Lecture 1: Introduction to Pharmacology

Cholinergic antagonistsAnticholinergic drugs(parasympatholytics)Pharmacology I/ ANS, Lecture 4 Dr. Hiwa K. Saaed, HD, MSc. PhDPharmacology & Toxicology

125 March 20142Drugs that block cholinergic receptors (M and/or N).

The actions of sympathetic stimulation are left unopposed.

Cholinergic antagonists

225 March 20143They are classified to two subclasses:Muscarinic (M1-M5) receptor antagonists: the most useful clinically.Nicotinic receptor antagonists: further subdivided to:

NMJ Blocking agents: inhibit the efferent impulses to skeletal muscle via the (NM) receptorGanglionic Blocking agents: inhibit the nicotinic neuronal receptor (NN) of both parasympathetic and sympathetic gangliaCholinergic antagonists3Sites of action of cholinergic antagonists25 March 20144

4Muscarinic antagonists:25 March 20145Atropine (prototype): comes from the plant Atropa belladonna and is known as a belladonna alkaloid. Belladonna in Latin means pretty lady. Inhibit all M functions.Scopolamine (hyoscine): Rx of motion sickness ; natural occurring alkaloidPropantheline, Dicyclomine: Rx of peptic disease, hypermotilityClidinium (Librax), isopropamide (stelabid), Mebeverine (Duspataline)Homatropine:Cyclopentolate, Tropicamide: mydriasis and cycloplegiaPirenzepine & telenzipine: Selective M1 blocker. Rx of Gastric ulcerOxybutinin: somewhat selective for M3 receptors

525 March 20146Trospium: nonselective comparable in efficacy and SE with oxybutininDarifenacin and Solifenacin: selective M3 blockerTolterodine: selective M3 blocker Rx of urinary incontinenceFlavoxate: also indicated for overactive bladderBenztropine: Rx of ParkinsonismIpratropium, Tiotropium: Rx of Asthma

*Imipramine a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in elderly

Muscarinic antagonists:6Atropine (hyoscyamine) Mechanism of action:25 March 20147It causes reversible, nonselective blockade of muscarinic receptors.Therefore, High concentration of Ach or an equivalent muscarinic agonists can be used to counteract the effects of atropine

7Pharmacologic actions of atropine25 March 20148CNS: at toxic doses can causerestlessness, hallucinations, and delusions.CVS: At low doses, atropine reduces heart rate through central stimulation of the vagus nucleus.At high doses, atropine blocks muscarinic receptors of the heart and thus induces tachycardia825 March 20149GIT: reduces salivary gland secretion and GI motility.Pulmonary system: reduces bronchial secretions and stimulates bronchodilation.Urinary system: blocks muscarinic receptors in the bladder wall, which results in bladder wall relaxation.Eye: causes paralysis of the sphincter muscle of the iris and ciliary muscle of the lens, resulting in mydriasis and cycloplegiaSweat glands: Suppresses sweating, especially in children.

Pharmacologic actions of atropine9Atropine effects in order of increasing dose25 March 201410Decreased secretions (Salivary, bronchiolar, sweat)Mydriasis and cycloplegiaHyperthermia (vasodilation)TachycardiaSedationUrinary retention and constipationBehavioral excitation and hallucinations

10Therapeutic uses of atropine25 March 201411BradycardiaMydriasis and cycloplegia- beneficial when a thorough fundus examination or an accurate refraction is required.NB: atropine contraindicated in a patients who has narrow-angle glaucoma, because this may result in acute crisis due to closure of the canal of SchlemmGIT and bladder spasms: organophosphate poisoning.11Pharmacokinetics25 March 201412Atropine as a tertiary amine, it is well absorbed from the GIT and conjunctival membrane. It is excreted through both hepatic metabolism and renal function. Atropines duration of action is ~ 4 hrs, except when it is placed in the eye, where it usually lasts about 14 days12Adverse effects25 March 201413Dry mouth (dry as bone) Inhibition of sweating especially in young children (hot as a hare)Tachycardia and coetaneous vasodilation (red as beet)Blurring of vision (blind as a bat)Hallucinations and delirium (mad as a hatter)

Urine retention13Scopolamine25 March 201414Like atropine, this drug is a belladonna alkaloid. But it has a longer duration of action and more potent CNS effect Nonselective competitive blockade of muscarinic receptorsTherapeutic uses: Prevention of motion sicknessAdverse effects: similar to those of atropine

Others:Homatropine, cyclopentolate & Tropicamide: In ophthalmology, they are given topically for mydriasis and cycloplegia.Pirenzepine: a selective M1 muscarinic inhibitor, used for treating gastric ulcers1425 March 2014

15152. Neuromuscular blocking agents25 March 2014

161625 March 201417

17NM blockers25 March 201418I. Nondepolarizing blocking agents (antagonists)Tubocurarine (prototype)Pancuronium: longer duration of actionAtracuriumVecuroniumII. Depolarizing blocking agents (agonists):Succinylcholine3-6 minutes if given as a single dose.Metabolized by plasma cholinesterase

18Mechanism of action: At low dose: these drugs competitively block cholinergic transmission at the nicotinic receptors by preventing the binding of Ach to its receptor.Their action can be reversed with edrophonium or neostigmine ????At high dose: block the ion channels of the end plate. This action can not be reversed by CE inhibitors.25 March 201419

I. Nondepolarizing NM blockersI. Nondepolarizing NM blockers25 March 201420All NM junction blockers must be given I.V because oral absorption is poor.Therapeutic use: They are used as adjuvant drugs for anesthesia- they promote muscle relaxation; the muscle of the eye and face are affected first, whereas the respiratory muscles are affected last.

20Sequence of Paralysis25 March 201421Fingers, orbit (small muscles)limbsTrunk neckIntercostalsDiaphragmRecovery in Reverse21II. Depolarizing NM junction blockers25 March 201422Succinylcholine: Mech. of action: Phase I- opens the Na channels-membrane depolarization-transient fasciculations. Flaccid paralysis will follow in a few minutesPhase II: the membrane partially repolarize. However, these receptors are now desensitized to Ach, Thus preventing the formation of further action potentials. In other words, is now acting in a manner similar to tubocurarine.

2225 March 201423As an adjuvant to GA to facilitate rapid intubation.Orthopedic procedures for alignment of fractures.In electroshock treatment of psychiatric disorders.Therapeutic Use23Drug InteractionCholinesterase inhibitors: can overcome the action of nondepolarizing neuromuscular blockersHalogenated hydrocarbon anesthetics: Drugs such as halothane sensitize the neuromusclular junction to the effects of neuromuscular blockers.Aminoglycoside antibiotics: inhibit Ach release from cholinergic nerves by competing with calcium ions. (Synergistic)Calcium-channel blockers: These agents may increase the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers.25 March 20142425 March 201425

2525 March 2014

26Adverse effects of NM blockers:25 March 201427Bronchoconstriction caused by histamine releaseDecreased tone and motility in GI tractDepolarizing agents can cause increased K+ efflux in patients with burns, trauma, or denervation and lead to hyperkalemiaHypotensionArrhythmiasApnea due to respiratory paralysis (check for psudocholinesterase genetic polymorphism)Malignant hyperthermia (succinylcholine+halothane especially); Rx by dantroline. It blocks the release of Ca+2 from the sarcoplasmic reticulum which subsequently reduces skeletal muscle contraction.Q. Do NM junction blocking agents block autonomic ganglia as well???

27Classification of BlockersAgentPharmacologicalPropertiesOnset time (min)Duration(min)EliminationSuccinylcholineUltra-short acting;Depolarizing1-1.56-8Plasma cholinesteraseD-tubocurarineLong duration;Competitive4-680-120Renal and liverAtracuriumIntermediate duration;Competitive2-430-40Plasma cholinesteraseMivacuriumShort duration;Competitive2-412-18Plasma cholinesterasePancuroniumLong duration;Competitive4-64-6Renal and liverRocuroniumIntermediate duration;competitive1-21-2Renal and liver25 March 201428283. Ganglionic blockers25 March 201429Nicotine, Hexamethonium, Mecamylamine, TrimethaphanGanglionic blockers compete with Ach to bind with nicotine receptors of both Parasympathetic and Sympathetic gangliaGanglionic blockers divided into two groups:Drugs such as nicotine, which initially stimulate the ganglia and then block them because of a persistent depolarizationDrugs such as hexamethonium, mecamylamine, and trimethaphan, which block ganglia without any prior stimulation.

2925 March 201430The physiologic effects of ganglionic blockers can be predicted depending on which division of the ANS exercises dominant control of the organ in question:

Heart: tachycardia results because the parasympathetic system is normally dominant on the heart.Arterioles and veins: vasodilation, increased peripheral blood (sympathetic normally dominant)

3. Ganglionic blockers3025 March 201431Eye: cycloplegia, mydriasis (parasympathetic normally dominant) GIT: reduced motility; diminished gastric and pancreatic secretions (parasympathetic normally dominant)Urinary system: urinary retention (parasympathetic normally dominant)Sweat glands: reduced sweating (sympathetic normally dominant)

3. Ganglionic blockers3125 March 201432Therapeutic useBecause they lack the selectivity, the ganglionic blockers very rarely used clinically. In the past, these drugs were used in hypertensive emergencies. 3. Ganglionic blockers32