Anticholinergic Agents
Content
Antimuscarinic agents
Antimuscarinic agents •tertiary amines: atropine, pirenzepine, tropicamide •quaternary amines for gastrointestinal application: propantheline, glycopyrrolate •quatenary amine for use in asthma: ipratropium •quatenary amine for Parkinson’s disease: benztropine Muscarinic receptors and effects of activation •Muscarinic M1 at CNS neurons, sympathetic postganglionic neurons, some presynaptic sites •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M3 at exocrine glands, vessels (smooth muscle and endothelium) •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M5 at CNS neurons •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M2 at myocardium, smooth muscle, some presynaptic sites •Effect of stimulation: opening of potassium channels, inhibition of adenylyl cyclase and cAMP production •Muscarinic M4 at CNS neurons •Effect of stimulation: inhibition of cAMP production Natural occurring antimuscarinic agents •Atropine (hyoscyamine) •tertiary ammonium alkaloid ester formed by union of benzyl alcohol, tropic acid and tropine •naturally occurring in plant Atropa belladonna or deadly nightshade, and in Datura stramonium or jimsonweed (Jamestown weed) or thorn apple •occurring as l-hyoscyamine, but the compound readily racemizes, so commercial preparation is racemic d,lhyoscyamine •potency of l-hyoscyamine to d-hyoscyamine is at least 100:1 •l-hyoscyamine provides antimuscarinic activity •Scopolamine (hyoscine hydrobomide) •tertiary ammonium alkaloid ester formed by union of benzyl alcohol, tropic acid and scopine •scopine differs from tropine only in having an oxygen bridge between C6 and C7 •naturally occurring as l-hyoscine in Hyoscyamus niger, or henbane, and Scopolia carniolica •potency of l-hyoscine to d-hyoscine is at least 100:1 •l-hyoscine more active than d-hyoscine Semisynthetic antimuscarinic agents •tertiary ammonium analogs •produced by esterifying a natural base e.g. tropine with different acids (homatropine, mandelic acid ester of tropine) •quaternary ammonium analogs •developed to produce more peripheral effects with reduced central nervous system effects •Glycopyrrolate •a quaternary amine, •crosses the BBB and placenta to a minimal degree •relatively devoid of adverse CNS effects •originally used in the treatment of peptic ulcer disease, then used as an anaesthetic premedicant •compared with the belladonna alkaloids, glycopyrrolate possesses a marked antisialogogue action which is of long duration (6-8 hours) •potency relative to atropine is 2:1 to 5:1 •Dosages, onset of action, and duration f action •atropine 5-20 mcg/kg, 1min, 3 h •hyoscine 5-10 mcg/kg, 1min, 2h •glycopyrrolate 3-10 mcg/kg, 1min, 6h
Structure activity •the intact ester of tropic acid and tropine is essential for the action of atropine •neither the free acid nor base exhibits significant antimuscarinic activity •presence of a free -OH group in the acid portion of the ester also important for antimuscarinic activity •substitution of other aromatic acids for tropic acid modifies but does not necessarily abolish antimuscarinic activity •quaternary derivatives of atropine and scopolamine when administered parenterally, are more potent than their parent compounds in both muscarinic receptor and ganglionic blocking activity •lack central nervous system effects because of poor penetration into the brain •absorption after oral administration is poor and unreliable Mechanism of action •binds to a specific amino acid binding site on the muscarinic receptor protein, which normally binds with the nitrogen atom of acetylcholine •atropine is highly selective for muscarinic receptors, M1,2,3 •atropine causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors •blocks the formation of inositol triphosphate and the inhibition of adenylyl cyclase that are brought about by muscarinic agonists •potency at nicotinic receptor lower, clinically, actions at these receptors are undetectable •Sensitivity to atropine
most sensitive salivary glands bronchial glands sweat glands intermediate cardiac muscle smooth muscle least secretion of acid by gastric parietal cells
•Distribution •tertiary amine are well distributed after absorption •atropine: onset time 1 min; 15-20% bound to plasma protein; Vd 1-3 L/kg; peak effect in central nervous system within 30-60 minutes •hyoscine: onset time 1 min; effect in CNS > atropine •quaternary ammonium compounds •poorly taken up by brain and relatively free of central nervous system effects at low concentrations •Glycopyrrolate: onset time 1 minute •Metabolism •atropine •60% of dose excreted unchanged in urine •most of the rest hydrolysed and conjugated, and excreted in urine •clearance 8-10 ml/min/kg •t½β of 2 hours •only effects on the iris and ciliary muscle persist for 72 hours or longer while the effect of atropine in all other parasympathetic organs declines rapidly •scopolamine •6% of dose excreted unchanged in urine •clearance 10-20 ml/min/kg •t½b of 2-4 hours Pharmacodynamics •Effect on central nervous system •atropine •CNS stimulant. Stimulates respiratory centre and causes auditory hyperacusis. May cause restlessness and delirium, but possible sedation in the elderly, antiemetic •can cause anticholinergic syndrome, (excitement, drowsiness, memory disturbances, hallucinations, ataxia, coma). Treat with physostigmine, an anticholinesterase which crosses BBB •hyoscine •Central sedative, causing drowsiness, sedation, amnesia, but can also cause restlessness and agitation in the elderly. Better antiemetic than atropine, blocks motion sickness due to vestibular disturbance, transdermal patch available for nausea/vomiting cause by opioids. Can cause anticholinergic syndrome •glycopyrrolate •Does not cross the BBB, CNS effects and anticholinergic syndrome do not occur
increasing dosage of atropine
Pharmacokinetics •Absorption •natural occurring alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut, across the conjunctival membrane and skin •only 10-30% of a dose of quaternary antimuscarinic drug is absorbed after oral administration due to the decreased lipid solubility of the charged molecule
•Effect on eye •mydriasis: unopposed sympathetic dilator activity •belladona, Italian for beautiful lady •action of hyoscine on iris sphincter stronger than atropine •cycloplegia: impaired contraction of ciliary muscle, loss of ability to accommodate, inability to focus for near vision •acute glaucoma in individuals with narrow anterior chamber angle •dry eyes from reduced lacrimal secretion •Effect on respiratory system •mild respiratory stimulant, effect of atropine > hyoscine •bronchodilation, effect of hyoscine < atropine, glycopyrrolate •Effect on cardiovascular system •vagolysis causes tachycardia and possible arrhythmias. •used to prevent or treat bradycardia from neostigmine, suxamethonium, halothane, central neural blockade, vagal/surgical stimuli, oculocardiac reflex; effect of atropine > hyoscine > glycopyrrolate
Heart rate (beats/min) 80 70 60 50 0 2 4 6 8 10 Atropine dose (mg/kg) Porter TR et al: J Clin Invest 1990; 85:1362
•Effect on gastrointestinal tract •dry mouth •tone of gut reduced; walls of the viscera is relaxed, tone and propulsive movements are diminished; prolonged gastric emptying time; intestinal transit time is lengthened •lowers gastro-oesophageal sphincter tone, increasing the incidence of regurgitation; hyoscine less effect than atropine •reduced volume and secretion of gastric acid, pepsin, and mucin, used to treat or prevent gastrointestinal motility •effect of glycopyrrolate > atropine and hysocine •Effect on genitourinary tract •smooth muscle of the bladder wall and uterus •relaxed, and voiding of urine is slowed •useful in the treatment of spasm induced by mild inflammatory conditions and certain neurologic conditions •urinary retention in presence of prostatic hypertrophy •Effect on glands •thermoregulatory sweating is suppressed by atropine •in adults, body temperature is elevated by this effect only if large doses are administered •in infants and children, ordinary doses cause “atropine fever” •reduction of secretion, effect of hyoscine and glycopyrrolate > atropine Therapeutic application •central nervous system system •Parkinson’s disease, motion sickness •ophthalmology •measurement of refractive error, examination of the retina, prevent synechia (adhesion) formation in uveitis and iritis (homatropine) •respiratory system •antisialogogue, asthma (ipratropium), chronic obstructive lung disease •cardiovascular system •vagolysis, hyperactive carotid sinus reflexes •gastrointestinal tract •previously used for treatment of peptic ulcer, diarrhoea (atropine with diphenoxylate, Lomotil) •urinary tract •bladder spasm after inflammation, after urologic surgery, neurologic disease, relieve ureteric spasm •cholinergic poisoning •cholinesterase inhibitor insecticides, ingestion of wild mushrooms
•explanations for bradycardia at low dose •previously thought to be due to central stimulation of vagal nucleus •blockade of presynaptic muscarinic (M1) receptors on vagal postsynaptic fibres that normally limit acetylcholine release at the sinoatrial node, (i.e. more acetylcholine release and bradycardia) •atropine blocks vasodilatation produced by sympathetic cholinergic nerves; and uninnervated muscarinic receptors on vessels •these receptors located on endothelial cells, cause release of NO· in response to circulating direct-acting muscarinic agonists •in toxic doses, antimuscarinic agents cause cutaneous vasodilatation especially in upper portion of body, mechanism unknown
Antimuscarinic agents •tertiary amines: atropine, pirenzepine, tropicamide •quaternary amines for gastrointestinal application: propantheline, glycopyrrolate •quatenary amine for use in asthma: ipratropium •quatenary amine for Parkinson’s disease: benztropine Muscarinic receptors and effects of activation •Muscarinic M1 at CNS neurons, sympathetic postganglionic neurons, some presynaptic sites •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M3 at exocrine glands, vessels (smooth muscle and endothelium) •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M5 at CNS neurons •Effect of stimulation: formation of IP3 & DAG, increased intracellular Ca2+ •Muscarinic M2 at myocardium, smooth muscle, some presynaptic sites •Effect of stimulation: opening of potassium channels, inhibition of adenylyl cyclase and cAMP production •Muscarinic M4 at CNS neurons •Effect of stimulation: inhibition of cAMP production Natural occurring antimuscarinic agents •Atropine (hyoscyamine) •tertiary ammonium alkaloid ester formed by union of benzyl alcohol, tropic acid and tropine •naturally occurring in plant Atropa belladonna or deadly nightshade, and in Datura stramonium or jimsonweed (Jamestown weed) or thorn apple •occurring as l-hyoscyamine, but the compound readily racemizes, so commercial preparation is racemic d,lhyoscyamine •potency of l-hyoscyamine to d-hyoscyamine is at least 100:1 •l-hyoscyamine provides antimuscarinic activity •Scopolamine (hyoscine hydrobomide) •tertiary ammonium alkaloid ester formed by union of benzyl alcohol, tropic acid and scopine •scopine differs from tropine only in having an oxygen bridge between C6 and C7 •naturally occurring as l-hyoscine in Hyoscyamus niger, or henbane, and Scopolia carniolica •potency of l-hyoscine to d-hyoscine is at least 100:1 •l-hyoscine more active than d-hyoscine Semisynthetic antimuscarinic agents •tertiary ammonium analogs •produced by esterifying a natural base e.g. tropine with different acids (homatropine, mandelic acid ester of tropine) •quaternary ammonium analogs •developed to produce more peripheral effects with reduced central nervous system effects •Glycopyrrolate •a quaternary amine, •crosses the BBB and placenta to a minimal degree •relatively devoid of adverse CNS effects •originally used in the treatment of peptic ulcer disease, then used as an anaesthetic premedicant •compared with the belladonna alkaloids, glycopyrrolate possesses a marked antisialogogue action which is of long duration (6-8 hours) •potency relative to atropine is 2:1 to 5:1 •Dosages, onset of action, and duration f action •atropine 5-20 mcg/kg, 1min, 3 h •hyoscine 5-10 mcg/kg, 1min, 2h •glycopyrrolate 3-10 mcg/kg, 1min, 6h
Structure activity •the intact ester of tropic acid and tropine is essential for the action of atropine •neither the free acid nor base exhibits significant antimuscarinic activity •presence of a free -OH group in the acid portion of the ester also important for antimuscarinic activity •substitution of other aromatic acids for tropic acid modifies but does not necessarily abolish antimuscarinic activity •quaternary derivatives of atropine and scopolamine when administered parenterally, are more potent than their parent compounds in both muscarinic receptor and ganglionic blocking activity •lack central nervous system effects because of poor penetration into the brain •absorption after oral administration is poor and unreliable Mechanism of action •binds to a specific amino acid binding site on the muscarinic receptor protein, which normally binds with the nitrogen atom of acetylcholine •atropine is highly selective for muscarinic receptors, M1,2,3 •atropine causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors •blocks the formation of inositol triphosphate and the inhibition of adenylyl cyclase that are brought about by muscarinic agonists •potency at nicotinic receptor lower, clinically, actions at these receptors are undetectable •Sensitivity to atropine
most sensitive salivary glands bronchial glands sweat glands intermediate cardiac muscle smooth muscle least secretion of acid by gastric parietal cells
•Distribution •tertiary amine are well distributed after absorption •atropine: onset time 1 min; 15-20% bound to plasma protein; Vd 1-3 L/kg; peak effect in central nervous system within 30-60 minutes •hyoscine: onset time 1 min; effect in CNS > atropine •quaternary ammonium compounds •poorly taken up by brain and relatively free of central nervous system effects at low concentrations •Glycopyrrolate: onset time 1 minute •Metabolism •atropine •60% of dose excreted unchanged in urine •most of the rest hydrolysed and conjugated, and excreted in urine •clearance 8-10 ml/min/kg •t½β of 2 hours •only effects on the iris and ciliary muscle persist for 72 hours or longer while the effect of atropine in all other parasympathetic organs declines rapidly •scopolamine •6% of dose excreted unchanged in urine •clearance 10-20 ml/min/kg •t½b of 2-4 hours Pharmacodynamics •Effect on central nervous system •atropine •CNS stimulant. Stimulates respiratory centre and causes auditory hyperacusis. May cause restlessness and delirium, but possible sedation in the elderly, antiemetic •can cause anticholinergic syndrome, (excitement, drowsiness, memory disturbances, hallucinations, ataxia, coma). Treat with physostigmine, an anticholinesterase which crosses BBB •hyoscine •Central sedative, causing drowsiness, sedation, amnesia, but can also cause restlessness and agitation in the elderly. Better antiemetic than atropine, blocks motion sickness due to vestibular disturbance, transdermal patch available for nausea/vomiting cause by opioids. Can cause anticholinergic syndrome •glycopyrrolate •Does not cross the BBB, CNS effects and anticholinergic syndrome do not occur
increasing dosage of atropine
Pharmacokinetics •Absorption •natural occurring alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut, across the conjunctival membrane and skin •only 10-30% of a dose of quaternary antimuscarinic drug is absorbed after oral administration due to the decreased lipid solubility of the charged molecule
•Effect on eye •mydriasis: unopposed sympathetic dilator activity •belladona, Italian for beautiful lady •action of hyoscine on iris sphincter stronger than atropine •cycloplegia: impaired contraction of ciliary muscle, loss of ability to accommodate, inability to focus for near vision •acute glaucoma in individuals with narrow anterior chamber angle •dry eyes from reduced lacrimal secretion •Effect on respiratory system •mild respiratory stimulant, effect of atropine > hyoscine •bronchodilation, effect of hyoscine < atropine, glycopyrrolate •Effect on cardiovascular system •vagolysis causes tachycardia and possible arrhythmias. •used to prevent or treat bradycardia from neostigmine, suxamethonium, halothane, central neural blockade, vagal/surgical stimuli, oculocardiac reflex; effect of atropine > hyoscine > glycopyrrolate
Heart rate (beats/min) 80 70 60 50 0 2 4 6 8 10 Atropine dose (mg/kg) Porter TR et al: J Clin Invest 1990; 85:1362
•Effect on gastrointestinal tract •dry mouth •tone of gut reduced; walls of the viscera is relaxed, tone and propulsive movements are diminished; prolonged gastric emptying time; intestinal transit time is lengthened •lowers gastro-oesophageal sphincter tone, increasing the incidence of regurgitation; hyoscine less effect than atropine •reduced volume and secretion of gastric acid, pepsin, and mucin, used to treat or prevent gastrointestinal motility •effect of glycopyrrolate > atropine and hysocine •Effect on genitourinary tract •smooth muscle of the bladder wall and uterus •relaxed, and voiding of urine is slowed •useful in the treatment of spasm induced by mild inflammatory conditions and certain neurologic conditions •urinary retention in presence of prostatic hypertrophy •Effect on glands •thermoregulatory sweating is suppressed by atropine •in adults, body temperature is elevated by this effect only if large doses are administered •in infants and children, ordinary doses cause “atropine fever” •reduction of secretion, effect of hyoscine and glycopyrrolate > atropine Therapeutic application •central nervous system system •Parkinson’s disease, motion sickness •ophthalmology •measurement of refractive error, examination of the retina, prevent synechia (adhesion) formation in uveitis and iritis (homatropine) •respiratory system •antisialogogue, asthma (ipratropium), chronic obstructive lung disease •cardiovascular system •vagolysis, hyperactive carotid sinus reflexes •gastrointestinal tract •previously used for treatment of peptic ulcer, diarrhoea (atropine with diphenoxylate, Lomotil) •urinary tract •bladder spasm after inflammation, after urologic surgery, neurologic disease, relieve ureteric spasm •cholinergic poisoning •cholinesterase inhibitor insecticides, ingestion of wild mushrooms
•explanations for bradycardia at low dose •previously thought to be due to central stimulation of vagal nucleus •blockade of presynaptic muscarinic (M1) receptors on vagal postsynaptic fibres that normally limit acetylcholine release at the sinoatrial node, (i.e. more acetylcholine release and bradycardia) •atropine blocks vasodilatation produced by sympathetic cholinergic nerves; and uninnervated muscarinic receptors on vessels •these receptors located on endothelial cells, cause release of NO· in response to circulating direct-acting muscarinic agonists •in toxic doses, antimuscarinic agents cause cutaneous vasodilatation especially in upper portion of body, mechanism unknown
