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Pharma Sheet Dr.Muneer
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ANS / lec. 13
Bara’a Rawashdeh
Munir Gharaibeh
21/11/2012
Pharma Sheet Dr.Muneer
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Note: no need to refer to the slides ^_^
Chemistry & Pharmacokinetics:
• Tetraethylammonium (TEA)
– The first to be recognized as having this action, has a very short
duration of action.
• Hexamethonium:
– The first drug effective for management of hypertension.
• Decamethonium:
– The "C10" analog of hexamethonium, is a depolarizing
neuromuscular blocking agent.
• Mecamylamine:
– A secondary amine, was developed to improve absorption from the
gastrointestinal tract because the quaternary amine ganglion-
blocking compounds were poorly and erratically absorbed after oral
administration.
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• Trimethaphan A short-acting ganglion blocker, is inactive orally and is given
by intravenous infusion.
**Mechanism of Action:
• Ganglionic nicotinic receptors, like those of the skeletal muscle
neuromuscular junction, are subject to both depolarizing and
nondepolarizing blockade
• Nicotine itself and even acetylcholine (if amplified with a cholinesterase
inhibitor) can produce depolarizing ganglion block.
• Drugs now used as ganglion blockers are classified as nondepolarizing
competitive antagonists.
• However, hexamethonium actually produces most of its blockade by
occupying sites in or on the nicotinic ion channel, not by occupying the
cholinoceptor itself.
In contrast, trimethaphan appears to block the nicotinic receptor, not the channel
pore. Blockade can be surmounted by increasing the concentration of an agonist,
e.g. acetylcholine.
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Organ System Effects of Ganglionic Blockers
• Central Nervous System:
– Mecamylamine, crosses the blood-brain barrier and readily enters
the CNS. Sedation, tremor, choreiform movements, and mental
aberrations have been reported as effects of mecamylamine.
• Eye:
– Cycloplegia with loss of accommodation. Ganglionic blockade often
causes moderate dilation of the pupil because parasympathetic tone
usually dominates this tissue.
• Cardiovascular System:
– Ganglionic blockade causes a marked decrease in arteriolar and
venomotor tone. The blood pressure may fall precipitously because
both peripheral vascular resistance and venous return are decreased.
– Hypotension is especially marked in the upright position (orthostatic
or postural hypotension).
– Cardiac effects include diminished contractility and, because the
sinoatrial node is usually dominated by the parasympathetic nervous
system, a moderate tachycardia.
• Gastrointestinal Tract
– Secretion is reduced, Motility is profoundly inhibited, and
constipation can be marked.
• Other Systems
– Ganglionic blockade causes hesitancy in urination and may
precipitate urinary retention in men with prostatic hyperplasia.
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Sexual function is impaired in that both erection and ejaculation may
be prevented by moderate doses.
– Sweating is reduced by the ganglion-blocking drugs.
Response to Autonomic Drugs:
– Patients receiving ganglion-blocking drugs are fully responsive to
autonomic drugs acting on muscarinic, alpha , and beta adrenergic
receptors because these effector cell receptors are not blocked.
– In fact, responses may be exaggerated or even reversed e.g.
intravenously administered norepinephrine may cause tachycardia
rather than bradycardia), because homeostatic reflexes, which
normally moderate autonomic responses, are absent.
Clinical Applications & Toxicity of Ganglionic Blockers
• Ganglion blockers are used infrequently because more selective autonomic
blocking agents are available.
• Mecamylamine
– blocks central nicotinic receptors and has been advocated as a
possible adjunct with the transdermal nicotine patch to reduce
nicotine craving in patients attempting to quit smoking.
• Trimethaphan
– is occasionally used in the treatment of hypertensive emergencies
and dissecting aortic aneurysm; in producing hypotension, which can
be of value in neurosurgery to reduce bleeding in the operative field.
• The toxicity of the ganglion-blocking drugs is widespread because of
involvement of all the autonomic nervous system.
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• For most patients, these effects are intolerable except for acute use.
Sympathomimetics or Adrenergic Drugs:
These are the drugs which produce effects similar to the effects produced
by endogenously released adrenergic neurotransmitters.
These drugs can work at adrenergic receptors, as well as other sites of the
adrenergic neuron and can affect various steps of the life cycle of the
neurotransmitter.
Life Cycle of Norepinephrine:
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Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent
carrier (A).
Tyrosine is converted to dopamine , and transported into the vesicle by the vesicular
monoamine transporter (VMAT), which can be blocked by reserpine .The same carrier
transports NE and several other amines into these granules.
Dopamine is converted to NE in the vesicle by dopamine - - hydroxylase.
Physiologic release of transmitter occurs when an action potential opens voltage-
sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with
the surface membrane results in expulsion of norepinephrine, cotransmitters, and
dopamine - - hydroxylase.
Release can be blocked by drugs such as guanethidine and bretylium.
After release, norepinephrine diffuses out of the cleft or is transported into the
cytoplasm of the terminal by the norepinephrine transporter (NET), which can be
blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional
cells.
Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-
associated proteins; VAMPs, vesicle-associated membrane proteins.
Biosynthesis of Catecholamines:
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Metabolism of Catecholamines:
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Autonomic and hormonal control of cardiovascular function:
Two feedback loops are present: the autonomic nervous system loop and the hormonal
loop.
The sympathetic nervous system directly influences four major variables: peripheral
vascular resistance, heart rate, force, and venous tone. It also directly modulates renin
production.
The parasympathetic nervous system directly influences heart rate.
Angiotensin II stimulates aldosterone secretion, and directly increases peripheral
vascular resistance and facilitates sympathetic effects
The net feedback effect of each loop is to compensate for changes in arterial blood
pressure.
Thus, decreased blood pressure due to blood loss would evoke increased sympathetic
outflow and renin release.
Conversely, elevated pressure due to the administration of a vasoconstrictor drug
would cause reduced sympathetic outflow, reduced renin release, and increased
parasympathetic (vagal) outflow.
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Alpha1 receptors are coupled via G proteins in the Gq family to phospholipase C
leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
(DAG)
* Alpha2 receptors inhibit adenylyl cyclase and decrease cAMP.
* Beta Receptors stimulates adenylyl cyclase and increase cAMP.
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Dopamine Receptors:
The D1 receptor is typically associated with the stimulation of adenylyl cyclase
for example, D1-receptor-induced smooth muscle relaxation is presumably due
to cAMP accumulation in the smooth muscle of those vascular beds in which
dopamine is a vasodilator.
D2 receptors have been found to inhibit adenylyl cyclase activity, open
potassium channels, and decrease calcium influx.
Adrenergic Receptors
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Dopamine Receptors
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Dopamine Receptor Subtypes
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Catecholamines
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Noncatecholamines
Structure Activity Relationships
Substitution on the Benzene Ring
Substitution on the Amino Group
Substitution on the Alpha Carbon
Substitution on the Benzene Ring :
◦ Maximal α and β activity is found with catecholamines, i.e. drugs having –
OH groups at the 3 and 4 positions on the benzene ring.
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◦ The absence of one or the other of these groups, particularly the hydroxyl
at C3, without other substitutions on the ring may dramatically reduce the
potency of the drug. For example, phenylephrine is much less potent than
epinephrine; indeed, α –receptor affinity is decreased about 100-fold and
β activity is almost negligible .
No –OH groups on the ring means:
1-COMT is not effective, so the drug is effective orally.
2- Lipid solubility increases, so the drug has a CNS effect. For example, ephedrine and
amphetamine are orally active, have a prolonged duration of action, and produce
central nervous system effects not typically observed with the catecholamines.
Substitution on the Amino Group:
◦ Increasing the size of alkyl substituents on the amino group tends to
increase β –receptor activity. For example, methyl substitution on
norepinephrine, yielding epinephrine, enhances activity at β 2 receptors.
◦ Beta activity is further enhanced with isopropyl substitution at the amino
nitrogen (isoproterenol).
◦ Beta2-selective agonists generally require a large amino substituent
group. The larger the substituent on the amino group, the lower the
activity at α receptors; for example, isoproterenol is very weak at α
receptors.
Substitution on the Alpha Carbon
◦ Substitutions at the α carbon, block oxidation by monoamine oxidase
(MAO) and prolong the action of such drugs, particularly the
noncatecholamines.
◦ Ephedrine and amphetamine are examples of - α carbon substituted
compounds .
Done By: Bara’a Rawashdeh