Direct cholinergic agonists

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Transcript Direct cholinergic agonists

Cholinergic agonists & Cholinergic antagonists
Adrenergic agonists & Adrenergic antagonists
Part I. Cholinergic agonists cholinergic agonists
2.cholinesterase inhibitors.
two main targets of drug action: the postsynaptic receptor
and the acetylcholinesterase enzyme, which breaks down
direct-acting cholinergic agonists have a direct action on
the receptor for acetylcholine. Some drugs are specific for
the muscarinic receptor; others are specific for the nicotinic
The indirect-acting cholinomimetics act by blocking the
metabolism of acetylcholine by cholinesterases.
These drugs effectively increase the concentration of
acetylcholine at all cholinergic synapses.
The enzyme that is specific for acetylcholine is called
acetylcholinesterase, and it is found on both the pre- and
postsynaptic membranes.
There are other cholinesterases that also metabolize
acetylcholine and drugs with related structures. These other
cholinesterases are sometimes called pseudocholinesterases
or nonspecific cholinesterases, and they are abundant in the
Direct cholinergic agonists
1. esters: - structurally related to acetylcholine, e.g.
bethanechol (used in the treatment of urinary retention)
2. alkaloids: pilocarpine; muscarine
The effects of all of these agents are exclusive
side effects often listed for these drugs include sweating
(increased secretion), salivation, GI distress, and cramps
(due to increased motility).
Effects of Autonomic Nerves Activity on Organ Function
Effects of Autonomic Nerves Activity on Organ Function
nicotine is a direct agonist at nicotinic receptors. nicotine is
used therapeutically to help patients stop smoking.
Cholinesterase inhibitors
Reversible (water soluble e.g. Physostigmine, Neostigmine)
and irreversible inhibitors (lipid soluble e.g.
The reversible inhibitors include the quaternary amines
and the carbamates. They compete with acetylcholine for
the active site on the cholinesterase enzyme. This group
includes the drugs with names ending in "-stigmine" and "nium."
The irreversible inhibitors phosphorylate the enzyme and
inactivate it. These cholinesterase inhibitors are widely
used as insecticides e.g.: Parathion and are commonly
referred to as nerve gases e.g.Sarin .
Because the organophosphates are lipid soluble, they
rapidly cross all membranes, including skin and the bloodbrain barrier.
Pralidoxime (2-PAM) and Atropine are used to treat
poisoning with organophosphates
These drugs [reversible cholinestrease inhibitors] have all the
same actions (and side effects) as the direct acting drugs
(muscarinic). In addition, because they increase the
concentration of acetylcholine, they have effects at the
neuromuscular junction (nicotinic).
These drugs will cause the same side effects as the direct
cholinergic agonists.
They also affect nicotinic receptors, primarily at the
neuromuscular junction. This is the basis of their therapeutic
They cause fasciculations and weakness in normal people
and can improve muscle strength in patients with myasthenia
gravis. Myasthenia gravis is an immune disease in which
there is loss of acetylcholine receptors at the neuromuscular
junction, resulting in weakness and fatigability of skeletal
These drugs [reversible cholinestrease inhibitors] can
have effects on the cholinergic system in the CNS, if the
drug can cross the blood-brain barrier. The effects range
from tremor, anxiety, and restlessness to coma.
The organophosphates, because of their lipid solubility,
rapidly cross into the CNS.
Neostigmine, Pyridostigmine are used in the treatment of
myasthenia gravis. Other uses of the reversible
cholinesterase inhibitors are in the treatment of openangle glaucoma and the reversal of nondepolarizing
neuromuscular blockade after surgery (e.g. tubocurarine
but not succinylcholine).
Part II. Cholinergic antagonists
The prototypic muscarinic antagonist is Atropine.
All of the muscarinic antagonists are competitive antagonists
for the binding of acetylcholine to the muscarinic receptor.
Muscarinic antagonists are used preoperatively to reduce
secretions. [although sweating glands are enervated by
sympathetic nerves, ACh is the neurotransmitter and the
receptors is muscarinic.]
Scopolamine (also called hyoscine) is used to prevent
motion sickness.
Muscarinic antagonists e.g. oxybutynin are used for urinary
frequency, urgency caused by bladder overactivity.
Ganglionic blockers: they block the action of Ach at
the nicotinic receptor of all autonomic ganglia.
These drugs are very rarely used clinically.
Neuromuscular blockers:
The competitive neuromuscular blocking drugs are used to
produce skeletal muscle relaxation.
Succinylcholine is a depolarizing neuromuscular blocker.
Botulinum toxin blocks the release of acetylcholine at all
cholinergic synapses.
Tubocurarine: is among the drugs that compete with
acetylcholine for the receptor but do not initiate ion channel
Part III. Adrenergic agonists
Direct-acting Agonists
Epinephrine has a number of uses, including the treatment of
allergic reactions and shock.
The control of localized bleeding and the prolongation of the
action of local anesthetics.
Norepinephrine has a relatively low affinity for b2 receptors.
The main effect of al stimulation (with an agonist such as
phenylephrine) is vasoconstriction.
Local application of a vasoconstrictor to the nasal passages
decreases blood flow locally and decreases secretions, thus
acting as a nasal decongestant.
Dopamine- at low doses, Dopamine causes renal and
coronary vasodilation. At high doses, dopamine acts much
like epinephrine. It also activates b1 receptors in the heart.
Indirect-acting Agents
The indirect-acting sympathomimetic agents act by releasing
previously stored norepinephrine. Amphetamine and its
relative, methylphenidate, are central nervous ,stem
stimulants used to treat attention deficit hyperactivity
disorder in children.
Amphetamine and others of its relatives are indirect-acting
sympathomimetics that have been abused because of their
psychostimulant abilities.
Norepinephrine increases total peripheral resistance and
mean arterial pressure. Epinephrine predominantly affects
the heart through b1 receptors, causing an increase in heart
rate and cardiac output.
Isoproterenol causes a marked decrease in total peripheral
resistance and n increase in heart rate and cardiac output.
Part IV. Adrenergic antagonists
a2 Agonists reduce sympathetic nerve activity and are used
to treat hypertension. (clonidine)
most of the a antagonists allow vasodilation and thus,
decrease blood pressure.
The side effects of the a -blockers are directly related to
their a Blocking activity. All of` the a blockers are
reversible inhibitors of the a receptor. except
pheoxybenzamine, which is irreversible.
b-BLOCKERS- the b -blockers have widespread use in the
management of cardiac arrhythmias, angina, and
hypertension.e.g. propranolol
b1 Selective antagonists are often referred to as
cardioselective e.g. acebutolol.
b2 anatgonists causes contraction of smooth muscledangerous to asthma patients
The adverse effects of these drugs are, for the most part,
directly related to their b blocking abilities.
Some b -blockers are said to have intrinsic
sympathomimetic activity. This means they have partial
agonist activity, even though they are classified as b blockers.