Anti-cholinergic Drugs or Cholinergic AntagonistsHazel Anne L. Tabo

Review: Prototype Cholinergic Drugs Choline esters: Acetylcholine Direct Cholinomimetic alkaloids: Pilocarpine for glaucoma Indirect Cholinomimetics: 1. Reversible anticholinesterase: Physostigmine, Neostigmine 2. Irreversible anticholinoesterase: Isofluorophosphate

Effects on organs systems: Cholinergic Drugs A. Muscarinic receptors 1. smooth muscles (eye, GIT, respiratory, urinary bladder, blood vessels) 2. heart decreased activity (rhythm, contraction) 3. exocrine glands increased secretion (lacrimal, nasal, salivary, sweat) B. Nicotinic receptors 1. autonomic ganglia nicotinic I 2. adrenal medulla nicotinic I 3. neuromuscular end plate nicotinic II *CNS (+) muscarinic & nicotinic receptors

Anticholinergic DrugsI. Antimuscarinic Drugs1.A. Naturally-occurring Belladona alkaloids 1.B. Semisynthetic compounds 1.C. Synthetic substituents

II. Ganglionic blocking agents III. Neuromuscular blockers

I. Antimuscarinic drugs (MOA) 1. Naturally-occurring Belladona alkaloids1.1 Atropine 1.2 - Scopolamine

2. Semisynthetic compounds &2.1 Quarternary ammonium derivatives 2.2 Tertiary amine

Synthetic substituents3.1 Quarternary ammonium derivatives 3.2 Tertiary amine

Belladona plantsAtropa belladona Atropine

Datura metel Scopolamine

I. Anti-muscarinic: Atropine Name was derived from Atropos (Gk. Myth), chooses how a person was to die. dl-Hyoscyamine (from Atropa belladona, Deadly nightshade; Datura stramonium, Jimsonweed; Mandragora officinarum, mandrake) MOA: competitively binds to muscarinic receptors and non-drowsiness (cannot pass through BBB) unlike scopolamine Tx: In asthmatics, blocks the gland secretions In eyes: longer duration (72h)

Scopolamine Hyoscine (from Hyoscyamus niger, Henbane; D. metel, Metel plant) MOA: similar to atropine but can cause drowsiness & amnesia Used in twilight sleep mothers in labor by eliminating the memory of pain by attacking the brain functions of proprioception & control; mimic Alzheimers dementia (memory loss) Its discovery led to analogues like Diphenhydramine (antihistamine)

Mechanisms of Action & effectAtropine Scopolamine

Antimuscarinic activity Duration of effect

Competitive antagonist competitive antagonist of muscarinic receptors at muscarinic receptors specifically M1 Effect would vary max. 72 hrs (eyes) Does not pass through BBB (blood-barrier barrier); Nondrowsiness Effective up to 3 days

CNS effect

Motion sickness (dermal patch) confusion, agitation, rambling speech, hallucinations, paranoia, delusions

II. Semisynthetic compounds2.1 - Quarternary ammonium derivatives - Homatropine methylbromide - Methscopolamine bromide - Methylatropine nitrate Tx: GI and Genito-urinary bladder spasms 2.2 Tertiary amines - Homatropine hydrobromide Tx: as mydriatic (pupillodilator) & cycloplegic (paralysis of ciliary muscles) loss of visual accomodation

he iris contains two sets of musclesThe iris contains two sets of muscles (regulates light entry into the eye): 1. Dilator pupillae - a radial group for enlargement of the pupil. Stimulation: Noradrenergic receptors (sympathetic) 2. Sphincter pupillae - a circular group set to decrease pupil size on contraction. Stimulation: Muscarinic receptors (parasympathetic)

PharmacokineticsAbsorption absorbed from the eyes, GI tract, mucous membranes, skin distributed widely

Distribution

Metabolism & Excretion

slightly protein-bound (implications?) metabolized in the liver & kidneys

Pharmacodynamics & Therapeutics Can produce stimulating or depressing effects Used to treat spastic or hyperactive conditions of the GI and urinary tracts Treatment of nausea and motion sickness (scopolamine) Treatment of intestinal cramping Given before endoscopy (general depressant) Given before surgery to reduce oral, gastric and respiratory secretions (adjunct to narcotic painkillers) Prevent a drop in heart rate caused by vagal nerve stimulation during anesthesia Symptomatic sinus bradycardia and arrythmias caused by anesthesia Cycloplegic effects Antidote: organophosphate poisoning

III. Synthetic substituentsA. Quaternary ammonium derivatives (Muscarine) A.1 - Propantheline bromide - antispasmodic A.2 - Ipratropium bromide - bronchial asthma (inhalational) B. Tertiary amines (Physostigmine) B.1 Cyclopentolate, Tropriamide as mydriatic and cycloplegic B.2 Dicyclomine anti-spasmodic B.3 Trihexyphenidyl antiparkinsonism B.4 - Pirenzipine specific muscarinic blocker

Atropine: prototype drug Treatment for SLUDGE (Salivation, Lacrimation, Urination, Diaphoresis, Gastrointestinal motility, Emesis) - Organophosphate poisoning (DIFP). Treatment for DUMBBELSS (Diarrhea, Urination, Miosis, Bradycardia, Bronchoconstriction, Excitation (as of muscle in the form of fasciculations and CNS), Lacrimation, Salivation, and Sweating (only sympathetic innervation using Muscarinic receptors).

II. Ganglionic Blocking Agents Nicotinic I and II receptors 1. Persistent Depolarizing Blockers noncompetitive: Nicotine 2. Non-depolarizing Ganglionic Blockers competitive: later effect of Nicotine Effects: Sympathetic blockade Parasympathetic blockade

1. Persistent Depolarizing (non-competitive) Ganglionic Blockers Nicotine Lobeline Tetraethylammonium (TEA) Dimethylphenylpiperazinium

2. Nondepolarizing (competitive) Ganglionic Blockers A. Quaternary ammonium compounds 1. Hexamethonium 2. Trimethaphan camsylate most useful 3. Pentolinium tartrate 4. Tetraethylammonium chloride B. Secondary amines 1. Mecamylamine HCl 2. Pempidine chloride

Effects 1. Referred sympathetic blockade 2. Referred parasympathetic blockade

Referred sympathetic blockade Hypotension low BP Anhidrosis (decreased perspiration) Sexual dysfunction

Referred parasympathetic blockade Xerostomia dryness of mouth Mydriasis pupillodilation Cycloplegia paralysis of pupillary dilators: loss of visual accomodation Tachycardia fast cardiac activity Constipation slow intestinal motility Urinary retention low urine output

III. Neuromuscular Blockers 1. Depolarizing blockers 1.A. Succinylcholine - prototype 1.B. Decamethonium 2. Non-depolarizing blockers 2.A. d-Tubocurarine - prototype 2.B. Pancuronium bromide 2.C. Vecuronium bromide 2.D. Atracurium besyclate

Mechanism of Action: Succinylcholine Phase I or Depolarizing block - efflux of K+ (opening of Na+ channels) Phase II or Desensitization block - continuous depolarization in time - longer duration

Effects of Succinylcholine Skeletal muscle Eye extraocular muscles Hyperkalemia (high potassium in blood) Others: CVS, GIT

MOA: d-Tubocurarine Non-depolarizing neuromuscular blocker competes with nicotinic receptor site Effects: Histamine release (vasodilation) - cutaneous flush (face & arms) - bronchospasm - hypotension (reflex tachycardia) High-dose Ganglionic block

Clearance of Curarine drugs Excreted in urine as unchanged forms (d-tubocurarine, pancuronium bromide, vecuronium bromide) Low excretion in urine: Atracurium besylate Hofmann elimination and ester hydrolysis in the plasma Hofmann elimination - is a temperature- and pH-dependent process, and therefore atracurium's rate of degradation in vivo is highly influenced by body pH and temperature: an increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process.