ANS pharma chapter 2

Question 1

acetylcholine-like effects (cholinomimetics) consist of 2 major subgroups on the basis of their mode of action

(ie, whether they act directly at the acetylcholine receptor or
indirectly through inhibition of cholinesterase).

Answer 1

Acetylcholine may be considered the prototype that acts
directly at both muscarinic and nicotinic receptors. Neostigmine
is a prototype for the indirect-acting cholinesterase inhibitors.

Question 2

Muscarinic agonists are parasympathomimetic; that is, they mimic
the actions of parasympathetic nerve stimulation in addition to other
effects.

Answer 2

Nicotinic agonists act on both ganglionic

or neuromuscular cholinoceptors; agonist selectivity is limited.

Question 3

Muscarinic mechanisms—Muscarinic receptors are G protein-
coupled receptors (GPCRs)

Answer 3

Gq protein coupling of M1 and M3 muscarinic receptors to phospholipase C, a membrane-bound enzyme, leads to the release of the second messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate
(IP3).

Question 4

DAG modulates the action of protein kinase C, an enzyme

important in secretion, whereas IP3

Answer 4

evokes the release of calcium
from intracellular storage sites, which in smooth muscle results in
contraction.

Question 5

M2 muscarinic receptors couple to adenylyl cyclase
through the inhibitory Gi
-coupling protein.

Answer 5

INHIBITORY MECHANISM
couples the same M2 receptors via the βγ subunit of the G protein
to potassium channels in the heart and elsewhere; muscarinic
agonists facilitate opening of these channels.

M4 and M5 receptors
may be important in the central nervous system (CNS)

Question 6

NICOTINIC MECHANISM

Answer 6

nicotinic acetylcholine receptor
is located on a channel protein that is selective for sodium and
potassium. When the receptor is activated, the channel opens
and depolarization of the cell occurs as a direct result of the
influx of sodium, causing an excitatory postsynaptic potential
(EPSP). If large enough, the EPSP evokes a propagated action
potential in the surrounding membrane. The nicotinic receptors
on sympathetic and parasympathetic ganglion neurons (NN, also
denoted NG) differ slightly from those on neuromuscular end
plates (NM).

Question 7

vasodilation is not a parasym-
pathomimetic response (ie, it is not evoked by parasympathetic

nerve discharge, even though directly acting cholinomimetics cause

vasodilation).

Answer 7

results from the release of endothe-
lium-derived relaxing factor (EDRF; nitric oxide and possibly other

substances) in the vessels, mediated by uninnervated muscarinic
receptors on the endothelial cells.

Question 8

reflex, resulting in strong com-
pensatory sympathetic discharge to the heart. As a result, injections

of small to moderate amounts of direct-acting muscarinic cholino-
mimetics often cause tachycardia, whereas parasympathetic (vagal)

nerve discharge to the heart causes bradycardia.

Answer 8

Another effect seen
with cholinomimetic drugs but not with parasympathetic nerve

stimulation is thermoregulatory (eccrine) sweating; this is a sympa-
thetic cholinergic effect

Question 9

The blood vessels are dominated by sympathetic inner-
vation; therefore, nicotinic receptor activation results in vasocon-
striction mediated by sympathetic postganglionic nerve discharge.

Answer 9

gut is dominated by parasympathetic control; nicotinic drugs

increase motility and secretion because of increased parasympa-
thetic postganglionic neuron discharge.

Question 10

clinical conditions benefit from an increase in cholinergic

activity

Answer 10

, including glaucoma,Sjogren’s syndrome, and loss of normal

PANS activity in the bowel and bladder.

Question 11

Direct-acting nicotinic
agonists are used in smoking cessation and to produce skeletal muscle
paralysis

Answer 11

succinylcholine

Question 12

Indirect-acting agents are

used when increased nicotinic activation is needed at the neuromus-
cular junction

Answer 12

Nicotine and

related neonicotinoids are used as insecticides despite reported toxic
effects on bee colonies.Varenicline is a newer nicotinic agonist with
partial agonist properties. It appears to reduce craving in persons
addicted to nicotine through a nonautonomic action.

Question 13

AMANITA POISONING

Answer 13

mushrooms (Inocybe species and Amanita mus-
caria) and are responsible for the short-duration type of mushroom

poisoning, which is characterized by nausea, vomiting, and diar-
rhea.

dangerous and potentially lethal form of

mushroom poisoning from Amanita phalloides and related species
involves initial vomiting and diarrhea but is followed by hepatic
and renal necrosis. It is not caused by muscarinic agonists but by
amanitin and phalloidin, RNA polymerase inhibitors.)

Question 14

indirect-acting cholinomimetic drugs have been
synthesized in 2 major chemical classes: carbamic acid esters(carbamates) and phosphoric acid esters (organophosphates).
member: edrophonium is an alcohol
(not an ester) with a very short duration of action.
These drugs are acetylcholinesterase (AChE) inhibitors. Neo-
stigmine is a prototypic carbamate, whereas parathion, an impor-
tant insecticide, is a prototypic organophosphate.

Answer 14

inhibitors bind to cholin-
esterase and undergo prompt hydrolysis. The alcohol portion of

the molecule is then released. The acidic portion (carbamate ion
or phosphate ion) is released much more slowly from the enzyme
active site, preventing the binding and hydrolysis of endogenous
acetylcholine. As a result, these drugs amplify acetylcholine effects
wherever the transmitter is released.

Question 15

edrophonium

Answer 15

Edrophonium, though not an
ester, has sufficient affinity for the enzyme active site to similarly
prevent access of acetylcholine for 5–15 min. After hydrolysis,
carbamates are released by cholinesterase over a period of 2–8 h.
Organophosphates are long-acting drugs; they form an extremely

stable phosphate complex with the enzyme. After initial hydroly-
sis, the phosphoric acid residue is released over periods of days to

weeks. Recovery is due in part to synthesis of new enzyme.

Question 16

Clinical Uses

Answer 16

The clinical applications of the AChE inhibitors are predictable
from a consideration of the organs and the diseases that benefit
from an amplification of cholinergic activity. These applications
are summarized in the Drug Summary Table. Carbamates,
which include neostigmine, physostigmine, pyridostigmine,
and ambenonium, are used far more often in therapeutics than
are organophosphates. The treatment of myasthenia is especially
important. (Because myasthenia is an autoimmune disorder,
treatment may also include thymectomy and immunosuppressant

drugs.) Rivastigmine, a carbamate, and several other cholinester-
ase inhibitors are used exclusively in Alzheimer’s disease. A por-
tion of their action may be due to other, unknown mechanisms.

Although their effects are modest and temporary, these drugs are
frequently used in this devastating condition. Some carbamates

(eg, carbaryl) are used in agriculture as insecticides. Two organo-
phosphates used in medicine are malathion (a scabicide) and

metrifonate (an antihelminthic agent).
Edrophonium is used for the rapid reversal of nondepolarizing

neuromuscular blockade (Chapter 27), in the diagnosis of myas-
thenia, and in differentiating myasthenic crisis from cholinergic

crisis in patients with this disease. Because cholinergic crisis can

result in muscle weakness like that of myasthenic crisis, distin-
guishing the 2 conditions may be difficult. Administration of a

short-acting cholinomimetic, such as edrophonium, will improve
muscle strength in myasthenic crisis but weaken it in cholinergic

Question 17

therapeutic uses, some AChE inhibitors
(especially organophosphates) have clinical importance because
of accidental exposures to toxic amounts of pesticides. The most
toxic of these drugs (eg, parathion) can be rapidly fatal if exposure

is not immediately recognized and treated.

Answer 17

tion of vital signs (see Chapter 58), the antidote of first choice

is the antimuscarinic agent atropine, but this drug has no effect
on the nicotinic signs of toxicity. Nicotinic toxicity is treated by
regenerating active cholinesterase.

Question 18

Immediately after binding to
cholinesterase, most organophosphate inhibitors can be removed
from the enzyme by the use of regenerator compounds such as
pralidoxim (see Chapter 8), and this may reverse both nicotinic
and muscarinic signs. If the enzyme-phosphate binding is allowed
to persist, however, aging (a further chemical change) occurs and
regenerator drugs can no longer remove the inhibitor.

Answer 18

antihelminthic agents; examples are malathion
and parathion. Some of these agents (eg, malathion, dichlorvos)
are relatively safe in humans because they are metabolized rapidly
to inactive products in mammals (and birds) but not in insects.

Some are prodrugs (eg, malathion, parathion) and must be metab-
olized to the active product (malaoxon from malathion, paraoxon

from parathion). The signs and symptoms of poisoning are the

same as those described for the direct-acting agents, with the fol-
lowing exceptions: vasodilation is a late and uncommon effect;

bradycardia is more common than tachycardia; CNS stimulation
is common with organophosphate and physostigmine overdosage

and includes convulsions, followed by respiratory and cardiovas-
cular depression. The spectrum of toxicity can be remembered

with the aid of the mnemonic DUMBBELSS (diarrhea, urination,
miosis, bronchoconstriction, bradycardia, excitation [of skeletal
muscle and CNS], lacrimation, and salivation and sweating).