PMCOL 343 - Drug Pathways

Cholinergic Agonists

• Muscarinic agonists are parasympathomimetic.

• Nicotinic agonists act in autonomic ganglia and skeletal muscle.

Choline Esters

• Choline esters include acetylcholine (ACh), carbachol, bethanechol, and methacholine.

• Drugs ending in “-chol” are parasympathomimetic.

• Choline esters are poorly absorbed from the GI tract.

• ACh and carbachol activate both nicotinic and muscarinic receptors.

Choline Esters - Drug Differences

• Bethanechol activates muscarinic receptors.

• Carbachol and bethanechol are not hydrolyzed by acetylcholinesterase.

• Methacholine is used as a challenge test for asthma.

• During the methacholine challenge, the lungs eventually react.

Muscarinic Agonists

• Muscarinic agonists include muscarine, oxotremorine, and pilocarpine.

• These drugs are parasympathomimetic.

• A useful memory tip is that these names end in “-rine”.

Muscarinic Agonists - Heart

• Muscarinic agonists slow the heart and decrease the force and rate of contraction.

• Effects seen in the whole person are complicated by reflexes.

Muscarinic Agonists - Blood Vessels

• Muscarinic agonists can cause endothelium-dependent dilation of blood vessels.

• M3 muscarinic agonists release nitric oxide (NO) from the endothelium.

• NO stimulates soluble guanylyl cyclase, producing cyclic GMP.

• Cyclic GMP relaxes vascular smooth muscle.

Muscarinic Agonists - Endothelium

• Muscarinic receptor effects can reverse vascular smooth muscle actions.

• Muscarinic agonists only affect blood vessels with intact endothelium.

• The vascular effect depends on M3 muscarinic receptors in endothelial cells.

• M3 activation releases NO, which causes vascular smooth muscle relaxation.

Muscarinic Agonists - Respiratory

• mAChR activation contracts bronchiole smooth muscle.

• mAChR activation increases secretion.

• These effects can exacerbate asthma.

Muscarinic Agonists - GI Tract

• mAChR activation increases secretion of saliva and stomach acid.

• mAChR activation increases GI motility and peristalsis.

Muscarinic Agonists - Bladder

• mAChR activation stimulates the detrusor muscle.

• mAChR activation relaxes the trigone and internal sphincter.

• These effects promote voiding of urine.

Nicotinic Agonists

• Nicotine is a nicotinic agonist.

Nicotine - CNS Effects

• Low levels of nicotine cause mild CNS stimulation.

• Higher doses cause emesis.

• The highest levels can cause coma.

• Nicotine can be used as an insecticide, causing insects to become overstimulated and paralyzed to death.

Nicotinic - Ganglia

• nAChR activation stimulates both sympathetic and parasympathetic branches of the ANS.

• Cardiovascular effects are sympathomimetic, including hypertension and cardiac stimulation.

• GI effects are parasympathomimetic, including increased secretion and motility.

Nicotine - Skeletal Muscle

• nAChR activation causes depolarization and excitation of skeletal muscle.

• Contractile responses range from disorganized fasciculation to strong contraction of the whole muscle.

• nAChRs are ion channels.

Anticholinesterases

• Anticholinesterases indirectly stimulate nicotinic and muscarinic receptors by preventing hydrolysis of ACh.

• Blocking cholinesterase leaves more ACh in the synapse, facilitating action potentials.

• Effects are similar to those of direct-acting cholinergic agonists.

• They can be used as insecticides, nerve gases, anti-glaucoma drugs, antidysrhythmics, and for memory enhancement in Alzheimer’s.

Anticholinesterases - Alcohols

• Simple alcohols include edrophonium.

• Edrophonium is reversible.

• Edrophonium is used therapeutically.

Anticholinesterases - Carbamates

• Carbamic esters of alcohols with quaternary or tertiary ammonium groups include neostigmine.

• Neostigmine is reversible.

• Neostigmine is used therapeutically.

Anticholinesterases - Organophosphates

• Organophosphates include malathion and soman.

• The molecular mechanism of action differs among the three groups of anticholinesterases.

Anticholinesterases - Absorption

• Anticholinesterases are well absorbed from the skin, gut, lungs, and conjunctiva.

• Many of their effects resemble those of direct-acting cholinergic agonists.

Anticholinesterases - Eyes

• Anticholinesterases cause miosis.

• They cause myopia.

• They decrease intraocular pressure.

Anticholinesterases - Respiration

• Anticholinesterases cause bronchiole constriction.

• They increase respiratory secretion.

Anticholinesterases - GI And Bladder

• Anticholinesterases increase gut motility.

• They stimulate the bladder.

Anticholinesterases - Heart

• Anticholinesterases cause bradycardia.

• They decrease cardiac output.

Anticholinesterases - Vascular Effects

• Vascular effects are dominated by increased sympathetic tone.

• This occurs through potentiation of cholinergic ganglionic transmission.

• There is little overall change in blood pressure.

Anticholinesterases - Neuromuscular

• Anticholinesterases increase strength of contraction.

• Higher concentrations cause muscle fasciculations by moving cells closer to firing.

• The highest concentrations cause depolarizing neuromuscular blockade.

Nerve Gas Poisoning

• Nerve gas or insecticide poisoning can cause cardiac arrest.

• It can cause fluid accumulation in the lungs and bronchoconstriction.

• It can block respiratory skeletal muscle contraction.

• These effects can produce respiratory failure.

Atropine - Nerve Gas

• Atropine can limit the effects of nerve gases.

• Atropine can stop many parasympathetic drug effects.

Cholinomimetic Uses

• Cholinomimetics can be used to treat glaucoma, urinary retention, and postoperative ileus.

• Glaucoma involves high intraocular pressure.

• Treatment of glaucoma allows fluid to leave the eye.

• Treatment can involve a muscarinic agonist or anticholinesterase.

Myasthenia Gravis

• Myasthenia gravis is an autoimmune disease involving decreased expression of nAChRs at the neuromuscular junction.

• It is characterized by weakness and fatigability.

• Difficulty opening the eyes can occur, and respiration may be affected.

• It resembles the neuromuscular block produced by D-tubocurarine.

Myasthenia Gravis - Treatment

• Anticholinesterases work better than direct-acting cholinergic agonists for myasthenia gravis.

Neuromuscular Blockers

• Neuromuscular blockers are nicotinic antagonists.

• Their main therapeutic use is producing paralysis during surgery.

• Examples include pancuronium and succinylcholine.

D-Tubocurarine

• The prototypic neuromuscular blocker was curare, specifically D-tubocurarine.

• D-tubocurarine is no longer used because better drugs are available.

α-Bungarotoxin

• α-Bungarotoxin is associated with nicotinic receptor blockade.

• It is listed with Strychnos toxifera.

Muscarinic Antagonists

• The prototypic muscarinic antagonist is atropine.

• Atropine is derived from Atropa belladonna, the deadly nightshade.

Antimuscarinics - Parkinson’s

• Parkinson’s disease is characterized by a relative excess of cholinergic activity and a lack of dopaminergic activity in the striatum.

• Antimuscarinic drugs can be used to control tremor associated with Parkinson’s disease.

Antimuscarinics - Motion Sickness

• Vestibular disturbances such as motion sickness involve muscarinic cholinergic effects.

• Scopolamine is used to treat motion sickness.

• Hair cells express M2, M4, and M5 activity.

• Excessive effects can cause sedation.

Antimuscarinics - Heart

• The heart is under parasympathetic tone.

• Blockers such as atropine increase heart rate and force of contraction.

• They also increase atrioventricular conduction.

Antimuscarinics - Respiratory

• Blocking parasympathetic tone in normal individuals causes slight bronchodilation.

• It also decreases mucus secretion.

• These effects are useful during surgery to attenuate mucus secretion in the lungs.

• Ipratropium is useful in chronic obstructive pulmonary disease (COPD).

Sympathomimetic Drugs

• Mimics the effects of the sympathetic nervous system in target tissues.

Direct Sympathomimetics

• Directly acting sympathomimetics are α- and/or β-adrenoceptor agonists.

• Examples include adrenaline, noradrenaline, and isoproterenol (isoprenaline or INA).

Indirect Sympathomimetics

• Indirectly acting sympathomimetics displace stored catecholamines from vesicles.

• Examples include amphetamine and tyramine.

• They can also inhibit catecholamine re-uptake.

• Examples include cocaine and tricyclic antidepressants.

Adrenoceptor History

• John Newport Langley introduced the idea of drug receptors in the autonomic nervous system.

• Sir Henry Dale advanced ideas of receptor antagonism and identified vasomotor reversal.

• Raymond Ahlquist identified α- and β-adrenoceptor subtypes.

Vasomotor Reversal

• Vasomotor reversal describes the rise and fall of sympathomimetic drug effects.

• α1 activation causes contraction through Gq.

• β2 activation causes relaxation through Gs.

α-Adrenoceptors - Agonist Affinity

• α-adrenoceptor agonist affinity is represented as αA ≥ N >> I.

• Another α-adrenoceptor relationship is αI > A ≥ N.

β1 Adrenoceptors

β1 adrenoceptors have equal affinity for adrenaline and noradrenaline.

β2 Adrenoceptors

• β2 adrenoceptors have a higher affinity for adrenaline than noradrenaline.

α1 Adrenoceptors

• α1 adrenoceptors are selectively blocked by prazosin.

• α1 adrenoceptors include α1A, α1B, and α1C subtypes.

α2 Adrenoceptors

• α2 adrenoceptors are selectively blocked by yohimbine.

• α2 adrenoceptors include α2A, α2B, and α2C subtypes.

Adrenoceptor Sensitivity

• α receptors are less sensitive to agonists than β receptors.

Adrenoceptor Selectivity

• α- and β-adrenoceptors differ in their selectivity for sympathomimetic agonists.

α1 Molecular Mechanism

• M3 muscarinic receptors relax vascular smooth muscle, whereas α1 adrenergic receptors contract it.

• Both receptors act through Gq-PLC and Ca2+.

• M3 muscarinic receptors on endothelial cells cause relaxation through release of NO.