Pharmacology of Muscarinic Receptor Blockade

Acetylcholine is an agonist at both muscarinic and nicotinic receptors The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked

Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission X Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP

Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected. X X

In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance X

Atropine

Characteristics of Atropine Source –Atropa belladonna –Datura stramonium Known as Jamestown weed or jimsonweed Chemical nature –An alkaloid Alternate name is d,l-hyoscyamine Nature of blockade –Competitive

Response to ACh in the Presence of Atropine Log dose of acetylcholine Response control atropine Atropine competitively inhibits muscarinic reponses to ACh

Actions of Atropine at Tissue Sites Eye –Sphincter muscle of the iris: mydriasis –Ciliary muscle: cycloplegia Atropine limits focusing to distant objects Accomodation is blocked by atropine

Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent Reproduced from Basic and Clinical Pharmacology

Actions of Atropine At Smooth Muscles And Glands Eye Lacrimal glands Mucus glands of the pharynx and nasal cavity Bronchial smooth muscle Gastric glands Intestinal glands Pancreas Mucus glands of the respiratory tract Lacrimal glands Eccrine sweat glands

Cardiovascular Actions of Atropine Heart rate –Low dose –High dose Systemic blood vessels Peripheral resistance Cutaneous blood vessels

Response to Doses of Atropine Reproduced from Basic and Clinical Pharmacology

M 1 Receptor Activation at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber ACh (----) M1 M2

M 1 Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber Pirenzepine is an M 1 antagonist x ACh M1 M2

Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are among the results. Such actions are accentuated in the presence of inhibitors of AChE (they also block plasma pseudocholinesterase). i.v. infusion

Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac and hypotensive responses to tachycardia and hypertension, mediated through the nicotinic receptors. x x x i.v. infusion

Effect Of Atropine in Relation to Dosage...

Dose of Atropine DOSEEFFECT 0.5 mgSlight decline in heart rate Some dryness of mouth Inhibition of sweating

Dose of Atropine DOSEEFFECT 1.0 mgDefinited dryness of mouth Thirst Inreased heart rate, sometimes preceded by slowing Mild dilatation of pupil

Dose of Atropine DOSEEFFECT 2.0 mgRapid heart rate Palpitation Marked dryness of mouth Dilated pupils Some blurring of near vision

Dose of Atropine DOSEEFFECT 5.0 mgAll the previous symptoms are marked Difficulty in speaking and swallowing Restlessness and fatigue Headache Dry hot skin Difficulty in micturition Reduced intestinal peristalsis

Dose of Atropine DOSEEFFECT 10 mgPrevious symtoms are more marked and morePulse, rapid and weak Iris practically obliterated Vision very blurred Skin flushed, hot, dry, and scarlet Ataxia Restlessness and excitement Hallucinations and delirium Coma

The previous five slides are reproduced from Goodman and Gilman’s The Pharmacological Basis of Therapeutics

Scopolamine (1) Source - Hyoscyamus niger (henbane) Chemical nature of the molecule Nature of blockade Changes in the dose response curve of muscarinic agonists in the presence of scopolamine Lower doses of scopolamine ( mg) produce greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine

Scopolamine (2) Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used

Therapeutic Uses of Antimuscarinic Agents

Therapeutic Uses of Muscarinic Antagonists (1) Cardiovascular System - atropine is generally used for the following cases –Improper use of choline esters –Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct –Hyperactive carotid sinus (syncope and severe bradycardia) –Second degree heart block

Therapeutic Uses of Muscarinic Antagonists (2) Gastrointestinal Tract –Peptic ulcers In Europe, Japan, and Canada, M 1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used In the U.S. H 2 histamine antagonists such as cimetidine are used –Spasticity of the g.i. tract M 3 muscarinic antagonists are being investigated –Excessive salivation associated with heavy metal poisoning and parkinsonism –Production of partial blockade of salivation in patients unable to swallow

Therapeutic Uses of Muscarinic Antagonists (3) Urinary Bladder –Reverse spasm of the ureteral smooth muscle (renal colic) –Increase bladder capacity in cases of enuresis –Reduce urinary frequency in cases of hypertonic bladder

Therapeutic Uses of Muscarinic Antagonists (4) Central Nervous System –Parkinson’s disease –Motion sickness –Produce tranquilization and amnesia prior to surgery and in certain cases such as labor (not a prominent use anymore) –Anesthesia, to inhibit salivation (not a prominent use anymore) –Prevent vagal reflexes induced by surgical manipulation of organs

Therapeutic Uses of Muscarinic Antagonists (5) Posioning by inhibitors of acetylcholinesterase Mushroom poisoning due to muscarine In conjunction with inhibitors of acetylcholinesterase when they are used to promote recovery from neuromuscular blockade after surgery Injudicious use of choline esters Prevent vagal reflexes induced by surgical manipulation of visceral organs Atropine is used for the above

Toxicity of Atropine

Contraindications to the Use Of Antimuscarinic Agents Narrow Angle Glaucoma

Flow of Aqueous and Its Escape From the Eye

Contraindications to the Use of Antimuscarinic Agents Narrow angle glaucoma Hypertrophy of the prostate gland Atony of the bladder Atony of the G.I. Tract

Tertiary Muscarinic Antagonists and Their Uses Ophthalmic applications –Cyclopentolate –Tropicamide –Homatropine Parkinson’s disease –Benztropine –Trihexphenidyl

Tertiary Muscarinic Antagonists and Their Uses Used for antispasmodic purposes –Flavoxate - urinary bladder –Oxybutynin - urinary bladder –Tolterodine - urinary bladder –Dicyclomine –Oxyphencyclimine In general, they are useful for spasms of the g.t. tract, bile duct, ureters,

Tolterodine Therapeutic use - reduce urinary urgency Metabolism –Cytochrome P450 –Active metabolite is DD-01 Drug interactions –Ketoconazole –Erythromycin

Quaternary Ammonium Antagonists (1) General characteristics Pharmacology and therapeutic uses Distinct side effects with high and sometimes therapeutic doses

Quaternary Ammonium Antagonists (2) Methantheline (N + ) Propantheline (N + ) Methscopolamine (N + ) Homatropine methylbromide (N + ) Oxyphenonium (N + )

Quaternary Ammonium Antagonists (3) Anisotropine (N + ) Glycopyrrolate (N + ) Isopropamide (N + ) Mepenzolate (N + ) Ipratropium (N + )

Ipratropium Uses Distinctiveness from atropine

M 1 Muscarinic Receptor Antagonists Pirenzepine – Blocks the M 1 and the M 4 receptor – Its usefulness for peptic ulcer Telenzepine –Blocks the M 1 receptor –Its usefulness for peptic ulcer

M 2 Muscarinic Receptor Antagonists Tripitamine – Blocks the M 2 receptor – Blocks the action of acetylcholine at cardiac muscle fibers Gallamine –Blocks M 2 muscarinic and the N N nicotinic sites

M 3 Muscarinic Receptor Antagonist Darifenacin – Blocks the M 3 receptor – Blocks the actions of acetylcholine at smooth muscles and glands

Drugs of Other Classes With Antimuscarinic Activity (1) Tricyclic antidepressants –Imipramine –Amitriptyline –Protriptyline –Others.: DEMONSTRATION.: DEMONSTRATION

Drugs of Other Classes With Antimuscarinic Activity (2) Phenothiazine Antipsychotic Agents –Chlorpromazine –Thioridazine –Perphenazine –Others.: DEMONSTRATION.: DEMONSTRATION

Drugs of Other Classes With Antimuscarinic Activity (3) Dibenzodiazepine antipsychotic agents –Clozapine –Olanzepine Dibenzoxazepine antipsychotic agents –Loxapine.: DEMONSTRATION.: DEMONSTRATION

Drugs of Other Classes With Antimuscarinic Activity (4) H 1 Histamine receptor blocking agents –Diphenhydramine –Dimenhydrinate –Promethazine –Carbinoxamine –Dimenhydrinate –Pyrlamine –Tripelennamine –Brompheniramine –Chlorpheniramine –Cyproheptadine.: DEMONSTRATION.: DEMONSTRATION