Cholinergic Pharmacology

Choline is accumulated in cholinergic presynaptic nerve endings via an active transport mech-
anism linked to a Na'  pump.

Choline uptake  is inhibited by hemicholinium. ACh is synthesized from choline and acetyl-CoA
via choline acetyltransferase (ChAT)  and accumulated  in synaptic vesicles.

Presynaptic membrane depolarization opens voltage-dependent Ca2+  channels, and  the influx
of  this ion causes fusion of  the synaptic vesicle membranes with the presynaptic membrane,
leading to exocytosis of ACh. Botulinum toxin interacts with synaptobrevin and other proteins
to prevent ACh release.

Some cholinergic nerve endings have presynaptic autoreceptors  for ACh that on activation may
elicit a negative feedback of  transmitter  release.
Inactivation via  acetylcholinesterase  (AChE)  is  the major  mechanism  of  termination of
postjunctional  actions of ACh.
AChE is a target for  inhibitory drugs  (indirect-acting cholinomimetics). Note that such drugs
can influence cholinergic function only at innervated sites where ACh is released.
Reversible AChE  inhibitors include edrophonium, physostigmine,  and neostigmine. Irreversible
AChE inhibitors include echothiophate, malathion, and parathion.
Postjunctional receptors  (N and M)  activated by ACh  are major  targets for  both activating
drugs (direct-acting cholinomimetics) and cholinoceptor blocking agents.
Cholinomimetics
Nicctinic: nicotine
Muscarinic: bethanechol, methacholine, pilocarpine
Cholinoceutor Blockers
Nicotinic (NN):  hexamethonium, mecamylamine
Nicotinic (NM):  tubocurarine, atracurium, succinylcholine
Muscarinic: atropine, benztropine, glycopyrrolate, scopolamine .

Table  Muscarinic Receptor Activation

Target	Receptor			Response
Eye                  Sphincter                                                  Ciliary muscle	M3 M3			Contraction-miosis Contraction-accommodation for near vision
Heart                SA  node                            AV node	M2 M2			↓ Heart rate  (HR)-negative  inotropy ↓Conduction velocity-negative dro- motropy No effects on ventricles, Purkinje system
Lungs                 Bronchioles                                Glands	M3                                                              M3			Contraction-bronchospasm Secretion
GI tract             Stomach                           Glands                          Intestine	M3 M1 M3			↑ Motility-cramps Secretion Contraction-diarrhea,involuntary defecation
Bladder	M3			Contraction  (detrusor), relaxation (trigonelsphincter), voiding, urinary  incontinence
Sphincter	M3			Relaxation, except lower esophageal,  which contracts
Glands		M3	Secretion-sweat (thermoregulatory), salivation, and lacrimation
Blood vessels		M3	Dilation (via NOIendothelium-derived  relaxing factor)-no  innervation, no  effects of  indirect agonists

 Nicotinic receptor activation

Target	Receptor			Response
Adrenal medulla		Nn	Secretion of epinephrine and NE
Autonomic ganglia		Nn	Stimulation-net  effects depend on PANSISANS innervation and dominance
Neuromuscular junction		Nm	stimulation-twitchihyperactivity  of skeletal muscle

TOXICITY OF AChE INHIBITORS

Long-acting irreversible  inhibitors  (both carbamates and organophosphates) have wide use in
agriculture  as  insecticides.  Malathion  and  parathion  are  pro-drugs  rapidly bioactivated  by
insect P450 to form AChE  inhibitors, which covalently bond to serine hydroxyl  groups at the
esteratic site of the enzyme. Such bioactivation occurs only slowly by human P450; nonetheless,
these insecticides may  cause human  toxicity with symptoms of cholinergic excess via activation
of both M and N receptors.

Acute Toxicity

Acute toxicity includes pupillary constriction, stimulation of GI tract (cramps,  nausea, vomiting,
and diarrhea  [NVD])  and urinary tract (incontinence, urination),  bronchoconstriction  (wheez-
ing, dyspnea),  increased glandular secretions (sweating, salivation,  lacrimation),  bradycardia and
hypotension, skeletal  muscle  fasciculations  and  then paralysis  (e.g.,  respiratory muscles), and
CNS effects (behavioral excitation, depression of cardiovascular  [CV] and respiratory centers).

Management

M blockers such as atropine (enters CNS), plus pralidoxime (2-PAM), may regenerate AChE,
particularly at the skeletal neuromuscular junction (NMJ).  Because time-dependent "aging" of
the phosphorylated enzyme may decrease the effectiveness of the regenerator, 2-PAM should be
used ASAP.

Chronic Toxicity

Chronic toxicity of AChE inhibitors: peripheral nerve demyelination with both muscle weak-
ness and sensory loss 

Classic Clue
AChE inhibitor poisoning:
Dumbbelss ,Diarrhea ,Urination,Miosrs ,Bradycardia ,Bronchoconstriction,Excitation  (Muscle and CNS) ,
Lacrlmatlon ,Salivation ,Sweating .


MUSCARINIC RECEPTOR ANTAGONISTS (PARASYMPATHOLYTICS)

Atropine,  the Prototype

Atropine is the prototype of  the class. As  a tertiary amine, it enters CNS, where it acts as an M
receptor antagonist.

Other M blockers differ mainly in their pharmacolunetic properties, which can influence their
clinical uses.

Pharrnacologic Effects

Atropine effects in order of  increasing dose are:
Decreased secretions (salivary,  bronchiolar, sweat)
Mydriasis  and cycloplegia
Hyperthermia (with resulting vasodilation)
Tachycardia
Sedation
Urinary retention and constipation
Behavioral excitation and hallucinations

Toxicity

Overdose of M  blockers: Poisoning most commonly  follows excessive  ingestion of over-the-
counter (OTC) antihistamines and  cold medications, or  attempts  to induce hallucinations.
Note that M-blocking side effects (and possible toxicity) occur with both tricyclic antidepres-
sants and phenothiazines. Management is largely symptomatic, although physostigmine can be
useful and may counter both peripheral and central effects.

 Clinical Uses and/or Characteristics of M Blockers 




NICOTINIC RECEPTOR ANTAGONISTS

Ganglion Blocking Agents 

Effects

Ganglion blocking agents are competitive antagonists at NN  receptors on cell bodies in auto-
nomic ganglia.

Effects are predictable, knowing ANS innervation to effectors and relative dominance  in terms
of PANS and SANS. Net effect of  a ganglion blocker is to reduce the predominant tone.





Drugs
Hexamethonium-prototype with no clinical use.

Mecamylamine-used  in severe hypertension,  for controlled hypotension  in  surgery, and for
smoking cessation.

Physiologic Effects

Ganglion blockers prevent ANS reflexes,  including changes  in heart rate elicited by increases or
decreases in mean blood pressure. This characteristic can be of value  in questions of drug  iden-
tification because it helps to determine if  a drug action  (e.g., on heart rate) is direct or due to
an autonomic reflex response.

Example: Hexamethonium will block the reflex bradycardia  that occurs when phenylephrine
(an alpha-adrenoceptor  agonist)  causes vasoconstriction,  but  it will not block  a bradycardia
that results from the direct activation by ACh of M receptors in the heart.

SKELETAL NMJ BLOCKERS
See CNS section.

Nondepolarizing

These  act  as  competitive antagonists at  NM receptors at muscle  end  plate.  Drugs include
tubocurarine, atracurium, and pancuronium.

Depolarizing

These act as agonists at NM  receptors. They induce initial fasciculation, then paralysis through
persistent membrane depolarization. Succinylcholine  is a drug in this class.