1. CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE-INHIBITING DRUGS
CHOLINOMIMETIC AGENTS:
CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE-INHIBITING DRUGS
Two types of classification:
By their spectrum of action depending on the type of receptor (muscarinic or nicotinic)
By their mechanism of action (direct acting or indirectly acting)

2. CHOLINOMIMETIC AGENTS:

3. SPECTRUM OF ACTION OF CHOLINOMIMETIC DRUGS
Cholinoceptors are either:
1. muscarinic (G protein-linked) or
2. nicotinic (ion channel)
Cholinoceptors are members of either G protein-linked (muscarinic) or ion channel (nicotinic) families;
Muscarinic receptors:
- Contain 7 transmembrane domains whose third cytoplasmic loop is coupled to G proteins
- In general, regulate the production of intracellular second messengers

4. In general, Muscarinic receptors regulate the production of intracellular 2nd messengers

6. Muscarinic receptors are located on:
plasma membranes of cells in the CNS,
in organs innervated by parasympathetic nerves (e.g. heart, smooth muscles, glands)
on some tissues that are not innervated by these nerves, eg, endothelial cells
on those tissues innervated by cholinergic postganglionic sympathetic nerves, e.g. sweat glands, blood vessels in skeletal muscles.
Selectivity of muscarinic receptors depends on receptor subtypes and the type of G proteins

8. Nicotinic receptors are located on:
on plasma membranes of parasympathetic and sympathetic postganglionic cells in all autonomic ganglia,
on membranes of muscles innervated by somatic motor fibers,
and in the central nervous system
Nicotinic receptors = part of a transmembrane polypeptide whose subunits form cation-selective ion channels

9. Postreceptor Mechanism
Subtypes and characteristics of cholinoceptors.
Receptor Type
Other Names
Location
Structural Features
Postreceptor Mechanism M1
M1a
Nerves
7 transmembrane segments, G protein-linked
IP3, DAG cascade M2
M2a, cardiac M2
Heart, nerves, smooth m.
↓cAMP,activation of K+ channels M3
M2b, glandular M2
Glands, smooth m., endothelium
m41
?CNS
↓ cAMP
m51

10. Subtypes and characteristics of cholinoceptors (cont’d)NM
Muscle type, end plate receptor
Skeletal muscle neuromuscular junction
Pentamer (α2βδγ)
Na+, K+ depolarizing ion channel NN
Neuronal type, ganglion receptor
Postganglionic cell body, dendrites
α and β subunits only as α2β2 or α3β3

11. Selectivity of drug action:
Selectivity of action based on several factors:
muscarinic receptors Vs. nicotinic receptors;
Some drugs stimulate nicotinic receptors at neuromuscular junctions preferentially/ less effect on nicotinic receptors in ganglia;
Pharmacokinetic selectivity: using appropriate routes of administration (e.g topical muscarinic stimulants to modulate ocular function)
Unselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function because acetycholine has multiple sites of action where it initiates both excitatory and inhibitory effects.
Fortunately, drugs available have a degree of selectivity, so that desired effects can be achieved while avoiding or minimizing adverse effects.
Selectivity of action based on several factors,
some drugs stimulate muscarinic receptors or nicotinic receptors;
Some drugs stimulate nicotinic receptors at neuromuscular junctions preferentially and have less effect on nicotinic receptors in ganglia;
Organ selectivity can also be achieved by using appropriate routes of administration (e.g topical muscarinic stimulants to modulate ocular function)

12. MODE OF ACTION OF CHOLINOMIMETIC DRUGS
Direct-acting agents directly bind to and activate cholinoceptors.
Indirect-acting agents: inhibit the action of AChE → the concentration of endogenous ACh ↑ in the synaptic clefts (amplifiers)
Neostigmine (1) activates neuromuscular nicotinic cholinoceptors directly in addition to (2) blocking cholinesterase

13. BASIC PHARMACOLOGY OF THE DIRECT-ACTING CHOLINOCEPTOR STIMULANTS

14. The direct-acting cholinomimetic drugs can be divided into:
- esters of choline (including ACh)
- alkaloids ( muscarine and nicotine).
A few of these drugs are highly selective for the muscarinic or for the nicotinic receptor.
Many have effects on both receptors (Ach)

15. Chemistry:
esters of choline are permanently charged and relatively insoluble in lipids - contain the quaternary ammonium group:
1) acetylcholine
2) methacholine
3) carbachol
4) bethanecol

16. Longer duration of action

17. Pharmacokinetics 1.The choline esters:
Poorly absorbed & poorly distributed into the CNS (hydrophilic);
All hydrolyzed in the GIT (and less active by the oral route);
Differ markedly in susceptibility to hydrolysis by cholinesteras, Ach: (5-20 sec),
Presence of the β-methyl group  ↓the potency of these drugs at the nicotinic receptor
Ach: very rapidly hydrolyzed; a large I.V.bolus injection has a brief effect, (5-20 sec), whereas I.M. & S.C. injections produce only local effects
Methacholine: 3 times more resistant to hydrolysis & produces systemic effects even when given SC.
The carbamic acid esters, carbachol and bethanechol: extremely resistant to hydrolysis by cholinesterase & have longer durations of action.
Presence of the β-methyl group (methacholine, bethanechol) ↓the potency of these drugs at the nicotinic receptor

18. Susceptibility to Cholinesterase
Properties of choline esters.
Choline Ester
Susceptibility to Cholinesterase
Muscarinic Action
Nicotinic Action
Acetylcholine chloride
++++
+++
Methacholine chloride +
None
Carbachol chloride
Negligible ++
Bethanechol chloride

19. Cholinomimetic alkaloids & synthetic analogs:
1) muscarine
2) nicotine
3) pilocarpine
4) lobeline

20. Structures of cholinomimetic alkaloids
TOXIC
Tertiary amines: better absorption and distribution
well absorbed from most sites of administration;
nicotine, a liquid, sufficiently lipid-soluble to be absorbed across the skin;
muscarine, a quaternary amine, less completely absorbed from the GIT than the tertiary amines but is nevertheless toxic when ingested, e.g. in certain mushrooms;
excretion of these amines is chiefly by the kidneys
oxotremorine , an extremely potent synthetic muscarinic agonist, has been used as a research tool. It is well distributed into the CNS.
lobeline, a plant derivative with less potency than nicotine but with a similar spectrum of action
Structures of cholinomimetic alkaloids

21. Mechanism of Action:
Activation of the parasympathetic nervous system modifies organ function by two major mechanisms:
ACh released can activate muscarinic receptors on effector organs;
ACh released can interact with muscarinic receptors on nerve terminals to inhibit the release of their neurotransmitter
2. By this mechanism, acetylcholine release and circulating muscarinic agonists
indirectly alter organ function by modulating the effects of the parasympathetic and sympathetic nervous systems and
perhaps nonadrenergic, noncholinergic (NANC) systems.

22. Result of activation of muscarinic receptors:
activation of the IP3, DAG cascade. DAG → opening of smooth muscle Ca channels; IP3 → release of Ca from endoplasmic and sarcoplasmic reticulum.
↑ cGMP.
↑ K+ flux across cardiac cell membranes and ↓ it in ganglion and smooth muscle cells (by binding of an activated G protein directly to the channel).
in some tissues (eg, heart, intestine) ↓adenylyl cyclase activity.

23. The mechanism of nicotinic receptor activation:
Nicotinic receptors NN and NM are ion channels
binding an agonist → channel opening → Na+ and K+ ions diffuse rapidly down their concentration gradients → depolarization of the postsynaptic membrane.
In case of prolonged agonist occupancy of the receptor, the effector response is abolished; ie, the postganglionic neuron stops firing-ganglionic effect-), and the skeletal muscle cell relaxes-neuromuscular endplate effect-
“depolarizing blockade”
Furthermore, continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane;
Thus, a state of “depolarizing blockade” is induced that is refractory to reversal by other agonists
This effect can be exploited for producing muscle paralysis.

26. Effects of direct-acting cholinoceptor stimulants
Effects of direct-acting cholinoceptor stimulants. Only the direct effects are indicated; homeostatic responses to these direct actions may be important.
Organ
Response
Eye
Sphincter muscle of iris
Contraction (miosis)
Ciliary muscle
Contraction for near vision (accomodation)
Heart
Sinoatrial node
Decrease in rate (negative chronotropy)
Atria
Decrease in contractile strength (negative inotropy). Decrease in refractory period
Atrioventricular node
Decrease in conduction velocity (negative dromotropy). Increase in refractory period
Ventricles
Small decrease in contractile strength
Blood vessels
Arteries
Dilation (via EDRF). Constriction (high-dose direct effect)
Veins

27. Effects of direct-acting cholinoceptor stimulants (cont’d)
Lung
Bronchial muscle
Contraction (bronchoconstriction)
Bronchial glands
Stimulation
Gastrointestinal tract
Motility
Increase
Sphincters
Relaxation
Secretion
Urinary bladder
Detrusor
Contraction
Trigone and sphincter
Glands
Sweat, salivary, lacrimal, nasopharyngeal
The trigone (a.k.a. vesical trigone) is a smooth triangular region of the internal urinary bladder formed by the two ureteral orifices and the internal urethral orifice. The area is very sensitive to expansion and once stretched to a certain degree, the urinary bladder signals the brain of its need to empty.

29. Organ System Effects 1. Eye- contraction of iris sphincter (miosis)
contraction of the ciliary muscle (accommodation).
the iris is pulled away from the angle of the anterior chamber→the trabecular meshwork at the base of the ciliary muscle is opened up → ↑outflow of aqueous humor into the canal of Schlemm (drains the anterior chamber)→ ↓ intraocular pressure (IOP)

31. Organ System Effects (cont’d)
The net effect on the heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness
2. Cardiovascular system (heart)
Primary effects of muscarinic agonists:
(1) ↓in peripheral vascular resistance & (2) changes in HR (all mediated by M2)
direct effects on heart rate are modified by homeostatic reflexes.
- I.V. infusions of of min effective dose of Ach (20-50 g/min) → vasodilation → ↓BP → reflex ↑in HR
- Larger doses of ACh → bradycardia and ↓ conduction velocity through the AV node in addition to ↓BP

32. Organ System Effects 2. Cardiovascular system (the vessels)
In the intact organism, muscarinic agonists produce marked vasodilation (EDRF (largely NO)  ↑ c-GMP)
Isolated blood vessels Ach contraction
In the intact organism, muscarinic agonists produce marked vasodilation. (needs intact endothelium for release of NO (endothelium-derived relaxing factor, or EDRF) → smooth muscle relaxation via activation of guanylyl cyclase and ↑ cGMP in smooth muscle;

33. Organ System Effects
Exception: Pilocarpine if given I.V. may produce hypertension after a brief initial hypotensive response.
The longer-lasting ↑ BP is due to sympathetic ganglionic discharge caused by activation of M1 receptors in the postganglionic cell membrane, which close K+ channels and elicit slow excitatory (depolarizing) postsynaptic potentials smooth muscle contraction ↑ BP
This effect can be blocked by atropine (antimuscarinic agent)
The cardiovascular effects of all the choline esters are similar to those of acetylcholine—the main difference being in their potency and duration of action. Because of the resistance of methacholine, carbachol, and bethanechol to acetylcholinesterase, lower doses given intravenously are sufficient to produce effects similar to those of acetylcholine, and the duration of action of these synthetic choline esters is longer. The cardiovascular effects of most of the cholinomimetic natural alkaloids and the synthetic analogs are also generally similar to those of acetylcholine.

34. Organ System Effects 5. Genitourinary tract
stimulation of detrusor muscle and relaxation of trigone and sphincter muscles of the bladder→↑voiding.
human uterus is not notably sensitive to muscarinic agonists.
6. Miscellaneous secretory glands: muscarinic agonists ↑secretion of thermoregulatory sweat, lacrimal, and nasopharyngeal glands

35. Organ System Effects 7. CNS
contains both muscarinic and nicotinic receptors,
Brain: mainly muscarinic sites
Spinal cord: mainly nicotinic sites.
However, nicotine has an effect on brain stem and cortex (what is it?)
in spite of that, nicotine and lobeline have important effects on the brain stem and cortex.

36. Nicotine effects on CNS:
The mild alerting action of nicotine absorbed from inhaled tobacco is best known of nicotine effects on brainstem and cortex
In higher concentrations → nicotine induces tremor, emesis, and stimulation of the respiratory center
At still higher concentrations→ convulsions and fatal coma

37. Organ System Effects (cont’d)
8. Peripheral nervous system
The autonomic ganglia are important sites of nicotinic synaptic action
Nicotinic agonists cause marked activation of these nicotinic receptors and initiate AP in postganglionic neurons
Nicotine itself has greater affinity for NN than for NM
The action is the same on both parasympathetic and sympathetic ganglia

38. Organ System Effects (cont’d)
8. Peripheral nervous system
In cardiovascular system, the effects of nicotine are chiefly sympathomimetic: IV injection of nicotine →↑BP & sympathetic tachycardia may alternate with a vagally mediated bradycardia.
In the GI and urinary tracts, the effects are largely parasympathomimetic: nausea, vomiting, diarrhea, voiding of urine
Prolonged exposure: depolarizing blockade of ganglia

39. Organ System Effects 9. Neuromuscular
nicotinic agonist applied directly → immediate depolarization of the neuromuscular endplate (  permeability Na+ & K+)→ contraction of muscle;
depolarizing nicotinic agents that are not rapidly hydrolyzed (eg, nicotine): rapid development of depolarization blockade; transmission blockade persists even when the membrane has repolarized (flaccid paralysis)
- flaccid: soft, lacking rigidity