[03.10a] Cholinergics V2.2.pdf

Cholinergics

Drugs that either activate choline receptors or inhibit cholinesterase

Cholinomimetics

Another name for Cholinergic Drugs

Cholinesterase

The enzyme that destroys acetylcholine

Muscarinic or Nicotinic

The two types of acetylcholine receptors

Autonomic Nervous System (ANS) and Central Nervous System (CNS)

Where muscarinic or nicotinic receptors are found

Neuromuscular Junction (NMJ; skeletal muscles)

Where nicotinic receptors are found

Cholinoreceptors or cholinoceptors

Other names for acetylcholine receptors

Acetylcholine

The main neurotransmitter for muscarinic and nicotinic receptors

Agonists and Antagonists

What alter the quaternary structure of the receptor to either activate or inhibit it

Anticholinergics

Drugs that are direct inhibitors of cholinergic receptors

G-protein linked

The type of receptors muscarinic receptors are

IP3, DAG cascade

The secondary messenger mechanism activated by M1, M3, and M5 muscarinic receptors

Decreasing cAMP

The pathway activated by M2 and M4 muscarinic receptors

CNS, autonomic ganglia in organs innervated by parasympathetic nerves, some tissues innervated by postganglionic sympathetic cholinergic nerves

Locations where muscarinic receptors are found

Nerves (CNS), Salivary glands, Parietal cells

Locations of M1 receptors

CNS excitation, memory, locomotor activity, gastric acid secretion

Effects of M1 receptor activation

Heart

Location of M2 receptors

Gi/o-linked (with activation of K+ channels)

Mechanism of M2 receptors

Decrease in heart rate, decrease in force, decrease in AV conduction

Effects of M2 receptor activation

Glands (exocrine), Smooth muscle, Endothelium

Locations of M3 receptors

Smooth muscle contraction, vasodilatation, glandular secretion

Effects of M3 receptor activation

CNS

Location of M4 receptors

CNS

Location of M5 receptors

Ion channel-linked

The type of receptors nicotinic receptors are

Sodium channels

What N1 and N2 nicotinic receptors activate to depolarize effector organs

Postganglionic cells in all autonomic ganglia, skeletal muscles

Where nicotinic receptors are found

Skeletal muscle, NMJ

Location of NM or N1 nicotinic receptors

CNS, Postganglionic cell body, Dendrites, Autonomic ganglia, Adrenal medulla

Location of NN or N2 nicotinic receptors

Skeletal muscle effects

The predominant effect of a nonselective cholinergic drug due to its preferential binding to NMJ over ganglia

Pharmacokinetic Selectivity

Achieved by altering the route of administration for more specificity and no systemic effects

Topical medicine

The form of administration for muscarinic or cholinergic effects in the eye to achieve pharmacokinetic selectivity

Acetylcholine

The cholinergic neurotransmitter

Nerve, heart and smooth muscle, glands and endothelium

Where muscarinic receptors are found

Neuromuscular end plate, skeletal muscle, autonomic ganglion cells, CNS

Where nicotinic receptors are found

Direct-acting Drugs

Drugs that act directly on receptors to activate them

Alkaloids and Choline esters

The two kinds of direct-acting cholinergic drugs based on chemical structure

Indirect-acting Drugs

Drugs that inhibit acetylcholinesterase

Reversible (simple alcohols, carbamates) and Irreversible (organophosphates)

The two types of indirect-acting cholinergic drugs based on reversibility and structure

Lobeline, Muscarine, Nicotine, Pilocarpine (LMNP)

The four direct-acting alkaloid cholinomimetics

Acetylcholine, Methacholine, Carbachol, Bethanechol (CHOL)

The four direct-acting choline esters

Methacholine

The choline ester misspelled as "Metacholine" in Figure 5

Hydrophilic

The characteristic of choline esters that makes them poorly absorbed in the CNS and have little CNS toxicity

Hydrolyzed in the GI tract

How choline esters are processed in the digestive system

Acetylcholine chloride

The choline ester highly susceptible to cholinesterase

Carbachol and Bethanechol

The choline esters with negligible susceptibility to cholinesterase, making them more resistant and longer lasting

Beta-methyl group

The chemical group in some choline esters that reduces potency at NM and NN receptors, leading to no nicotinic action

Methacholine (acetyl-β-methylcholine) and Bethanechol (carbamoyl-β-methylcholine)

Methylated choline esters that have no nicotinic action

Acetylcholine and Carbachol

Choline esters that can bind to both muscarinic and nicotinic receptors

Bethanechol

The preferred choline ester for systemic administration to have fewer side effects, as it affects muscarinic receptors

Naturally occurring cholinomimetic drugs

What alkaloids are

Pilocarpine, Lobeline, Nicotine, Muscarine

Examples of alkaloid cholinomimetic drugs

Well-absorbed from most sites (except Muscarine) and chiefly excreted by the kidneys

Pharmacokinetic properties of most alkaloids

Acidic

The condition of urine that accelerates the clearance of alkaloids

Lipid-soluble and absorbed by the skin

Pharmacokinetic properties of Nicotine

Nicotine patches

An example of nicotine administration through the skin

Less completely absorbed but still toxic when ingested

Pharmacokinetic property of Muscarine

Poisonous mushrooms (Amanita muscaria)

A source of Muscarine

MUscarine, Pilocarpine (MuPasa)

Alkaloids with chiefly muscarinic actions

Nicotine, Lobeline (NaLa)

Alkaloids with chiefly nicotinic actions

Activating muscarinic receptors on effector cells and modulating effects of the ANS and NANC systems

The two pharmacodynamic mechanisms of cholinomimetics

ACh interacting with muscarinic receptors on nerve terminals to inhibit the release of their neurotransmitters

Example of ACh modulating ANS effects

Gq

The G-protein linked to M1 and M3 receptors

IP3 and DAG

Secondary messengers that increase calcium concentrations when M1 and M3 are activated

Release of calcium from smooth endoplasmic reticulum, opening of smooth muscle calcium channels

Mechanisms of increased intracellular calcium

Increases cellular cGMP, increases potassium (K+) flux across cardiac cell membranes, decreases K+ flux in ganglion and smooth muscle cells

Other effects of M1 and M3 activation

Gi and Gq

The G-proteins linked to M2 and M4 receptors, respectively, with M4 being Gi/o in other sources

Inhibit adenylyl cyclase activity, decrease cAMP, modulate increase in cAMP levels induced by hormones, reduced physiologic response

Effects of M2 and M4 activation

Activation of potassium (K+) channels

Mechanism of Gi-linked M2 and M4 receptors

Bradycardia

The effect of large doses of ACh on heart rate

M2 receptors

The receptors that mediate bradycardia due to large doses of ACh

Activate K+ channels, inhibit cAMP production, decrease slow inward Ca current (ICa), reduction in hyperpolarization-activated current

Mechanisms of M2-mediated bradycardia

Na, K, Ca (sometimes)

Ions whose channels open upon nicotinic receptor activation

Depolarization of the nerve cell or neuromuscular end plate membrane

The result of nicotinic receptor activation

Muscle contraction

The result of ACh binding to nicotinic receptors, depolarization, Na entry, and action potential

Contraction (Miosis)

Direct-acting cholinomimetic effect on the sphincter muscle of the iris

Contraction of near vision (Accommodation)

Direct-acting cholinomimetic effect on ciliary muscles

Increase aqueous outflow

Direct-acting cholinomimetic effect related to ciliary muscle contraction

Decrease heart rate (Negative Chronotropy)

Direct-acting cholinomimetic effect on the SA Node

Decrease in contractile strength (Negative Inotropy) and decrease in refractory period

Direct-acting cholinomimetic effects on the Atria

Decrease in conduction velocity (Negative Dromotropy) and increase in refractory period

Direct-acting cholinomimetic effects on the AV Node

Small decrease in contractile strength

Direct-acting cholinomimetic effect on Ventricles

Dilation (via EDRF/NO) and Constriction (high-dose direct effect)

Direct-acting cholinomimetic effects on Blood Vessels

Reduction of PVR and reduced BP (M3)

The result of vasodilation in blood vessels

Contraction (Bronchoconstriction) and Secretion

Direct-acting cholinomimetic effects on Bronchial muscle and glands

Increase in motility, relaxation of sphincters, stimulation of secretion

Direct-acting cholinomimetic effects on the GI Tract

Contraction of detrusor and relaxation of trigone/sphincter

Direct-acting cholinomimetic effects on the Urinary Bladder

Secretion

Direct-acting cholinomimetic effect on Sweat, Salivary, Lacrimal, Nasopharyngeal Glands

Parasympathetic nervous system (rest and digest)

The ANS division activated by direct-acting cholinoreceptor stimulants

Bronchoconstrictive effect

The effect of cholinomimetics on lungs

Methacholine

The cholinomimetic used in bronchoprovocation tests

Edrophonium

An example of a simple alcohol indirect-acting cholinomimetic

Neostigmine, Pyridostigmine, Physostigmine

Examples of carbamate indirect-acting cholinomimetics

Organophosphate (organic derivatives of phosphoric acid)

The type of indirect-acting cholinomimetics considered deadly

Malathion, Parathion

Organophosphates found in pesticides and chemical warfare drugs

Echothiophate

An organophosphate that can be clinically used due to being less poisonous

Hydroxyl (-OH) group

The group present in Edrophonium

Carbamic acids esters of alcohols

The chemical structure of carbamates

Poorly absorbed in conjunctiva, skin, gut, and lungs

Absorption characteristic of quaternary carbamates

Negligible CNS distribution

Characteristic of quaternary carbamates due to poor lipid solubility

Physostigmine and Carbaryl

Carbamates that are exceptions to negligible CNS distribution due to their lipid solubility