Pharma 12

We talked in the previous lecture that Acetylcholine is hydrolyzed by acetylcholine esterase and that contaminate the action of acetyl choline. Catecholamine is terminated by uptake into the nerve terminal and storage. This occurs in two steps: 1- from synapse to the axoplasm 2- from axplasm into the synaptic vesicle Note: Certain drugs affect these processes and are important in therapeutics.

From synapse to the axoplasm:

We have 2 classes of drugs acting on this transport mechanism: Cocaine and Tricyclic antidepressant. * Cocaine (a drug of abuse) inhibits this reuptake mechanism. Cocaine increases the levels of catecholamine at the synapse -Catecholamines –In general- in CNS can be stimulated. Cocaine is a stimulating agent –so causing addiction-. *Also Tricyclic antidepressant drugs increase the level of catecholamine in synapse by inhibiting the uptake mechanism.

From axoplasm into the synaptic vesicle:

It is inhibited by 2 classes of antihypertensive agents: Reserpine and Bretylium guanithidine. *Reserpine is a drug used to treat hypertension and acts by inhibiting reuptake or transform into the synaptic vesicle. -When you prevent the storage in the synaptic vesicle Æ it goes under depletion (the amount of catecholamines in the synaptic vesicle is small) so if nerve stimulation occurs, the amount of catecholamines leaving the vesicle is small Æ so we will have normal blood pressure. -Note: Blood pressure depends on: catecholamine, cardiac output and peripheral vascular system. * Bretylium guanithidine: these agents inhibit the release of catecholamines. So it participates in reducing blood pressure.

*Catecholamine scheme is more complicated and controlled than Acetylcholine one. In acetylcholine scheme, there are factors can be used to inhibit certain processes but they are not important therapeutically. But they are important therapeutically in catecholamine.

* What will happen if catecholamines diffused from the vesicle to the axoplasm and catecholamines can't return back to the synapse? Catecholamines will be metabolized by mitochondrial enzymes. -However if catecholamines are secreted to the blood, they will go with the blood flow to the liver and then metabolized there.

Catecholamine synthesis:

Notes: ’ Dopa: Dihydroxyphenyl alanine. ’ Types of catecholamine: Dopamine, Norepinephrine and Epinephrine. ’ Dopamine doesn't contain a hydroxyl group on C (take a look at the figure). ’ Norepinephrine contains a hydroxyl group on C. This hydroxyl group (which is found in norepinephrine but not in dopamine) makes many differences between norepinephrine and dopamine: different receptors, actions and locations. ’ If we methylate the amine group in norepinephrine (nor methyl) we will have epinephrine. This methyl group makes the Epinephrine more selective to the β-receptors than norepinephrine. (More bulk Æmore selective for β-receptors).

Tyramine: -

(in the same figure) A monoamine compound derived from the amino acid tyrosine by Lamino acid decarboxylase. It is taken up by the same transport mechanisms for catecholamines and get stored in the vesicles. It displaces catecholamine. At the beginning, tyramine released into the vesicles in large numbers causing hypertensive crises (due to the large amount). Synthesized in the body but in small amounts. Found also in: cheese (especially stored cheese) and wine. If the person eats too much

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cheese and drinks a lot of wine, s/he will suffer from high blood pressure if the metabolism of tyrosine is inhibited. Tyramine is metabolized by monoamine oxidase (MAO), the same that metabolize catecholamine. You inhibit MAO by MAO inhibitor (ex: antidepressant drugs). So if someone is taken an antidepressant drug (MAO inhibitor), he mustn’t eat cheese or drink wine, otherwise he will suffer from hypertension crises.

Catecholamine:

™ Structure: catechol + amine ™ Catechol: benzene ring with 2 hydroxyl groups in Ortho and Meta positions. We call this structure in organic chemistry chatecol nucleus. ™ Inhibited by 2 enzymes: 1-MAO (monoamine oxidase): it links to catecholamine by o- monoamine oxidase. It is a mitochondrial enzyme in the liver and nervous tissue. It oxidizes the amine group and the carbon next to it. 2-COMT (catechol-o-methyltransferase): -conjugate to catecholamine mainly in the liver and other tissues.

Notes:  It doesn’t matter which one (MAO, COMT) acts first we will have the same end result.  whatever the enzymes acts first or if you are talking about epinephrine or norepinephrine, the final product is Vanil Mandelic Acid (VMA or 3-methoxy-4-hydroxy-mandelic acid)  VMA: if we have excessive sympathetic stimulation and we expect that the concentration of epinephrine or norepinephrine is high (hard to measure) and we found that VMA is highÆ we know that the concentration of epinephrine, norepinephrine or both of them is high.  Tumors in sympathetic chain (ex: phyochromocytoma) secretes tremendous amounts of catecholamine. If the patient comes to your clinic and told you that he is suffering from rapid hypertension for a short while then his pressure returns to the normal. You realize that the problem is: phyochromocytoma. The same problem happens also in some patients in fear, fight and flight Æ suddenly increasing in the hypertensionÆblood pressure id high (presence of catecholamine). So you –as a DR- ask him to bring a urine sample, and then check the VMA concentration.

Dopamine:

-metabolized by MAO and COMT also -The end product is Homovanillic acid -if there is an increase of the homovallinic acid in the urine, this leads to an increase concentration of dopamine.

Autonomic Receptors:

-Adrenoreceptors contain also epinephrine.

Notes:

-These are receptors of all of the body (We will focus on A.N.S) -These receptors are: muscarinic and nicotinic, in peripheral nervous system and C.N.S -In peripheral N.S you have cholinergic receptors in A.N.S and in motor nervous system. -Muscarinic receptors consist of 5 subtypes (M1-M5). They are not identical -Nicotinic receptors consist of 2 subtypes (Nn, Nm) -M1 receptor: *sympathetic postganglionic neuron: in sweat glands *subpresynaptic site: for regulation in autoreceptor (acting On the same neuron) or heteroreceptor (activated by Substances released from other nerve terminal) -M2 receptor: smooth muscle found in: blood vessels, GI tract and urinary tract. -M5: cerebral vessels: brain blood vessels. -Nn: nicotinic nervous system -Nm: nicotinic muscular system

Adrenoreceptors:

™ Subtypes of adrenergic receptors are: ɑ1, ɑ2, β1, β2 and β3. ™ ɑ1 : smooth muscles in GI tract, urinary tract and blood vessels ™ ɑ2: mainly presynaptic adrenergic nerve terminals. It is responsible

for inhibition (regulation). Autoreceptors. Small amount in smooth muscles. ™ β1: found in renal tubules. It is responsible for rennin secretion in renal tubules, in addition to β1 in the heart. Postsynaptic adrenergic nerve terminal contain B1 receptor which function is regulation (stimulation for catecholamine, positive and negative feedback) ™ Β2: found in the heart. But mainly we have B1 more than B2 in the heart. -in vessels we have mainly a1 and B2. -a1 in the vessel is stimulatory (vasoconstriction) -B2 in the vessel is inhibitory (vasodilation) -so a1 and B2 have different functions in the vessel. ™ B3: found mainly in lipocytes. -Maybe Drugs that modify B3 receptors are useful in treating obesity. (Not sure till now)

Dopamine Receptors:

-dopamine is central neurotransmitter

**D1 receptors: • Found mainly in the brain. • Present in renal vascular bed. • Responsible for vasodilation in renal blood vessels to protect the kidney from ischemia (kidney weight= 5/1000 of total body weight, but it receives 25/100 of the cardiac output) if there is ischemia in the kidney and D1 receptors are deactivated, kidney will go under necrosis. So D1 receptors are protective system for the kidney.

Presynaptic Regulation:

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B-adrenoceptors are B1 If the Norepinephrine is low in the body, B1 receptors will be stimulated. If the Norepinephrine is high in the body, a2 receptors will be stimulated.

-Vagal fibres from vagus nerve. -Note 1 (some vagal fibres….): adrenergic nerve terminals (sympathetic) and presynaptic cholinergic receptors stimulated by acetylcholine. Once the vagal fibres are stimulated, inhibition of the release of Norepinephrine will occur. -Note 2 (alternatively…): it isn’t necessary to have nerve terminals. Maybe the acetylcholine or any similar substances coming in the blood stream interact with the receptors and stimulate it (inhibition of catecholamine release).

-Serotonin: 5-hydroxytryptamine -P1 and P2: purine receptors for ATP and adenosine -Angiotensin 2: -Stimulate adrenergic nerve terminals Æ vasoconstrictionÆincrease blood flow. -Stimulate Aldosterone: reabsorption of Na+ and waterÆ increase in blood volumeÆincrease cardiac outputÆblood pressure.

Postsynaptic Regulation:

-Up-regulation: synthesis -Down regulation: blocking of the receptors -If you have excessive stimulation of Alpha receptors Æ down regulation occurs to achieve the balance. -When there is blocking of Alpha receptors Æ Up-regulation occurs to achieve the balance. -Down regulation and Up-regulation happen in seconds to days. -In seconds: endocytosis (down regulation because of excessive stimulation) -In days: when there is protein synthesis (stimulation or inhibition)

*You have to memorize these actions.

In The Eye:

: Myoses: constriction of pupil. : Medriosis: dilation of pupil. : Iris has 2 muscles: circular and radial

: : If the circular muscle is stimulated Æ constriction (myoses) : If the radial muscle is stimulatedÆ dilation (medriosis) : Ciliary muscle is stimulated by B-adrenergic receptors and M3 cholinergic receptors.

-M3 receptors contract the ciliary muscle to accommodate for near vision. (Accommodate: focus and adapt your eye for near vision) - B-receptors relax the ciliary muscle of eye for far vision.

In The Heart:

’ S.A node: pacemaker. ’ We have B1 and B2 sympathetic receptors. B1 are more in No. than B2. ’ B1 are also more important than B2. Æ Acceleration to the heart and any ectopic pace maker. They also increase the contractility of the heart ’ Parasympathetic activity receptors (M2 receptors) Æ decelerate the heart. M2 receptors also decrease the contractility of the heart especially in the atrium.

In blood vessels:

-What is the M3 sympathetic receptor??!!! Answer: certain neurons in sympathetic nervous system use acetylcholine. These neurons are called sympathetic cholinergic receptors. We have this type of receptors in: 1-sweat glands 2-some blood vessels. -Cholinergic system (M3, M5) relax smooth muscles of certain blood vessels indirectly. The receptors stimulate the endothelium to secrete EDRF (endothelium derived relaxing factor) which will relax the smooth blood vessels. (Two steps: 1- cholinergic receptors in endothelial cells secrete EDRF. 2- EDRF inhibit (relax) the smooth muscles in blood vessels) -EDRF: nitric oxide.

In Bronchiolar Smooth Muscles:

 In sympathetic: GI tract will be relaxed by a2 and B2 receptors and sphincter contracted Æ keep contents in.  In parasympathetic: wall contracted and sphincter relaxed Æ evacuation, defection and urination. Secretions are increased also by M3 stimulation all over the body. (GI, lacrimal and salivary secretions)  The pregnant uterus is relaxed by B2 receptors. So doctors must give B2 receptors to the pregnant woman who is going to deliver her baby before the expected date of delivery to relax the uterus. But non-pregnant woman won't be affected by both sympathetic and parasympathetic.

Note: sex organs when stimulated by sympathetic receptors Æ ejaculation.

Effects Of Autonomic Nerve Activation:

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