Cholinergicagonists Directly acting Indirectly acting (anticholinesterases) Choline esters Alkaloids «» Acetylcholine « Pilocarpine ‘+ Bethanechol ‘+ Muscarine + Carbachol eee Irreversible Carbamates Organophosphorus (OP) +» Physostigmine compounds + Neostigmine + Parathion + Pyridostigmine Malathion + Edrophonium + Sarin, soman, + Rivastigmine tabun (nerve gases) + Donepezil + Dyfios © Galantamine + Echothiophate + Carbaryl use as + Propoxur fuse? 2 (Baygon) jes.B Choline Esters Choline esters include acetylcholine, carbachol and bethanechol. P Acctylcholine Acetylcholine produces muscarinic and nicotinic effects by interacting with respective receptors on the effector cells (Table 3.3, p. 53). Muscarinic actions 1. Cardiovascular system a. Heart: The effects of ACh are similar to those following vagal stimulation. ACh, by stimulating M, receptors of the heart, opens K” channels resulting in hyperpolarization. Therefore, S~A and A-V nodal activity is reduced (Fig. 3.5). LU HR (negative chronotropic effect) Mz (LL FOC (negative inotropic effect) LL A-V conduction (negative dromotropic effect) ach —_® Fig. 3.5. The effects of acetylcholine (ACh) on heart.b. Blood vessels: Acetylcholine stimulates the M, receptors of vascular endothelial cells, which release endothelium-dependent relaxing factor (EDRE; NO), leading to vasodilatation and a fall in blood pressure (BP) (Fig. 3.6). ACh flim NO [EDRF] ween Endothelial cells BP Fig. 3.6 The effect of acetylcholine (ACh) on blood vessels. 2. Smooth muscles a. Gastrointestinal tract (Fig. 3.7) 7 Tone of the gut Ms) ictal acn 2 1 Petistaltic movements 7 Gl secretions —+ Relaxes the sphincter (may cause defaecation) Fig. 3.7 The effect of acetylcholine (ACh) on gastrointestinal (GI) tract.b. Urinary bladder (Fig, 3.8) Contracts the detrusor muscle Ach Ba, Relaxes trigone and sphincter (causes urination) Fig. 3.8 The effect of acetylcholine (ACh) on urinary bladder.. Bronchi (Fig. 3.9) uy Contracts the bronchial smooth muscle (bronchospasm) Ach & Increases tracheobronchial secretion — therefore, ‘cholinergic drugs are contraindicated in asthmatics Fig. 3.9 The effect of acetylcholine (ACh) on bronchi,3. Exocrine glands: All parasympathomimetic agents stimulate salivary secretion. They also increase lacrimal, sweat, bronchial, gastric and other gastrointestinal (GI) secretions. 4. Eye (Fig. 3.10): Acetylcholine does not produce any effect on topical administration because of its poor penetration throngh tissues. Sphincter pupillae Ciliary muscle o > Parasympathetic ‘Suspensory <—Comea + eam — Lens—> ; tris 7 ‘Canal of Schlerm Dilator pupiliae- Sympathetic Fig. 3.10 Autonomic innervation of the eye.Action of muscarinic agonists on eye can be depicted as follows: Acetylcholine (i-v.), pilocarpine, physostigmine M, receptors Contract sphincter Contract ciliary muscle pupillae (miosis) (spasm of accommodation) Open the trabecular meshwork around the canal of Schlemm_ ’ Facilitate drainage of aqueous humor and reduce intraocular pressure (IOP) in glaucomaNicotinic actions ‘To elicit nicotinic actions, larger doses of ACh are required. 1. Autonomic ganglia: Higher doses of ACh produce dangerous muscarinic effects, especially on the heart. Hence, prior administration of atropine is necessary to elicit nicotinic actions.Parasympathetic Se Adrenaline: >, 0G-, Bros Baw anh By-agonit ‘Anaphylactic shock, Bronchial asthma (ecute}, Cordiac arrest, te prolong the Duration of local anaesthesia, to control Epistaxis and other capillary 002ing (ABCDE) = Noradrenaline 47, O- and Bragonist Hypotensive states = Koprenaline: B,-and P,-agonist Heart block, cardiac arrest = Dobutemine Relatively selective B,-agonist Gordioganic shock duc te scute myocardial infarction (MD, congestive cardiac failure (CCF) or cardiac surgery + Salbutamol (Alibutera) Selective By-agonists Bronchial asthma, to suppress premature + Tesbutaline labour (as uterine relaxant) + Salmeterol + Fomnoterol = Phenylephrine Selective a, agonists Vasopressor agents, nasal decongestants, + Methoxamine as mydriatic (phenylephrine), allergic or vasomotor rhinitis = Naphazoline + Gagonists Nasal decongestants = Oxymetazeline (@-stimul ation), * xylometazoline Structural damage can occur due to Intense was constriction (es, stimulation) = Clonidine, Methyldopa eagoniss, Hypertension = Apradionidine: = Brimonidine agonists Glaucoma (opicalh 7. indirectly acting They act by releasing NA in the penphery; NA, DA and Schydroxytryptamine (HT) conteallly Narcolepsy, attention-deficit hyperkinetic disorder (ADHD) ©, Gy B, and Bi, (diect action) releases NA (indivect action) Intra venous ephedrine is used tor the eatment of hypotension duc to spinal anaesthesia 66, a, By and Dy + releases NA Cardiogenic shock, CCF with oligunaAdrenergic Agonists 1. Directly acting Receptor Action Therapeutic Uses * Adrenaline >, =, Brrr Br and ‘Anaphylactic shock, Bronchial asthma By-agonist facute), Cardiac arrest, to prolong the Duration of local anaesthesia, to control Epistaxis and other capillary oozing (ABCDE) * Noradrenaline 0%,-, Oty- and B, -agonist Hypotensive states * Isoprenaline By and B-agonist Heart block, cardiac arrest * Dobutamine Relatively selective Cardiogenic shock due to acute B,-agonist myocardial infarction (MI), congestive cardiac failure (CCF) or cardiac surgery * Salbutamol (Albuterol) Selective fi-agonists Bronchial asthma, to suppress premature * Terbutaline labour (as uterine relaxant) + Salmeterol * Formoterol + Phenylephrine Selective a,-agonists ‘Vasopressor agents, nasal decongestants, * Methoxamine ‘as mydriatic (phenylephrine), allergic or vasomotor thinitis * Naphazoline at, + t,-agonists * Oxymetazoline + Xylometazoline Nasal decongestants (a.,stimulation), Structural damage can occur due to intense vasoconstriction («,-stimulation) * Clonidine, a-Methyldopa _o,-agonists Hypertension * Apraclonidine a, agonists * Brimonidine Glaucoma (topical8 Direct-acting Sympathomimetics D Adrenaline (Epinephrine): 0, @-, B+ B,-and B,-Agonist It is a catecholamine, which is secreted mainly by adrenal medulla. Adrenaline is a direct acting nonselective adrenergic agonist. Pharmacological actions Adrenaline acts on 04-, 04-, B,-) B,- and B,-receptors. 1. Cardiovascular system a. Heart; Adrenaline is a powerful cardiac stimulant. It acts mainly by interacting with B -receptors and produces various effects. They are as follows: i. Increase in heart rate (positive chronotropic effect). ii, Increase in myocardial contractility (positive inotropic effect). iii, Increase in conduction velocity (positive dromotropic effect). iv. Increase in cardiac output. v. Increase in automaticity. vi. Cardiac work and its oxygen requirement is markedly increased. vii. Increase in the excitability and tendency to cause cardiac arrhythmias. b. Blood vessels and BP: Blood vessels of the skin and mucous membranes (¢t,-receptors) are constricted by adrenaline. It also constricts renal, mesenteric, pulmonary and splanchnic vessels, but dilates the blood vessels of skeletal muscle and coronary vessels (f,). Intravenous administration of adrenaline in moderate doses produces biphasic effect. There is an initial rise in BP due to a, (blood vessels) and B, (heart) actions, followed by a fall in BP due to f,-mediated vasodilatation in skeletal muscle. Administration of adrenaline after a-blocker produces only a fall in BP (B,-action), This is referred to as vasomotor reversal.= > x 2 .. Respiratory system: Adrenaline rapidly relaxes (B,) bronchial smooth muscle. It is a potent bronchodilator but has a short duration of action. It inhibits the release of inflammatory mediators from mast cells (i,). It also reduces secretions and relieves mucosal congestion by vasoconstrictor effect (0,). GIT: It relaxes the smooth muscle of the gut (ct, and f,). It reduces the intestinal tone and peristaltic movements. But the effects are transient. |. Bladder: It relaxes the detrusor muscle (f,) and contracts the sphincter (0,). As a result, it may cause difficulty in urination. CNS: In therapeutic doses, adrenaline does not cross the BBB and hence CNS effects are very minimal. But in high doses, it may cause headache, restlessness and tremor. Eye: Adrenaline has poor penetration through cornea when applied topically into the eye. Hence, it is administered as a prodrug (see p. 60). '. Metabolic effects: Adrenaline increases the blood glucose level by: i. Stimulating hepatic glycogenolysis (B,), which is the predominant effect. Reducing insulin secretion. iii, Decreasing the uptake of glucose by peripheral tissues. Other effects It reduces plasma K* levels by promoting the uptake of K* into the cells, particularly into the skeletal muscle (B,).Pharmacokinetics Adrenaline is not suitable for oral administration because of its rapid inactivation in the GI mucosa and liver. Adrenaline can be given subcutaneously (s.c.). In anaphylactic shock, the absorption of s.c. adrenaline is very poor, hence given intramuscularly. In cardiac arrest, it is given intravenously. It does not cross the BBBs is rapidly metabolized by COMT and MAO and the metabolites are excreted in urine. Adverse effects and contraindications The adverse effects of adrenaline are due to extension of its pharmacological actions. They are tachycardia, palpitation, headache, restlessness, tremor and rise in BP. The serious side effects are cerebral haemorrhage and cardiac arrhythmias. In high concentration, adrenaline may cause acute pulmonary oedema due to shift of blood from systemic to pulmonary circulation. Adrenaline is contraindicated in most of the cardiovascular diseases such as hypertension, angina, cardiac arrhythmias, CCF, etc. It should also be avoided in patients on B-blockers because it may cause hypertensive crisis and cerebral haemorrhage due to unopposed action on vascular c,-receptors. Therapeutic uses of adrenaline (ABCDE) 1. Anaphylactic shock: Adrenaline is the life-saving drug in anaphylactic shock. Adrenaline 0.3-0.5 mL of 1:1000 solution (1 mg/mL) is administered intramuscularly. It rapidly reverses the manifestations of severe allergic reactions (see p. 30, 37). 2. Bronchial asthma: Adrenaline is a powerful bronchodilator and has rapid onset but short duration of action. It is useful for acute attack. Its use has declined because of its dangerous cardiac-stimulant effect. The beneficial effects of adrenaline in bronchial asthma are shown in Figure 3.21. Adrenaline 0.3-0.5 mL of 1:1000 solution is given subcutaneously, It can be given by nebulization (as inhalation).Adrenaline / Causes Inhibits the release of inflammatory Bronchodilatati mediators fom mast 1) Gershon (h) cells (histamine, LTs, | bradykinin, PGF, PAF) | Decreases secretions Relieves mucosal ‘oedema and congestion Fig. 3.21 Effects of adrenaline in bronchial asthma: LTs, leukotrienes; PGF,,, prostaglandin F,, PAF, platelet activating factor.Table 3.10 Comparative Features of Adrenaline and Noradrenaline Adrenaline Noradrenaline Catecholamine Catecholamine Direct-acting sympathomimetic agent—o,,, o.-,B,, __Direct-acting sympathorrimetic agent—a,-, B,-, Breagonist B,-agonist Administered by s.c., i.m, and slow iv, routes Administered by i.v. infusion only Powerful cardiac stimulant—increases heart rate and Cardiac stimulant, but heart rate decreases due to force of contraction teflex bradycardia On iy. administration, in moderate doses, it No biphasic response seen because of its negligible produces typical biphasic response—initial rise in BP, action (ct,-blood vessels and B,-heart action) followed by a fall in BP due to B,-mediated vasodilatation in skeletal muscle Increase in blood glucose Slight increase in blood glucose only in lage doses Power bronchodilator No bronchodilating efiect Uses: Anaphylactic shock, Bronchial asthma (acute), Uses: To raise blood pressure in hypotensive states Cardiac resuscitation to prolong the Duration of local anaesthetics, Control Epistaxis and bleeding follow- ing tooth extraction, etc.‘Adrenergic Agonists Receptor Action Therapeutic Uses rectly acting © Amphetamine * Methamphetamine + Methylphenidate They act by releasing NA in the periphery; NA, DA and 5-hydroxytryptamine (5-HT) centrally Narcolepsy, attention-deficit hyperkinetic disorder (ADHD) Mixed acting * Ephedrine 04, 4, B, and B, (direct action) + releases NA (indirect action) Intravenous ephedrine is used for the treatment of hypotension due to spinal anaesthesia * Dopamine 04, Ch, B, and D, + releases NA Cardiogenic shock, CCF with oliguriaBi Indirect-acting Sympathomimetics D Amphetamine Amphetamine is an indirect-acting sympathomimetic agent and has a potent CNS-stimulant effect. It occurs in two isomers. The d-isomer has more potent CNS effects and the I-isomer on CVS. The side effects are restlessness, insomnia, confusion, fatigue, tremor, hallucinations and suicidal tendencies. The cardiac side effects are tachycardia, palpitation, hypertension, angina and cardiac arrhythmias. Treatment of acute intoxication 1, Acidification of urine with ascorbic acid (vitamin C) promotes the excretion of amphetamine, which is a basic drug. 2. Sedatives are effective to control CNS symptoms and sodium nitroprusside for severe hypertension. Uses 1. Narcolepsy: It is a sleep disorder characterized by recurrent episodes of uncontrollable desire for sleep. Amphetamine improves narcolepsy by its CNS-stimulant effect. 2. As an anorexiant; Amphetamine-like drugs reduce body weight by suppressing hypothalamic feeding centre. Tolerance to this effect develops rapidly. 3. Attention-deficit hyperkinetic disorder: Amphetamine acts paradoxically and controls the activity in children with hyperkinetic disorder. The main adverse effects are loss of appetite and insomnia. Methylphenidate and dextroamphetamine are also useful in this disorder.B Mixed-acting Sympathomimetics D Ephedrine: e- and f-Agonist with NA Release Ephedrine is a mixed-acting adrenergic agonist. It is an alkaloid, acts on 04,-, 0,-, B,-, {,-receptors and releases NA from sympathetic nerve endings. Pharmacological actions CNS stimulant Vasoconstrictor (ct,) t Nasal decongestant (ct,) Cardiac stimulant (f,) <—j Ephedrine |} —> Bronchodilator (f.,) ™ ‘Mydriatic (01,) (see p. 65, Table 3.6) Urinary retention Uses Intravenous ephedrine is the drug of choice to treat hypotension due to spinal anaesthesia as it increases peripheral vascular resistance, heart rate, cardiac output and thus BP. It was used in heart block, narcolepsy and more frequently in bronchial asthma. Now, it has been replaced by more selective drugs. The side effects are due to the extension of its pharmacological actions. They are insomnia, hypertension, tachycardia, palpitation, difficulty in urination; tachyphylaxis occurs on repeated administration.R BLOCKERS Adrenergic-receptor antagonists block the effects of sympathetic stimulation and adrenergic agonists mediated through o- and B-receptors. Adrenergic receptor antagonists a-Blockers ALPHA-ADRENERGIC BLOCKERS Pharmacological effects of a-blockers (Fig. 3.23) They block the o.-receptors, thus inhibiting the o.-receptor-mediated responses of sympathetic stimulation and adrenergic drugs. Classification Non-selective Selective Selective (a, and a,) Blockers Blockers Blockers © Prazosin * Yohimbine Terazosin , © Doxazosin Reverble Inrereratby ) > tamsulosin + Phentolamine © Phenoxybenzamine | Aiptosin « TolazolineBi Irreversible Nonselective a-Blocker P Phenoxybenzamine Phenoxybenzamine is a nonselective c.-adrenergic blocker that blocks both ot,- and ct,-receptors. It binds covalently to a-receptors and causes irreversible blockade. It also inhibits the reuptake of NA into the adrenergic nerve endings. Noradrenaline (agonist) Oy OL, receptors Phenoxybenzamine (antagonist) Non-competitive antagonism Pharmacological effects 1. Peripheral vascular resistance is reduced due to the blockade of vascular o,,-receptors. 2, Increased release of NA from the adrenergic nerve endings due to the blockade of presynaptic q,-teceptors. This may cause cardiac stimulation and produce tachycardia, palpitation, cardiac arrhythmias, etc.or a + cl motty Dilator pupitoe —/ a fe (Miosis) ,Felnaton of sphincter (iarthoea) ivdillen Urinary bladder Relasation cf trigone and c faq sphincter : 0 the resistance to os —_ a0 Oia anne in PH) Decrease in preload Fig, 3.23 Effect of a-blockade at various sites, GIT, gastrointestinal tract; BPH, benign prostatic hyperplasia; NA, noradrenaline. Other effects: Blackade of alpha-receptors in nasal blood vessels results in nasal stuffiness,Bf Reversible Nonselective w-Blocker ® Phentolamine Phentolamine is an imidazoline derivative. It competitively blocks the effects of NA at both o,,- and o1,-adrenergic receptors. It can also block 5-HT receptors, K* channels and cause histamine release from mast cells. Noradrenaline Oy Phentolamine (agonist) receptors (antagonist) Competitive antagonism Phentolamine is given intravenously and has rapid onset but short duration of action. It is used intraoperatively during surgery of phaeochromocytoma, in hypertensive emergencies (for details, see uses of o:-blockers) and to prevent tissue necrosis due to extravasation of o:,-agonists. Adverse effects They include tachycardia, palpitation, arrhythmias; angina and MI may be precipitated. ® Tolazoline Tolazoline is similar to phentolamine and is rarely used.BW Selective ax,-Blockers Prazosin is a potent and selective o,-adrenergic receptor blocker. It is given orally. It is well absorbed from GI tract, but undergoes extensive first-pass metabolism. The effects of a-blockade are depicted in the Fig. 3.23. Unlike nonselective c-blockers, selective o:,-blockers produce minimal or no tachycardia. Adverse effects First-dose phenomenon: Within 30-90 min of oral administration of prazosin, severe postural hypotension and syncopal attacks may be seen with first dose. Therefore, the initial dose should be small (1 mg). It is usually given at bed time so that the patient remains in bed for several hours and the risk of syncopal attack is reduced. Other selective «,-blockers * Terazosin is similar to prazosin, but less potent than prazosin. It is almost completely absorbed after oral administration and has a longer duration of action. + Doxazosin is the longest-acting, selective 01 -blocker. The haemodynamic effects, bioavailability and extent of metabolism are similar to prazosin. Alfuzosin blocks all subtypes of ct,-receptors (01,4, O44, and cp). It is orally effective and used in benign prostatic hyperplasia (BPH). Tamsulosin is an uroselective a. blocker (c1,,)-At low doses, it reduces the resistance to flow of urine with little effect on BP. It is administered orally and is the preferred c1,-blocker for the treatment of benign prostatic hyperplasia (BPH) in normotensive patients. It may cause retrograde ejaculation.Beta-adrenergic antagonists block the f-receptor- mediated effects of sympathetic stimulation and adrenergic drugs. Classification Beta blockers First generation Second generation ‘Third generation (Nonselective (By-Selective (B- blockers with B-adrenergic blockers) adrenergic blockers) _additional vasodilatory effect) * Propranolol Atenolol « Labetalol * Timolol « Acebutolol # Carvedilol * Nadolol « Bisoprolol * Caliprolol * Pindolol « Esmolol * Sotalol © Metoprolol Pindolol, acebutolol,labetalol and celiprolol have partial agonistic activity (intrinsic sympathomimetic activity). They stimulate B-receptors partially in the absence of catecholamines. Propranolol, acebutolol, carvedilol, labetalol, metoprolol, pindolol have membrane-stabilizing activity (local anaesthetic activity). Mechanism of action Propranolol is the prototype drug. B-Blockers competitively block the B-mediated actions of catecholamines and other adrenergic agonists Propranolol and other Catecholamines and other ° B-blockers (antagonists) adrenergic agonists B-Receptors |<—Pharmacological actions 1. Cardiovascular system: a. Heart: -Blockers depress all the cardiac properties. i. Decrease heart rate (negative chronotropic effect). ii. Decrease the force of myocardial contractility (negative inotropic effect). iii, Decrease cardiac output. iv. Depress $-A node and A-V nodal activity. v. Increase refractory period of A-V node. vi. Decrease conduction in atria and A-V node (negative dromotropic effect). vii. Decrease automaticity of ectopic foci. viii. Decrease cardiac work, thus reduce O, requirement of the myocardium. Only in high doses, some of them have membrane-stabilizing effect. >. Blood vessels: Blockade of f,-receptors of the blood vesscls initially may cause rise in peripheral vascular resistance due to the unopposed ct,-action. However, continued administration of these drugs leads to a fall in peripheral vascular resistance (PVR) in patients with hypertension (reduce both systolic and diastolic BP). They also reduce release of renin from juxtaglomerular apparatus due to blockade of B,- receptors. 2. Respiratory system: Blockade of B,-receptors in bronchial smooth muscle can produce severe bronchospasm in patients with COPD and asthma. Therefore, B-blockers should be avoided in patients with asthma and COPD. Selective B,-blockers such as atenolol, metoprolol, etc. are less likely to cause bronchospasm. o 9Pharmacokinetics Propranolol is highly lipid soluble and is well abscrbed from GI tract. However, the bioavailability of propranolol is low because of its extensive first-pass metabolism. It is highly bound to plasma proteins; has large volume of distribution; freely crosses BB3, and metabolites are excreted in urine. Adverse effects of -blockers They are mainly an extension of pharmacological actions. 1. €VS: + Bradycardia, heart block and may precipitate congestive heart failure in patients with low cardiac reserve. «Blockade of vascular fi,-receptors causes unopposed of, action, further reduces blood supply and may worsen peripheral vascular diseases. B-Blockers can exacerbate Prinzmetal’s angina (variant angina) due to unopposed ct, action, hence are contraindicated. 2. Respiratory system: Blockade of f-receptors in the bronchial smooth muscle can cause severe bronchospasm in patients with asthma and COPD. Hence, B-blockers are contraindicated in the above conditions. 3. CNS: Sleep disturbances, hallucinations, fatigue and mental depression. 4, Metabolic: Hypoglycaemia is common with nonselective (B-blockers especially in diabetics on hypo- glycaemic agents. B-Blockers may also mask the warning signs and symptoms of hypoglycaemia. 5. Muscular weakness and tiredness: These are cue to reduced blood flow to skeletal muscle. 6. Withdrawal symptoms: Abrupt withdrawal of B-blockers after chronic use is dangerous because they can precipitate angina or frank myocardial infarction and even sudden death. This is due to the upregulation (supersensitivity) of B-receptors in response to prolonged blockade (see p. 27, Table 1.5).Therapeutic uses of B-blockers L. Hypertension: B-Blockers are useful for all grades of hypertension (see page 103). These drugs are preferred especially in patients with coexisting angina, myocardial infarction or cardiac arrhythmias. The advantages of B-blockers are: + Sodium and water retention is rare. © Cheaper. © Have a long duration of action. + Well tolerated. . Angina pectoris and MI: B-Blockers reduce myocardial O, demand by decreasing heart rate, myocardial contractility and blood pressure. They improve exercise tolerance and reduce frequency of anginal episodes. Use of B-blockers early in acute phase of MI may limit infarct size. Long-term use of f-blockers may reduce mortality and reinfarction. . Cardiac arrhythmias: B-Blockers are mainly used in atrial archythmias such as atrial fibrillation, atrial flutter, etc; but rarely for ventricular arrhythmias. eTable 3.12 Differences Between Propranolol and Atenolol Propranolol ‘Atenolol Nonselective B-blocker Selective B,-blocker In large doses, has membrane-stabilizing effect (local Has no membrane-stabilizing effect anaesthetic) Highly lipid soluble, freely crosses BBB and produces Poorly lipid soluble, hence central side effects are central side effects rare Has shorter duration of action, but propranolol $_Has longer duration of action, given once daily formulation has a duration of 24h Less potent More potent 8 (-Blockers with Additional Vasodilatory Action D Labetalol It isa competitive blocker at B,-, B,- and o,-adrenergic receptors. It is administered orally or intravenously. It undergoes extensive first-pass metabolism after oral administration; hence its bioavailability is poor. Oral labetalol is useful in the treatment of essential hypertension and i.v. labetalol for hypertensive emergencies. The important side effects are postural hypotension and hepatotoxicity.