Download 1-Nicotinic receptors

Pharmacology-sheet #15
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Cholinomimetic Drugs
From the name we conclude that these are drugs that mimic the action of Acetylcholine,
either by directly binding to a receptor or by increasing the amount of acetylcholine.
They have the same structure as the Ach but with some modifications for example,
substituting one hydrogen molecule on the ach for a methyl group will increase the half life
of drug such as the Pilocarpine drug. The increased half-life is due to ach esterase not being
able to recognize and deactivate the drug easily (it’s not a substrate for acetylcholine
esterase).
Also some modification to the structure of ach may enable drugs to have lipophilic qualities
making it easier for them to pass membranes ex. Blood brain barrier.
Parasympathomimitic drugs, are drugs or poisons (because some of them are found
naturally occurring in plants especially mushrooms) that stimulate the parasympathetic
system.
They work as we said by:
1- directly acting  agonist
2- indirectly acting  inhibits endogenous enzymes that break Ach (ACH esterase) 
increasing Ach
*We talked before about Ach esterase inhibitors (nerve gas and insecticides). So these
increase amount of Ach
In the Parasympathetic system:
1-Nicotinic receptors:
-Located on the autonomic ganglia (both sympathetic and parasympathetic)
-Located on the neuro-muscular end plate
-Activated by nicotine but not muscarine
-Found in certain plants
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Pharmacology-sheet #15
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2-Muscurenic Receptors
Located on the parasympathetic neoro-effector site
activated by muscarine but not nicotine
*Ach activates both
Muscirine is a poison found certain types of mushrooms, if a patient ate these mushrooms
or was subjected to cholinomimitic poisoning the symptoms would be as if the
parasympathetic system were activated: Bradychardia, pin point pupil, sweating, blurred
vision, excessive lacrimation, bronchoconstriction, wheezing, dyspnea, coughing, vomiting
[abdominal cramping, diarrhea (because of contraction of walls and relaxation of sphincter
and increase acid secretion in stomach)], urinary incontinence (also because of wall
relaxation and sphincter relaxation)
Atropine is an antidote, it works as an ach antagonist/muscarinic receptor antagonist which
block the effects of poisoning (it is mainly a muscarinic antagonist)
Another benefit of changing the structure of Ach, is the increased selectivity of the drugs.
So some drugs are selective for muscarinic and some are for nicotinic, also they are
selective for the subtypes of these receptors so if I want a drug to work on the heart we
choose one which mainly affects the M2 receptors.
Smoking (nicotine) stimulates the autonomic ganglia thus stimulating fibers of the
sympathetic or parasympathetic systems.
Effects are mostly related to the sympathetic system:
1-tachicardia 2-hypertension 3- dilated pupil 4-muscle fasciculation (quick unregulated
contractions of the muscle which leads to weakness)
That’s why nicotine Is bad for people with heart problems
Tubocurarine drug is an antagonist for nicotinic receptors, old Mayan and Aztec tribes used
this drug as a tool for hunting. They would use pipes and needles with the tip full of the
drug to paralyze the animal’s muscles to catch it. tubocurarine won’t affect people who will
consume that animal because the drug will be broken down in the GIT.
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Pharmacology-sheet #15
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Tubocurarine maybe used in anesthesia to relax the muscles for intubation and to cut
through the muscles in operations (muscles relax)
Receptor location of muscarinic:
M1+M4  Brain and autonomic ganglia
M2  Heart
M3  Smooth muscle cells and endothelial cells
M5  we’ll talk about them in the CNS
Drugs:
1) Acetylcholine
- Not used as a drug because of its short half life.
- If injected into tissue:
1-activate muscarinic receptors
2-activates nicotinic receptors
3-stimulates post gang neuro-effector junction (somatic motor end plate)
-Not selective, but after operations the patient may have dilated pupils so the apply Ach to
cause meiosis “constriction” decreasing the amount of light entering the eye which may
damage the retina (but there are better drugs for this use)
2) Ach derivatives
-Selective and not degraded by Ach esterase
A. Metacholine + methanicole  more selective for muscarinic
B. Carbapole  can activate both Muscarinic and nicotinic but at therapeutic doses it only
activates muscarinic. One explanation is that muscarinic receptors are much more in
number than nicotinic receptors.
(These are Hydrophilic drugs so they cant cross membranes easily. We don’t use them for
preparation of the eye or in the CNS, although carbapole can cross the membrane and be
used in the eye but there are better drugs such as pilocarpine)
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Pharmacology-sheet #15
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C. Pilocarpine:
- Tertiary amine
- Not polar, can cross membranes relatively easily so it can cross the cornea of the eye and
bbb
- It’s a pure muscarinic receptor agonist
- Long half life
- Uses:
For glaucoma (increased intraocular pressure) accumulation in the anterior chamber of the
eye. Canal of schleme is controlled by a meshwork of cords and the muscle responsible for
the tone of these cords is the ciliary muscle. Parasympathetic stimulation causes its
contraction, pulling/contracting the meshwork opening it up, so excess fluid leaks out
decreasing the intraocular pressure.
This drug also increases the accommodation of the eye.
There are two types of glaucoma:
1- open angle
2-narrow angle
Pilocarpine may not work in some cases but in general pilocarpin helps in decreasing
glaucoma and mainly works in open angle situations.
So Pilocarpine (also Carbapole) work on the cilliary muscle through parasympathetic
stimulation (agonist) contracting and opening up the trabecular network releasing the
excess fluid.
Sympathetic nervous system  antagonist  treat glaucoma
parasympathetic nervous system  agonist  treat glaucoma (also meiosis)
sympathetic agonist  contraction of radial muscle  mydriasis
by counteracting sympathetic effect on the radial muscle  relaxation  opening the
passage for the fluids in the anterior compartment to decrease
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Pharmacology-sheet #15
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How does ach dilate the blood vessels?
Blood vessel anatomy:
-Endothelial layer (inner)
-Smooth muscle cell layer (middle)
-Adventitia layer (outer)
Endothelial and SMC both have M3 receptors:
Ach binds to M3 of the endothelial  activation of calcium channels  increase conc. of
calcium  activation of eNOS  converts arginine to nitric oxide (easily diffusing gas
with short half life)  diffuses to the next cell “Smooth muscle cell”  activates guanylyl
cyclase wich gives produces cGMP  activates multiple enzymes, PKG and certain
channels --> Relaxation of the smooth muscles  Vasodilation
BUT! If the endothelial cell layer was absent for what ever reason (pathological ex.
Atherosclerosis/endothelial dysfunction)  Ach binds directly to the M3 of the SMC
(skipping the endothelial cell) this causes calcium influx contraction of SMC 
Vasoconstriction
*At low doses the first mechanism happens causing vasodilation but at an increased
dose the drug binds to the SMC directly over coming the relaxation and causing
vasoconstriction.
*Sublingual nitrates release NO directly from the endothelial to the SMC  vasodilation
a low dose of muscarinic agonist can sometimes increase the heart rate why?
First thing that comes to mind is Bradycardia but this is not happening here.
This is because of the low dose affecting the blood vessels and causing vasodilation, so
the reflex mechanism of the heart would be tachycardia increasing the heart rate
but a high dose of ach or muscarinic agonist will directly activate the M2 receptors in the
heart these will decrease the heart rate
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