CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE-INHIBITING DRUGS

I. Direct Acting (Receptor Agonist)1. Muscarinic

A. Choline estersAcetycholine BethanecholMetacholine Carbachol

B. AlkaloidsMuscarine Pilocarpine

2. NicotinicA. Ganglionic

Nicotine VareniclineLobelineDMPP (dimethylphenylpiperazinium)

B. NeuromuscularNicotine

II. Indirect-Acting (Cholinesterase Inhibitors)1. Reversible Edrophonium Carbamates

Neostigmine Pyridostigmine AmbenoniumPhysostigmine Demacarium

2. Irreversible Phosphates

Echothiopate ParathionIsoflurophate MalathionSoman (nerve gas) Sarin

CHOLINOMIMETIC DRUGS Mimic acetylcholine

1. Acetylcholine receptor stimulants2. Cholinesterase inhibitors

Classified by:1. Spectrum of action (type of receptor activated)

1. Muscarinic2. Nicotinic

2. Mechanism of action1. Direct-acting Bind/activate cholinoceptors2. Indirect-acting Inhibits the hydrolysis of endogenous Ach

DIRECT-ACTING CHOLINOMIMETIC DRUGS Divided on the basis of their chemical structure Directly bind to and activate muscarinic or nicotinic receptors Many have effects on receptors like ACh Classified as:1. CHOLINE ESTERS

Acetylcholine, Metacholine, Carbachol, Bethanechol2. ALKALOIDS

Muscarine and Nicotine

CHOLINE ESTERS Includes 4 important choline esters Contains permanently charged quaternary NH4 group Relatively insoluble in lipids Poorly absorbed, poorly distributed in the CNS Hydrophilic Hydrolyzed in the GIT Differ markedly in their susceptibility to hydrolysis by cholinesterase

ACETYLCHOLINE Very rapidly hydrolyzed Large amounts must be infused IV to achieve concentrations high enough to produce

detectable effects

METHACHOLINE Addition of methyl CH3

3x more resistant to hydrolysis compared to ACh

CARBACHOL and BETANECHOL Carbamic acid ester derivative of ACh More resistant to hydrolysis by cholinesterase Longer duration of effect Addition of beta-methyl group (Methacholine and Betanechol reduces the potency of these

drugs at nicotinic receptor sites)

2. ALKALOIDS Act mostly with muscarinic receptors (Muscarine, Pilocarpine) Act with nicotinic receptors (Nicotine, Lobeline) Well absorbed from most sites of administration Excreted chiefly by the kidneys Acidification of urine accelerates clearance of these amines

NICOTINE Naturally occurring plant alkaloid found in tobacco Liquid Sufficiently lipid-soluble to be absorbed across the skin

MUSCARINE Quaternary amine Less completely absorbed from the GIT Toxic when ingested Eg, in certain mushrooms, it even enters the brain

LOBELINE Plant derivative Similar spectrum of action to nicotine but lower potency

DIMETHYLPHENYLPIPERAZINIUM (DMPP) Synthetic ganglionic nicotinic stimulant with little CNS effects Used as a research tool

MECHANISM OF ACTION (MOA)

Acts on four classes of cholinergic synapse– Autonomic effector sites innervated by parasympathetic postganglionic fibers– Sympathetic and parasympathetic ganglion cells and adrenal medulla innervated by

preganglionic autonomic fibers– Motor end-plates– Certain CNS synapse

On muscarinic receptors: 1. Activation of IP3, DAG cascade (results to opening of Ca++ channels and release of Ca++ from ER and SR) 2. Increase cellular cGMP 3. Increase K+ flux across membranes 4. Inhibition of adenylyl cyclase (some tissues) 5. Increase cAMP production

On nicotinic receptors:1. Opening of cation channels (Na , K)

ORGAN SYTEM EFFECTS Most of the effects of muscarinic cholinoceptor stimulants are readily predicted

o Knowledge of parasympathetic nerve stimulation Effects of nicotinic agonists are also predictable

o Knowledge of the physiology of the autonomic ganglia and skeletal muscle motor end plate

1. EYE Instilled to the conjunctival sac Causes contraction of the sphincter muscle of iris (miosis) Causes ciliary muscle contraction (accommodation)

2. CVS Reduction in peripheral resistance and changes in heart rate

3. RESPIRATORY SYSTEM Contraction of the smooth muscles of the bronchial tree Stimulate glands of the tracheobronchial mucosa to secrete

4. GIT Similar to the parasympathetic nervous system stimulation Increase in the secretory and motor activity of the gut Stimulation of the salivary and gastric glands Increase in peristaltic activity Relaxation of sphincters

5. BLOOD VESSELS Endothelium Derived Relaxing Factor (EDRF) is released to produce dilation Dilation of arteries Dilation of veins Constriction (high-dose direct effect)

6. GUT Stimulate the detrussor muscle Relax the trigone and sphincter Promote voiding

7. GLANDS Stimulate the thermoregulatory sweat, lacrimal and nasopharyngeal glands

8. CENTRAL NERVOUS SYSTEM• Tremor, emesis, stimulation of the respiratory center, convulsions, coma (Nicotine effects)

9. PERIPHERAL NERVOUS SYSTEM• Same on both sympathetic and parasympathetic ganglia

10. NEUROMUSCULAR END-PLATE• Depolarization of end-plate resulting to muscle fasciculation and contraction

INDIRECT-ACTING CHOLINOMIMETIC DRUGS Primary effect by inhibiting acetylcholinesterase which hydrolyzes acetylcholine to choline and

acetic acid Increase endogenous ACh concentration Stimulates cholinoceptors to evoke increase response Parasympathetic effects Some have direct action at nicotinic receptors Chief difference of the group are chemical and pharmacokinetics 3 chemical groups:

1. SIMPLE ALCOHOLS Quaternary NH4 group 2 to10 minutes Reversible Edrophonium

2. CARBAMIC ACID ESTERS OF ALCOHOL Contains quaternary or tertiary NH4 group 30 minutes to 6 hours Reversible Carbamates

o Neostigmineo Physostigmine

Exception, lipid soluble3. ORGANIC DERIVATIVES OF PHOSPHORIC ACID

Highly lipid soluble Very long duration Irreversible Echothiophate

o Retains the very long duration of other organophosphates o More stable in aqueous solution

Parathion and malathion (Thiophosphates) o Used as insecticides

MECHANISM OF ACTION Inhibition of Acetlycholinesterase thereby increasing the concentration of endogenous

acetylcholine

ORGAN SYSTEM EFFECTS Primary action is to amplify the actions of endogenous Ach Effects are similar, but not always identical, to the effects of direct-acting cholinomimetics

1. CENTRAL NERVOUS SYSTEM• Low conc = Activation of the alerting response, High conc = convulsions, coma, respiratory arrest

2. CVS• Increase both sympathetic and parasympathetic response effects• Decrease in cardiac output, decrease atrial contractility

3. NEUROMUSCULAR JUNCTION• Contraction of muscle fibers

4. EYE, RESPIRATORY, GI, URINARY SYSTEM

• Parasympathetic effects

CLINICAL PHARMACOLOGY OF CHOLINOMIMETICS1. EYE

GLAUCOMAo Reduce intraocular pressure o Cause contraction of the ciliary body o Facilitate outflow of aqueous humor o Diminish its secretiono Pilocarpineo Echothiophate (long-acting effect)

2. GIT and GUT POSTOPERATIVE ILEUS URINARY RETENTION POST OP

o Clinical disorders that involve depression of smooth muscle activity without obstructiono Betanechol

3. NEUROMUSCULAR JUNCTION MYASTHENIA GRAVIS

o Disease affecting the skeletal muscles neuromuscular junctiono Autoimmune processo Production of antibodies that decrease the functional nicotinic receptors at the

postjunctional end plateso Cholinesterase inhibitors are used for therapyo Edrophonium (diagnostic test)o Neostigmine, Pyridostigmine (long term therapy)

4. HEART SUPRAVENTRICULAR TACHYCARDIA

o Treated by short-acting cholinesterase inhibitor (Edrophonium)o Replaced by newer drugs (Calcium channel blockers)

5. ANTIMUSCARINIC DRUG INTOXICATION ATROPINE INTOXICATION

o Lethal in children o Causes prolonged severe behavioral disturbances and arrhythmias in adults o Causes severe muscarinic blockadeo Physostigmine

Antidote to atropine poisoning6. CNS

ALZHEIMER’S DISEASEo Tacrine o Donepezil, Galantamine, and Rivastigmine (newer drugs)o With anticholinesterase activity o With cholinomimetic action o Used for therapy

SMOKING CESSATION

o Varenicline Some selectivity for the 42 isoform of the NN receptor Orally active Half-life of 14-20 hours Toxicity: nausea, headache, and sleep disturbances

TOXICITYDIRECT-ACTING MUSCARINIC STIMULANTS

Nausea and vomiting Diarrhea Salivation Sweating Cutaneous vasodilatation Bronchial constriction Excitation Lacrimation Blocked by atropine

DIRECT-ACTING NICOTINIC STIMULANTSACUTE TOXICITY

40 mg or 1 drop of pure liquid is fatal (2 cigarettes) Central stimulant action Convulsion Coma Respiratory arrest or paralysis Hypertension Arrhythmia Treatment is symptom directed

o Atropineo Anticonvulsants

CHRONIC TOXICITY Smoking Increased risk Vascular disease Peptic ulcers 60 % carcinogenic

CHOLINESTERASE INHIBITORSACUTE TOXICITY

Major source of intoxication is pesticide Organophosphates Treated with large doses of atropine

CHRONIC EXPOSURE Neuropathy Demyelination of axons