Cholinergic antagonists Samuel Aguazim ( MD)

What are cholinergic antagonists? Drugs that bind to cholinergic receptors ( muscarinic and/or nicotinic), but do not trigger the usual intracellular response. The antagonize the effects of acetylcholine

Name 3 subclasses of cholinergic antagonists. 1. Muscarinic blockers 2. Neuromuscular blocking agents- inhibit the efferent impulses to skeletal muscle via the nicotinic muscle receptor (Nm) 3. Ganglionic blockers- inhibit the nicotinic neuronal receptor (Nn) of both parasympathetic and sympathetic ganglia

Muscarinic antagonists Give six examples of muscarinic blockers 1. atropine 2. scopolamine 3. homatopine 4. cyclopentolate 5. tropicamide 6. pirenzepine

Anti- muscarinic agents sites of action 1. Secretions by salivary, bronchial and sweat glands. 2. The eye and cardiac responses mediated by the vagus. 3. Urinary bladder and GI tract. 4. Gastric secretions. Note: All of the muscarinic antagonists are competitive antagonists for the binding of acetylcholine to the muscarinic receptor

Naturally occurring Atropine ( belladonna ) Scopolamine Homatropine

The effect and side effects of these drugs are the opposite of the drugs considered in the previous chapter Eye: Mydriasis, cyclopedia ( blurred vision) Skin : Reduced sweating, flushing GI: Reduced motility and secretions CVS: Increased Heart Rate ( High Doses) Respiratory : Bronchial Dilation and decreased secretion GU: Urinary retention CNS: drowsiness, hallucinations, coma

ATROPINE – high affinity for muscarinic receptors. acts both centrally and peripherally It causes reversible, nonselective blockade of muscarinic receptors. Mydriasis, cycloplegia. Eneuresis in children Low doses- bradycardia. High doses—tachycardia Dilates cutaneous vasculature

Atropine uses In ophthalmology – mydriatic/ cycloplegic Spastic disorders of GI and lower urinary tract. To treat Organophosphate poisoning To suppress respiratory secretions prior to surgery.

Synthetic quaternary ammonium antimuscarinic agents. Ipratropium Propantheline

Synthetic tertiary amine muscarinic antagonists Cyclopentolate Tropicamide Dicyclomine Pirenzipine

CNS Due to its greater lipid solubility, scopolamine has significant CNS effects even at low therapeutic doses. An adjunct for anesthesia due to an ability to decrease short term memory. Motion sickness (scopolamine) Antipsychotic therapy: used to treat the extrapyramidal symptoms

Eye Mydriasis Refract the eye during ophthalmic examinations. Caution : glaucoma

Heart Low doses initially produce bradycardia, but later doses produce tachycardia. Some times in Surgery/catheterization

Lung Broncho -dilation: Ipratropium Mainly used as inhalation in treating asthma and COPD. Atropine prior to surgery will decrease the respiratory secretions

GI tract Salivary secretions decrease Can cause dry mouth and difficulty in swallowing Only Pirenzepine has some potency to decrease hyperacidity..

Other uses With an opioid to relax the ureter in renal colic. To increase the capacity and decrease the frequency of bladder contractions, i.e. enuresis in children. To decrease the frequency of urination in spastic paraplegia.

Toxic effects decreased concentration and memory drowsiness sedation excitation ataxia asynergia disorientation hallucinations coma

ATROPINE PSYCHOSIS Disorientation, confusion, recent loss of memory, agitation, incoherent speech, restlessness, hallucinations, anxiety and delirium. Treatment – symptomatic only and discontinue the drug immediately.

Therapeutic uses of muscarinic antagonists 1. Premedication · Atropine · Given before operations to prevent unwanted M stimulation. · Want to eliminate bronchial secretions (don't want the patient to choke on their own secretions) · Want to block vagal stimulation to the heart and lungs (want to keep airways open) · During induction of anesthesia, there may be excessive vagal stimulation, which we want to eliminate.

Anticholinesterase toxicity Toxicity due to over dose of physostigmine and other anticholinesterases Atropine is used to treat this condition by blocking all M receptors.

2. Antispasmodic · Hyoscine N butyl Bromide · A quaternary derivative · Treats colic 3. Bronchodilator (asthma) · Ipratropium · A quaternary derivative · Given by inhalation, get a local effect

Homatropine · Much shorter action than atropine · It is the drug of choice when doing investigations of the eye, since it dilates the pupil for a short time only.

4.Treatment of peptic ulcers · Pirenzepine · Selective M1 antagonist · Not as good as H2 antagonists (e.g. cimetidine ) or proton pump inhibitors (e.g. omeprazole)

5. Parkinson's disease · Benztropine, trihexiphenidyl also used to treat the extrapyramidal symptoms due to Antipsychotic drugs 6. Motion sickness · Hyoscine, scopolamine

ADVERSE EFFECT OF ATROPINE DRY MOUTH INHIBITION OF SWEATING ESPECIALLY IN YOUNG CHILDREN TACHYCARDIA AND CUTANEOUS VASODILATION BLURRING OF VISION HALLUCINATIONS AND DELIRIUM

MUSCARINIC EFFECTS REMEMBER S --- salivation L --- lacrimation U --- urination D --- diaphoresis G --- GI E --- Eye & emesis

GANGLIONIC BLOCKERS NICOTINE TRIMETHAPHAN MECAMYLAMINE Ganglionic blockers work by interfering with the postsynaptic action of acetylcholine. They block the action of acetylcholine at the nicotinic receptor of all autonomic ganglia. These drugs are very rarely used clinically

SITE OF ACTION ALL NICOTINIC RECEPTORS IN ANS ( BOTH SNS AND PNS ) IN CNS

NICOTINE DOSAGE LOW DOSE HIGH DOSE GANGLION STIMULATION BLOCK

CNS/ NICOTINE LOW DOSE- EUPHORIA,RELAXATION HIGH DOSE- central respiratory paralysis hypotension- medullary paralysis

PERIPHERAL EFFECTS COMPLEX HR RAISES B.P.- RAISES GIT- MOTILITY RAISES

OTHERS TRIMETHAPHAN- SHORT ACTING HTN EMERGENCIES used in surgery, particularly neurosurgery, to produce a relatively bloodless operative field (controlled hypotension).

MECAMYLAMINE- LONG ACTING CHR. CASES of HTN

Neuromuscular Blocking Drugs They block the effects of acetylcholine by interacting with nicotinic receptor. Mainly during surgery to produce complete muscle relaxation, without giving higher anesthetic doses.

Neuro muscular blocking drugs Atracurium Doxacurium Mivacurium Pancuronium Rocuronium Succinylcholine Tubocurarine Vecuronium

Atracurium safe in renal failure, used in critically ill patients for mechanical ventilation. Short duration of action – so suitable for short surgical procedures.

Rocuronium & Succinylcholine Rapid onset of action – so used mainly in tracheal intubation in patients with gastric contents. Vecuronium – short duration of action, so used in short surgical procedures.

Imp side effects Tubocurarine – induce histamine release and also lower B.P. Pancuronium – Increased H.R. Succinylcholine – malignant hyperthermia, hyperkalemia and increased Intraocular pressure.