damage to the neuromuscular junction/NMJ/.the symptoms are diplopia, weakness, difficulty in swallowing, speaking and extreme muscle weakness, or skeletal muscle paralysis. Neostigmine improves muscle contraction by allowing Ach. It is used by S.C. route. Other drugs that can treat this disorder include corticosteroids and immunosuppressant. 2. t/t of postoperative paralytic ileus/urinary retention- Neostigmine is used S.C (0.5-1 mg). 3. Used to reverse the effect of muscle relaxants, E.g. tubocurarine/ postoperative decurarization after surgery. 4. In the t/t of Alzheimers disease- cerebroselctive AchEIs like Tacrine, rivastigmine, Donepezil, etc. Anti cholinesterase enzyme inhibitors poisoning:Commonly referred as organophosphate poisoning and it is most common with the irreversible inhibitors of AchE. Manifestation include: - SLUDE BAM- Salivation, Lacrimatrion, Urination, Emesis, Bradycardia/bronchoconstriction, Abdominal cramp, and Miosis. Signs and Symptoms of organophosphate poisoning a) Muscarinic Manifestations (1) .Bronchoconstriction and increased bronchial secretions (2) .Sweating, salivation, lacrimation (3) .Bradycardia, hypotension (4) .Miosis, blurring of vision (5) .Urinary incontinence b) Nicotinic Manifestations (1) Fasciculation, weakness or paralysis of skeletal muscle Depolarizing blockade of NMJ Paralysis of muscles of respiration (2) Hypertension (3) Tachycardia c) CNS manifestations: (presence of these signs varies with different agents). (1) .Restlessness, insomnia, confusion (2) .Tremors, ataxia 6

(3) .Convulsions (4) .Respiratory depression and cardiovascular collapse d) Delayed (2-3 weeks) neuropathy with some organophosphates Irreversible Inhibitors (Organophosphates) - react to form a stable, phosphorylated enzyme, which is essentially not hydrolyzed. The pharmacological effects of cholinesterase inhibition persist until new enzyme is synthesized. Organ phosphorous cholinesterase inhibitors are highly toxic compounds that were developed as potential chemical warfare agents (nerve gas). Certain agents in this class have therapeutic applications, but their principal interest is toxicological because of their widespread use as insecticides. The overall effect of organ phosphorous compounds is b/c of cholinergic crisis- i.e. excess Ach produced which brings excess stimulation of PNS. The most serious toxicity is respiratory paralysis. Treatment of organophosphate poisoning: - we use specific antidotes:1. Atropine-is Anticholinergics drug/antimuscarinic drug/ and must be given, 2 mg IV, repeated Q 10 minutes till pupil dilates. 2. Plus a cholinesterase reactivator- E.g. 2-PAM= PRALIDOXIME- it restores the phosphorylated AchE enzyme by organophosphates and reverses the enzyme function. from strong covalent bond. 2-PAM is injected slowly in a dose of 1-2 grams. ANTICHOLINERGIS/Parasympatholytics/ Muscarinic blocking drugs are compounds that selectively antagonize the responses to acetylcholine (ACh) and other parasympathomimetics that are mediated by activation of muscarinic receptors. These drugs are also referred as Muscarinic receptor antagonists/ Atropinics/. Mechanism of action: - are drugs that block competitively actions of Ach on autonomic effectors on M receptors. Drugs: - Atropine - hysocine/antispasmodics/ - Benz atropine and benzhexol/ antiparkinsonian drugs/ - pirenzepine/ antisecretory drug/ tropicamide/mydriatics/ - Ipratropium bromide/bronchodilator/. Prototype drug: - Atropine- is a competitive M receptor blocker

Pharmacological Actions of Atropine and Related Drugs

Tissue or System Skin Visual

Effects Inhibition of sweating (hyperpyrexia may result); flushing Cyclopedia (relaxation of ciliary muscle); Mydriasis (relaxation of sphincter Pupillae muscle); increase in aqueous Outflow resistance (increases intraocular Pressure in many cases of glaucoma) Decreased salivation; reduced tone and Motility in the gastrointestinal tract; Decrease in vagus-stimulated gastric, Pancreatic, intestinal, and biliary secretions Urinary retention (relaxation of the detrusor muscle); relaxation of ureter Bronchial dilation and decreased secretions Bradycardia at low doses (may be a CNS effect) and tachycardia at higher doses (peripheral effect); increased cardiac output if patient is recumbent Decreased concentration and memory; drowsiness; sedation; excitation; ataxia; asynergia; decrease in alpha EEG and increase in low-voltage slow waves (as in drowsy state); hallucinations; coma

Digestive

Urinary Respiratory Cardiovascular

Central nervous system

Clinical uses of Anticholinergics:1. As pre- anesthetic medication- e.g. Atropine is commonly used- decr. Tracheobronchial secretions during anesthesiology 2. Anti peptic ulcer drug: - e.g. Librax- w/c contains clinidium and chlordiazepoxide, pirenzepine

3. As antispasmodics- to relieve intestinal and renal colics. Abdominal cramps, e.g. hyoscine To relieve urinary frequency and urgency, enuresis in childrens, e.g. oxybutyninw/c has a vasoselective action in detrusor muscle in urinary bladder. 4. t/t of bronchial asthma, asthmatic bronchitis, and chronic obstructive pulmonary disease. E.g. Ipratropium bromide 5. As mydriatic and cyclopedia- they facilitate the ophthalmologic examination of the retina in fundoscopy diagnosis in refraction studies, Esp. in childrens below 5 Years e.g. Homatropine, atropine eye drop. Antimuscarinic drugs are widely used in Ophthalmology to produce mydriasis and cycloplegia. - can also be used in the t/t of specific ocular diseases like iritis, keratitis and corneal ulcer and t/t of pts following iridectomy.Atropine eye drop reduces the painful spasm. 6. Used as cardiac vagolytic- to avoid PNS supply to hear and used in the t/t of heart block(bradycardia and partial heart block). Atropine, IV used for such indications. 7. For t/t of parkinsonian disorder, benzhexol and Benz atropine preferred c/c of central effects. 8. In the t/t of motion sickness:- e.g. hyoscine 9. For t/t of Malathion/ organophosphate poisoning/. Atropine preferred and is the 1st line drug. Adverse effects of Anticholinergics- termed atropine like A/E. EVERY THING IS DRY a) PERIPHERAL (1) dry mouth (6) blurred vision and photophobia (2) Difficulty in (7) tachycardia Swallowing (8) increased B.P. (3) Marked thirst (9) micturition difficulty (4) Hot, dry, (10) respiratory/cardiovascular Flushed skin collapse (5) Dilated pupils b) CNS (1) Nervousness (7) muscular in coordination (2) Excitation (8) maniacal tendencies (3) Confusion (9) medullar stimulation (4) Hallucination progressing to depression (5) Weakness (10) coma (6) Giddiness 9

C/I: - Glaucoma, bladder outlet obstruction Neuromuscular blockers Are drugs that prevent acetylcholine from binding and activating nicotinic/nAch/ receptors on skeletal muscles and cause skeletal muscle paralysis/ relaxation/. Are given to produce relaxation of skeletal muscle during surgery, endotracheal intubations, mechanical ventilation and other procedures. Are divided in to two:- as 1. non-depolarizing neuromuscular blockers:- a. long acting . e.g. Tubocurarine; b. intermediate acting drugs- e.g. Atracurium, pancuronium, etc.; c. short acting drugs e.g. mivacurinum = they all are given IV and paralysis develops rapidly following IV injection. They competitively bind to nAch receptors on the motor end plate prevent binding of Ach prevent contraction muscle relaxation 2. Depolarizing drugs: - e.g. succinylcholine- has d/t mechanism of action and has short duration of action and is the most commonly used in endoscopy.

DRUGS ACTING ON THE SYMPATHETIC NERVOUS SYSTEM:The two principal neurotransmitter in SNS are: Noradrenaline/NA/ and adrenaline After NA is released from adrenergic neurons, it binds to and activate the sympathetic receptors/adrenoceptors/.( Please refer for the diagrammatic representation in page 3). There are two groups of adrenoceptors for SNS: - these are and receptors. Again each has other sub classes- E.g. 1, 2 and 1, 2, 3, etc. Body effects of activation of these receptors:1. Smooth muscles: - a. bronchial smooth. muscle- bronchodilation/ 2 receptors/; b. vascular smooth muscles: - vasoconstriction/ 1 receptors/; c. Git smooth muscles:relaxation of the muscle wall./ alpha 1receptor/. 2. Eye:- mydriasis and cyclopedias 3. Heart: - increased Heart rate Adrenergic drugs/Sympathomimetics/adrenergic receptor agonists/ Beta1 agonists:- terbutaline, dobutamine, isopretenolol, etc Beta2agonits:- salbutamol,salmetrol, formoterol, etc.

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Alpha1 agonits:- phenylepherine, xylometazoline, naphazoline Alpha2 agonists:- Methyldopa/aldomet/ Adrenaline has equal affinity for both receptors Adrenergic drugs can also be classified based on therapeutic use:Pressor agents - dopamine, adrenaline, ephedrine, dopamine

Use:-1. t/t of hypotensive states- shock, hypotensive drugs, spinal anesthesia 2. Used in combination with local anesthetics, e.g. adrenaline + lidocaine-prolong the duration of action of local anesthetics and decrease the systemic adverse effects. Used for control of local bleeding e.g. epistasis- adrenaline pack, phenylepherine/ephedrine 1% solution soaked in cotton can control bleeding from arteriolar and capillary blood vessels. Can also be used in t/t of blood shot eyes- phenylepherine eye drop preferred. Cardiac stimulants: - adrenaline, dobutamine, isoprenaline Use: - 1. Used in the t/t of cardiac arrest- adrenaline IV is the drug of choice. 2. Used in the t/t of cardiogenic shock- dobutamine/ dopamine used. 3. Bronchodilators Beta 2 agonists: - short acting:-salbutamol/ albuterol/. Terbutaline, and long acting Beta2 agonist:-salmeterol, formoterol, etc. Use: - 1. In the t/t of asthma- they are of best used in acute exacerbation of asthma/better short acting/ while long actings are preferred in t/t of nocturnal asthma. Salbutamol is available as spray, tablet and pediatric formulation. Adrenaline can also be used S.C. in the t/t of acute bronchial asthma. NASAL DECONGESTANTAS:-xylometazoline/naphazoline/Otrivin/, phenylepherine:Use:-1. Are used in the t/t of nasal congestion, in cases of rhinitis- where it involves reduction of the swelling of nasal mucosa due on allergic reactions. And they are used as nasal drops. Uterine stimulants (Myometerial relaxants):- Ritordine, salbutamol, terbutaline Use: - 1. used in the prevention of preterm delivery Other uses of adrenergic drugs:-

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1. Used in the t/t of hypertension- esp. centrally acting alpha2 agonists- e.g. methyldopa and clonidine/Aldomet/.They stimulate the alpha2 receptors in medulla and block the out flow of SNS stimuli to peripheral organs.

2. Adrenaline, IV is used in the first line t/t of anaphylaxis. ADRENERGIC RECEPTOR ANTAGONISTS

are competitive antagonists at alpha and beta receptors/adrenoceptors/ are of two groups:A. The receptor antagonists:- are of again two groups 1. selective alpha receptor antagonists:- w/c includes- prazosin, bunazosin, terazosin, etc 2. Non- selective blocker includes phenoxybenzamine. Phentolamine, etc. Phenoxybenzamine is an irreversible antagonist to alpha receptors and used occasionally in pheochromocytoma/ tumor of the adrenal gland that release excess NA/ actually used in combination with Beta receptor blockers in preparation of the pt for surgery.

Selective alpha receptor blocker are mainly used in the t/t of hypertension b/c they significantly reduce the peripheral vascular resistance/PVR/ and hence lower BP. They are often associated with orthostatic hypotension and reflex tachycardia due on rapid reduction of PVR. Because of this when they are used in the t/t of hypertension better to take at bed time.

Are also used in t/t of urinary retention in pts with Benign prostate hypertrophy/BPH/ to control urinary retention b/c they cause a relaxation of the smooth muscle of the bladder neck and prostate.

B. The RECEPTOR ANTAGONISTS/BETA BLOCKERS/:Are of three divisions/ classes:1. non-selective beta blockers- block non selectively beta receptor and includes Propranolol, Timolol, Nadolol, Sotalol 2. cardio selective beta blockers- are drugs that block selectively Beta1 receptors in the heart and includes:- Atenolol , Esmolol, Metoprolol 3. with mixed alpha and beta blockers: - Labetalol, Carvediol, etc. CLINICAL USES OF BETA BLOCKERS:12

A. CVS: - 1. Used in the t/t of hypertension selective as well as non selective beta blocker are both effective in the t/t of hypertension. They treat hypertension b/c they reduce heart rate, decrease the rennin production by kidney, and reduce the SNS out flow to the heart. They are the second most commonly used antihypertensive drugs against hypertension. 2. In the t/t of cardiac arrhythmia 3. in the t/t of angina pectoris

B. In the t/t of glaucoma: - Timolol eye drop (0.25-0.5%) is highly effective and 1st line drug in the t/t of glaucoma. C. used in the prophylaxis against migraine head ache/ attack, e.g. Propranolol is preferred. D. Used as adjunct t/t of thyrotoxicosis/ hyperthyroidism/, i.e. preoperatively. E. In the t/t of anxiety states, to control somatic symptoms associated with SNS over activity, e.g. Tremor, palpitations. E.g. Propranolol is commonly used. ADVERSE EFFECT RELATED TO BETA BLOCKERS:Depression (mental) Fatigue Bradycardia and cold extremities Precipitate asthma, etc.

CONTRAINDICATION/C/I/:- Beta blockers should not be used in asthmatic patients, esp. Non selective ones. - should not be used in diabetic pts taking insulin since coadminstration may mask the symptom of hypoglycemia.

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