Cholinoceptor-activating & Cholinesterase-inhibiting drugs

Overview Drugs affecting the ANS are divided into two groups according to the type of neuron involved in the mechanism of action: The cholinergic drugs: they act on receptors that are activated by acetylcholine (Ach) The adrenergic drugs: they act on receptors that are activated by norepinephrine or epinephrine Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS

Neurotransmission at cholinergic neurons Ca2+ Na+ Muscarinic Receptor ACh Choline Acetyltransferase Acetylcholinesterase Acetyl CoA + Acetylcholine Action Potential Choline α β Na+ H+ Nicotinic Receptor ACH Choline Acetate Choline Presynaptic neuron Postsynaptic target

Cholinergic Receptors (Cholinoceptors) Cholinoceptor denotes receptors that respond to acetylcholine Two families/subtypes of cholinoceptors were named after the alkaloids originally used in their identification: muscarinic (M) and nicotinic (N) receptors

I. Muscarinic (M) receptors These receptors, in addition to binding acetylcholine, also recognize muscarine, but show a weak affinity for nicotine These receptors have been found in organs innervated by parasympathetic nerves as well as on some tissues that are not innervated by these nerves, eg, endothelial, and on those tissues innervated by postganglionic sympathetic cholinergic nerves

I. Muscarinic (M) receptors Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5 have been identified Muscarinic receptors are G-protein coupled receptors (seven transmembrane domains) These receptors have different signal transduction mrchanisms based on the G-protein to which they are coupled

I. Muscarinic (M) receptors M1/M3/M5 activations stimulate IP3 and DAG. These receptors are primarily responsible for activating Ca+2-dependent responses, such as secretion by glands and the contraction of smooth muscle M2/M4 ativation inhibits adenylyl cyclase leading to decreased cAMP

II. Nicotinic (N) receptors These receptors, in addition to binding ACh, also recognize nicotine, but show a week affinity for muscarine N receptors are transmembrane polypeptide whose subunits form cation-selective ion channels N receptors are located on plasma membranes of postganglionic cells in all autonomic ganglia, of muscles innervated by somatic motor fibers (i.e. Neuromuscular junction), and of some CNS neurons

II. Nicotinic (N) receptors When the nicotnic AchR is stimulated, the channel opens and allows Na+ to rush into the cell This triggers depolarization of the cell and elicits a neruronal action potential (in postganglionic nerve) or nuscle contraction (in skeletal muscles) N receptors located at the neuromuscular junction are sometimes designated NM and the ganglionic (neuronal) receptors are designated NN

Subtypes and Characteristics of Cholinoceptors Receptor Type Other Names Location G protein Post-receptor Mechanism M1   Nerves Gq IP3, DAG cascade  M2 Cardiac M2 Heart, nerves, smooth muscle Gi  Inhibition of cAMP production, activation of K+ channels  M3 Glands, smooth muscle, endothelium M4 CNS Gi Inhibition of cAMP production M5 IP3, DAG cascade NM Muscle type, end plate receptor Skeletal muscle neuromuscular junction None Na+, K+ depolarizing ion channel NN  Neuronal type, ganglion receptor CNS postganglionic cell body, dendrites

Sympathatic innervation of adrenal medulla Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems Sympathatic innervation of adrenal medulla Sympathatic Parasympathatic Somatic Ganglionic transmittion NN receptor Adrenal medulla NN receptor NN receptor Neuroeffector transmittion Acetylcholine Norepinephrine Effector organ α or β Adrenergic receptor Effector organ M receptor Neuromuscular junction NM receptor

Cholinergic drugs Nonselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function Selectivity of action is based on several factors: Receptor selectivity: muscarinic vs. nicotinic Pharmacokinetic selectivity: using appropriate routes of administration so that desired effects can often be achieved while while minimizing systemic effects

Cholinomimetic agents Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces Include agents that act directly (cholinoceptor agonists/stimulants) or indirectly acting mechanisms (cholinesterase inhibitors)

Neurotransmission at cholinergic neurons Ca2+ Na+ Muscarinic Receptor ACh Choline Acetyltransferase Acetylcholinesterase Acetyl CoA + Acetylcholine Action Potential Choline α β Na+ H+ Nicotinic Receptor ACH Choline Acetate Choline Presynaptic neuron Postsynaptic target

Direct acting cholinergic stimulants

Direct acting cholinergic stimulants Cholinergic receptor agonists mimic the effects of ACh by binding directly to cholinoceptors They differ in their spectrum of action (muscarnic vs. nicotinic stimulation) and in their pharmacokinetics

Cholinomimetic agents The directly acting cholinomimetics can be subdivided into: Parasympathomimetic drugs: agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuro-effector junctions Agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction

Direct acting cholinergic stimulants These agents can be divided into two groups: Choline esters (acetylcholine, metacholine, carbachol, & bethanechol) Naturally occurring cholinomimetic alkaloids (muscarine, nicotine, pilocarpine, & lobeline)

Direct acting cholinergic stimulants Pharmacokinetics Choline esters Poorly absorbed and poorly distributed into the CNS because they are hydrophilic and susceptible to esterase hydrolysis in the GIT Methacholine is more resistant to hydrolysis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action

Direct acting cholinergic stimulants Pharmacokinetics Natural cholinomimetic alkaloids Tertiary amines (pilocarpine, nicotine, lobeline) is well absorbed from most sites of administration, and it can cross the BBB Quaternary amine (Muscarine) is less completely absorbed from the GIT than the tertiary amines but is toxic when ingested and it even enters the brain

Muscarinic agonists: Parasympathomimetics Cholinergic receptor agonists (also called acetylcholine-like agonists) mimic the effects of ACh by binding directly to cholinoceptors They show relatively few selectivity for M2/M4 vs. M1/M3/M5

Acetylcholine chloride Pharmacology of acetylcholine-like agonists Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action Acetylcholine chloride ++++ +++ Carbachol Negligible ++ Methacholine + None Bethanechol Muscarine Pilocarpine

Direct acting cholinergic stimulants Organ system effect Cardiovascular system ACh has four primary effects on the cardiovascular system: Vasodilation* Decrease in heart rate (negative chronotropic effect)** Decrease in the conduction velocity in the atrioventricular (AV) node (negative dromotropic effect)** Decrease in the force of cardiac contraction (negative inotropic effect)** * activation of endothelial M3 ** activation of M2 receptors

Direct acting cholinergic stimulants Organ system effect Eye Muscarinic agonists cause contraction of the smooth muscle of the: Iris sphincter*: resulting in miosis Ciliary muscle*: resulting in accommodation of the eye for near vision * activation of M3 receptor

Direct acting cholinergic stimulants Organ system effect Other Organ Systems Respiratory system*: bronchoconstriction & increase tracheobronchial secretion GIT***: stimulation of salivation and acid secretion, increased intestinal tone and peristaltic activity, and relaxation of most sphincters Genitourinary tract: stimulation of the detrusor muscle* and relax the trigone and sphincter muscles of the bladder**, thus promoting urination * M3 activation ** M2 activation ***M2 and M3 activation

Direct acting cholinergic stimulants Organ system effect Other Organ Systems Miscellaneous Secretory Glands*: stimulation secretion by thermoregulatory sweat, lacrimal, and nasopharyngeal glands CNS: Muscarinic agonists are able to produce marked CNS owing to activation of M1- receptors in the brain areas involved in cognition * M3 activation

Clinical uses of the direct acting cholinomimetics Glaucoma: cholinomimetics reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor (e.g pilocarpine and carbachol) Bladder and bowel atony after surgery: Bethanechol Xerostomia associated with Sjögren's syndrome and that caused by radiation damage of the salivary glands: pilocarpine & cevimeline

Toxicity Potentially severe adverse effects can result from systemic administration of cholinomimetic drugs and the comsumption mushrooms of the genus Inocybe (Muscarine) Overdosage is characterized chiefly by exaggeration of the various parasympathomimetic effects: NVD, urinary urgency, salivation, sweating, hypotension with reflex tachycardia, cutaneous vasodilation, and bronchial constriction

Toxicity Pilocarpine can cross the BBB and affect cognitive function especially among the elderly Cholinomimetics elicit miosis and spasm of accommodation, both of which disturb vision Treatment consists of the parenteral administration of atropine in doses sufficient to cross the BBB and measures to support the respiratory and CV systems and to counteract pulmonary edema

Nicotinic drugs Drugs that modulate nicotinic receptors have very limited application because of the localization of these receptor subtypes Pharmacological stimulation of ganglionic neuronal receptors (NN) has limited utility because this receptor affect both branches of the ANS The tissue and organ effect depend on the autonomic innervation of the organ involved

Nicotinic drugs Excessive stimulation of NM receptors can cause depolarization block: loss of electrical excitability due to inactivation of voltage-gated sodium channels If repeated doses of the agonist is used, the nicotinic cholinergic receptors can quickly become desensitized leading to fasciulations and paralysis

Nicotinic drugs In the brain, the α4β2 oligomer is the most abundant nicotinic receptor in the brain Activation of α4β2 nicotinic receptors is associated with greater release of dopamine in the mesolimbic system: mild alerting action and the addictive property of nicotine absorbed from tobacco

Nicotinic drugs Sustained desensitization may contribute to the benefits of nicotine replacement therapy in smoking cessation regimens In high concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center At still higher levels, nicotine causes convulsions, which may terminate in fatal coma

Nicotinic drugs Direct acting nicotine agonists have no therapeutic applications exept in smoking sessation (nicotine and varenicline) and producing skeletal muscle paralysis (succinylcholine)

Nicotin replacement therapy To help patients stop smoking Available in the form of gum, transdermal patch, nasal spray, or inhaler Sustained desensitization of α4β2 receptors in the CNS and reduces the desire to smoke and the pleasurable feelings of smoking

Varenicline (Chantix®) Is a partial agonist at α4β2 nicotinic receptors Varenicline prevents the stimulant effect of nicotine at presynaptic α4β2 receptors that causes release of dopamine ADRs: nausea, insomnia, and exacerbation of psychiatric illnesses, including anxiety and depression

Indirect acting cholinomimetics

Indirect acting cholinomimetics Acetylcholinesterase (AChE) is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its action Inhibitors of AChE indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine in synapses where acetylcholine is released physiologically (i.e. they have both muscarinic and nicotinic effets)

Indirect acting cholinomimetics There are three chemical groups of cholinesterase inhibitors: Simple alcohols bearing a quaternary ammonium group, eg, edrophonium Carbamates (eg, neostigmine) Organophosphates (eg, echothiophate)

Therapeutic Uses and Durations of Action of Cholinesterase Inhibitors Approximate Duration of Action Alcohols Edrophonium Myasthenia gravis, ileus, arrhythmias 5–15 minutes Carbamates and related agents Neostigmine Myasthenia gravis, ileus 0.5–2 hours Pyridostigmine Myasthenia gravis 3–6 hours Physostigmine Glaucoma Ambenonium 4–8 hours Demecarium 4–6 hours Organophosphates Echothiophate 100 hours

Indirect acting cholinomimetics The anti-ChE agents potentially can produce all the following effects: Stimulation of muscarinic receptor responses at autonomic effector organs Stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions) Stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS

Indirect acting cholinomimetics Organ system effect Central nervous system (CNS) In low concentrations, the lipid-soluble cholinesterase inhibitors cause diffuse activation on the electroencephalogram and a subjective alerting response In higher concentrations, they cause generalized convulsions, which may be followed by coma and respiratory arrest

Indirect acting cholinomimetics Organ system effect Eye, Respiratory Tract, GIT, & Urinary Tract The effects of the cholinesterase inhibitors are qualitatively quite similar to the effects of the direct-acting cholinomimetics

Indirect acting cholinomimetics Organ system effect Neuromuscular junction Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction At higher concentration, with marked inhibition of acetylcholinesterase, depolarizing neuromuscular blockade occurs and that may be followed by a phase of nondepolarizing blockade (i.e. nicotinic receptors can quickly become desensitized)

Clinical uses of the indirect acting cholinomimetics Glaucoma: physostigmine, demecarium, echothiophate, isoflurophate Gastrointestinal and Urinary Tracts: Neostigmine is most commonly used anticholinesterase agents in the treatment of adynamic ileus and atony of the urinary bladder, both of which may result from surgery

Clinical uses of the indirect acting cholinomimetics Myasthenia gravis Anticholinesterase agents help to alleviate the weakness by elevating and prolonging the concentration of ACh in the synaptic cleft, producing a greater activation of the remaining nicotinic receptors Anticholinesterase agents play a key role in the diagnosis and therapy of myasthenia gravis, because they increase muscle strength

Clinical uses of the indirect acting cholinomimetics Myasthenia gravis Carbamates (Pyridostigmine, neostigmine , and ambenonium): anticholinesterase agents used in the long-term therapy for myasthenia gravis Edrophonium (IV) is used for the diagnosis of myasthenia gravis and in differentiating myasthenic crisis from cholinergic crises (adequecy of treatment)

Clinical uses of the indirect acting cholinomimetics Antimuscarinic Drug Intoxication To treat overdoses of drugs with antimuscarinic actions, such as atropine Physostigmine (cholinesterase inhibitor) has been used for this application because it enters the CNS and reverses the central as well as the peripheral signs of muscarinic blockade

Clinical uses of the indirect acting cholinomimetics Alzheimer’s Disease Tacrine, donepezil, rivastigmine, & galantamine are approved for the palliative treatment of Alzheimer’s disease These agents can cross the BBB to produce a reversible inhibition of AChE in the CNS They produce modest but significant improvement in the cognitive function of patients with mild to moderate Alzheimer’s disease, but they do not delay progression of the disease

Toxicity Major cause of toxicity is accidental intoxication from the use pesticide use in agriculture and in the home With increasing inhibition of AChE and accumulation of ACh, the first signs are muscarinic stimulation, followed by nicotinic receptor stimulation and then desensitization of nicotinic receptors CNS symptoms include agitation, dizziness, and mental confusion (compounds of extremely high lipid solubility)

Toxicity Excessive inhibition can ultimately lead to a cholinergic crisis that includes: GIT distress: NVD & excessive salivation Respiratory distress: bronchospasm & increased bronchial secretions CV distress: bradycardia Visual disturbance: miosis, blurred vision Sweating Loss of skeletal motor function: progressing through incoordination, muscle cramps, weakness, fasciculation, and paralysis