Subject: Pharmacology Topic: ANS4 Lecturer: Dr.

Dela Cruz Date of Lecture: August 10, 2011 Transcriptionist: Jobell M. Editor: Pinay Pages: 13

I. E Receptor antagonists 1. Non SelectiveE Receptor Antagonists 2. Selective E1 receptor antagonists 3. Selective E2 receptor antagonists II. Receptor antagonists 1. Non selective antagonists 2.
1

    

Prazosin* Tamsulosin Terazosin Alfuzosin Doxazosin

3. Selective E2 Receptor Antagonist  Yohimbine* Prazosin selective E1 receptor antagonist affinity for E1 receptors is 1000x greater than affinity for E2 receptors duration of action of about 4 to 6 hours. affects both arterioles and veins Pharmacologic Actions: 1. Cardiovascular System vasodilatation of arteries and veins decrease total peripheral resistance decrease preload

selective antagonists

In this picture, presynaptic receptors: 2 receptors are for NE release, while E2 receptors inhibit NE release. Postsynaptic 1 receptors are for NE and E release. E Adrenergic Antagonists 1. Non Selective E Receptor Antagonist     Phenoxybenzamine Phentolamine Tolazoline Ergot derivatives o Ergotamine o Ergonovine o Dihydroergotamine o Methysergide

decrease blood pressure Dilatation of arterial and venous smooth muscles &decrease total peripheral resistance

2. Selective E1 Receptor Antagonist

In this picture, the presence of Prasozin dilates the arterial and venous vascular beds. See last page for bigger picture

SY 2011-2012

Effects on Effects on BP

the

Cardiovascular

System

extensively metabolized in the liver plasma half-life is approx. 2-3 hrs but duration of action is 7-10 hrs This is the case where the dose of the drug will not determine the duration of its action small fraction of the drug is excreted unchanged in the kidneys First dose phenomenon of Prasozin marked postural hypotension and fainting 30-90 minutes after the first dose associated with syncopal attacks Measures: start with the least effective doses administer drug at bedtime (Must be administered during bedtime because of the supine position which will not pool the blood down the extremities. In case of supine position, the blood will be pulled down the extremities by the gravity which can cause syncopal attacks. Prasozin is usually administered once a day.) Terazosin structural analog of Prazosin higher oral bioavalability (>90%) longer plasma half-life (approx. 12 hrs) induces apoptosis in prostate smooth muscles (treatment for Benign Prostatic Hypertrophy) &limits cell proliferation in the prostate &not related to E1 antagonism

BP = Cardiac Output x Total Peripheral Resistance SV HR (F1 effect) EDV Fc (F1 effect) (E1 effect) (F2 effect)

Venous return 2. Metabolic effects decrease LDL cholesterol and triglycerides increase HDL decrease hepatic glucose output 3. Genitourinary tract decreases tone of smooth muscles in the prostateand bladder neck inhibit ejaculation

Adrenergic antagonist such as Prasozin inhibits A1 receptor so the effect in the prostate and bladder is therefore decrease in tone of the muscles. Pharmacokinetics: well absorbed after oral administration 50-70% bioavailability peak plasma conc. attained in 1-3 hrs

Yohimbine competitive E2 antagonist an indolealkylamine alkaloid from bark of Pausinystaliayohimbe and in Rauwolfia root resembles structure anithypertensive drug of Reserpine an

Pharmacologic Actions: highly bound to plasma proteins (primarily to a1acid glycoprotein because the drug is basic) 5% as free drug 1. Cardiovascular System increase central sympathetic outflow

enhanced release of NE &activation of

1

&decrease total peripheral resistance receptors in the heart &enhanced decrease in blood pressure q E2 antagonist effects Baroreceptor reflex q & Increase HR and CO Fluid retention

&activation of E1 receptors in the blood vessels &activation of

1

receptors in the JGA

q enhance release of NE

increase cardiac output increase heart rate increase total peripheral resistance fluid retention BP increase blood pressure q

The Renin Angiotensin Aldosterone System

In this picture: Just remember that Aldosterone from the adrenal cortex causes sodium reabsorption by the kidney so the important effects will be increase in volume (water retention) and increase in arterial blood pressure. See last page for bigger picture

See last page for bigger picture Phenoxybenzamine binds covalently to alpha adrenergic receptor non-competitive, irreversible blocker slight selectivity for a1 receptor than for E2 receptor mainly used in the control of high blood pressure prior to surgery for Pheochromocytoma Pheochromocytoma means adrenal medulla. If there medulla, therefore there is secretion of catecholamines. increase in blood pressure. there is tumor in is tumor in adrenal also increase in the The net effect will be

2. vasodilatation due to postsynaptic E2 in blood vessels 3. Inhibition of platelet aggregation 4. increase Insulin release &decrease hepatic glucose output

a1 and a2 antagonist effects Dilatation of arterial and venous smooth muscles

e.g. Raynaud s disease 5. Benign Prostatic Hypertrophy Adrenergic Antagonists Adverse Effects: 1. Orthostatic hypotension 2. Reflex cardiac stimulation tachycardia, cardiac arrhythmias angina, myocardial infarction 3. Nasal congestion 4. Sexual dysfunction In this picture: Just remember that in the presence of an antagonist, the efficacy of NE is decreased. Phenoxybenzamine is non-competitive so increase in NE will not counteract the effect of the antagonist. Phentolamine a competitive antagonist equal affinity for E1 and E2 receptors antagonism for E2 receptors will cause the release of NE from sympathetic nerve endings also block 5-HT effects on the cardiovascular system is similar to those of Phenoxybenzamine F Adrenergic Antagonists 1. Non-subtype Selective F Receptor Antagonist (First Generation)     Propranolol Timolol Nadolol Pindolol

2. Selective F1 Receptor Antagonist (Second Generation) & Cardioselective Beta Blocker  Atenolol  Metoprolol  Acebutolol 3. Non-subtype Selective F Receptor Antagonist (Third Generation) with additional CVS Actions     Labetalol Carteolol Carvedilol Bucindolol

Ergot Alkaloids were the first adrenergic blocking agents to be discovered. Ergot is a fungus which grows on rye Both Ergotamine, and Dihydroergotamine are structural derivatives of a compound isolated from ergot which have potent competitive alpha antagonist effects. Ergotamine is a prophylaxis for migraine and Dihydroergotamine is used to contract uterus post partum to stop bleeding. General Therapeutic Uses: E antagonists 1. Hypertension 2. Pheochromocytoma 3. Congestive heart failure (Alpha antagonist decrease workload of the heart) 4. Peripheral vasospastic disease

4. Selective F1 Receptor Antagonist (Third Generation) Actions  Betaxolol  Nebivolol  Celiprolol Beta Blockers Pharmacologic Actions: 1. Cardiovascular system decrease heart rate (-) chronotropic effect with additional CVS

decrease myocardial contractility (-) inotropic effect attenuate the expected rise in heart rate during exercise or stress negative dromotropic effect slows conduction in the atria and A-V node decrease the spontaneous rate depolarization of ectopic pacemakers of

chronic prophylactic therapy with a beta blocker in patients who have had a myocardial infarct appears to help prevent the recurrence of a second fatal myocardial infarct net effect in patients with coronary artery disease is to decrease oxygen demand improves exercise tolerance in patients with angina long term use decrease total peripheral resistance 2.Respiratory system negligible effects on pulmonary function in normal persons bronchoconstriction in predispose patients cardioselective beta blockers less likely to cause respiratory problems in patients with bronchospastic diseases precaution still to be observed Can also induce bronchospasm because it also blocks 2 so there is contraction 3. Metabolic Nonselective beta blockers cause most of the metabolic effects such as: mild impairment of glucose tolerance inhibition of beta-receptor dependent glucosemobilization from the liver. mild elevation of plasma triglyceride and VLDL (less significant with drugs having ISA) It increases glucose output so Beta blockers are not good for hypertensive patients with diabetes. 4. Decrease intraocular pressure decrease aqueous humor production by the ciliary body 5. Block catecholamine induced tremor

increase refractory period in the A-V node Decrease blood pressure due to: decrease Cardiac output (
1

in the heart)

decrease renin secretion ( 1 in the JGA) BB without ISA (Beta Blocker without Intrinsic Sympathetic Action) decrease central sympathetic outflow (presynaptic 2 receptor)

See last page for bigger picture does not lower blood pressure in normal individuals reduce blood pressure in hypertensive patients (because of the predominant effect in 1 receptors more than 2 receptors so it causes decrease in blood pressure)

6. Block catecholamine-induced inhibition of mast cell degranulation

Inhibits Phase 0 of action potential resulting in: &impaired spontaneous firing of SA and AV node (bradycardia) &decreased AV node conduction (1,2,3 degree heart block) &decreased ventricular conduction (prolonged QRS) e.g. Propranolol, Acebutolol, Carvedilol

Pharmacologic Characteristics of Blockers Selectivity relative rather than absolute Non-selective equal affinity for both
1

Comparative Properties of Beta Blockers Propanolol* ++ 0 High 30% 35 34 34 37 6 90%

Pindolol and
1 2

+++ Low

100%

40%

receptors Acebutolol + + Low 2060% 4050% 85% 26%

Cardioselective Selective greater affinity for

1

Metoprolol* +
1

Mod

12%

at therapeutic doses only block

at higher doses may become non-selective Lipid solubility increases the ability to enter the CNS affects presynaptic Norepinephrine receptors to block release of

Carteolol

++

Low

2330% 50%

Labetalol*

Low

33%

34 15

Betaxolol*

High

80%

50%

decrease central sympathetic outflow Dilatation of blood vessels due to: e.g. Propanolol, Pindolol
2

agonist effects

Intrinsic sympathetic activity E1 antagonism blockers can activate b receptors in the absence of catecholamines partial agonist activity intrinsic activity are less than that of the full agonists prevent bradycardia and decrease in force of myocardial contraction in the resting heart (will not produce excessive bradycardia) e.g. Pindolol, Acebutolol Membrane stabilizing action Local anesthetic action (basically anti-arrhythmic because it acts on contracting muscles) Ca+ entry blockade Nitric oxide production Additional CVS Action of Beta Blockers
2 Agonist Effect NO Production

Third

Generation

Ca entry blockade

E1 receptor antagonism

Carteolol Carvedilol Labetalol

+ + + + +

Antioxidant Action

Drug

Betaxolol + Pharmacokinetics: completely absorbed from the GIT Propanolol Pharmacokinetics: highly lipophilic almost completely administration absorbed after oral extensive metabolism in the liver by oxidation and glucuronidation elimination half-life 8 hours undergoes extensive first pass metabolism in the liver. 25% bioavailability from oral route metabolized to 4-hydroxypropranolol, an active metabolite 90% of the drug in the circulation is bound to plasma proteins. plasma half-life 3-5 hours 80% bioavailability well distributed approx 50% bound to plasma proteins as antihypertensive agent, the full response on the blood pressure is not observed until after several weeks of administration. Metoprolol equipotent to Propranolol in affinity to the receptor 50-100x less affinity to
2 1

presence of food in the stomach will increase absorption 20-40% bioavailability

small fraction of the drug is excreted unchanged in the kidneys Betaxolol Pharmacokinetics: completely absorbed from the GIT presence of food or alcohol in the stomach does not affect absorption

elimination half-life 15 hours 15% of the drug is excreted unchanged in the kidneys Adrenergic Antagonists Therapeutic Uses: 1. Coronary artery disease &reduce myocardial work load and oxygen demand  Angina reduce the frequency of anginal attacks

receptor

Pharmacokinetics: almost completely administration absorbed after oral

only 40% bioavailability due to first pass hepatic metabolism primarily metabolized by CYP2D6 half-life is 3-4 hours 10% of the unchanged drug is recovered in the urine Labetalol competitive receptors antagonist to alpha and beta

2. Hypertension (mild to moderate) q Cardiac Output qrenin secretion q central sympathetic outflow Not for severe hypertension because it does not lower the blood pressure excessively 3. Congestive Heart Failure recent evidence that beta blockers decrease mortality in patients with CHF

more (5-10x) b receptor antagonism than a1 receptor antagonism

caution is necessary in initiating therapy due to risk of worsening CHF (because of negative inotropic effect) blockers currently approved for treatment of CHF: Metoprolol Carvedilol Bisoprolol 4. Anti- arrhythmic drugs with Membrane Stabilizing Action e.g. Propranolol, Metoprolol, Acebutolol 5. Glaucoma decrease the rate of synthesis of aqueous humour

life threatening bronchoconstriction in patients with bronchospastic diseases 4. Metabolic (Non selective b blockers) &dyslipidemia &blunts perception of hypoglycemic symptoms (tachycardia, tremors, nervousness) &blockcounterregulatory effects of catecholamines secreted during hypoglycemia 4. Metabolic
1 selective blockers improve serum lipid profile and are less likely to interfere with hypoglycemiainduced counter-regulatory mechanisms

Adrenergic Neuron Blockers e.g. Timolol 1. False Transmitter 6. Reduce signs and symptoms of hyperthyroidism Methyldopa blocks enhanced catecholamines responsiveness to 2. Prevents storage of Norepinephrine in granules Reserpine 3. Prevents release of Norepinephrine from vesicles Guanethidine 9. Control signs and symptoms of Alcohol withdrawal 10. Acute panic and anxiety symptoms Bretylium

inhibit peripheral conversion of T4 to T3 7. Migraine prophylaxis 8. Essential tremor

Adrenergic Antagonists Adverse Effects 1. Cardiovascular system bradyarrhythmias (may be life threatening) abrupt withdrawal after chronic therapy can produce rebound hypertension or angina may exacerbate or cause heart failure 2. Central nervous system lethargy, fatigue, nightmares insomnia and depression 3. Respiratory system negligible effects in normal persons In this picture: a-methyl NA is a false neurotransmitter so it is not recognized by the receptor but is acted upon by the same enzyme. See last page for bigger picture

Reserpine an alkaloid obtained from Rauwolfiaplant slow onset but long duration of action also cause depletion of other biogenic amines (serotonin, dopamine) mainly used as Antihypertensive Mechanism of action: very low concentration, blocks the transport of norepinephrine and other amines into synaptic vesicles, by blocking the vesicular monoamine transporter (VMAT2) Norepinephrine accumulates in the cytoplasm, where it is degraded by MAO

Guanethidine Mechanism of action: inhibit the release of norepinephrine from sympathetic nerve terminals causes a gradual and long-lasting depletion of norepinephrine in sympathetic nerve endings reduce or abolish the response of tissues to sympathetic nerve stimulation

In this picture: Guanethedine and Bretylium prevent the release of NE from the vesicles. large doses lead to accumulation in the nerve terminal that may cause structural damage to noradrenergic neuron no longer used clinically, now that better antihypertensive drugs are available In this picture: VMAT2 is blocked by Reserpine so NE is not transported to the vesicle. See last page for bigger picture associated with severe adverse effects due to loss of sympathetic reflexes Adverse Reactions: Adverse Effects: 1. Central nervous system mental depression lassitude, sedation, nightmares Parkinsonian syndrome 2. Gastrointestinal abdominal cramps increase gastric acid secretion mild diarrhea 1.Orthostatic hypotension 2.Bradycardia 3.Nasal congestion 4.Failure of ejaculation 5. Diarrhea o PSNS activity on GIT 6. Denervation supersensitivity marked BP response to sympathomimetics may lead to hypertensive crisis

END of TRANSCRITION What I added are the important things we need to know because the Power Point in itself is already comprehensive. I also included a practice test for you to assess whether you will be confident in this final part of ANS or you have to read again. J Let s go 2014! All for the glory of God!

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Test your knowledge Matching type A. ____1. Ergotamine ____2. Methysergide ____3. Yohimbine ____4. Terasozine ____5. Phenoxybenzamine B. _____6. Labetalol _____7. Nebivolol _____8. Propranolol _____9. Metoprolol _____10. Carteolol a. 1st Generation b. 2nd Generation c. 3rd Generation a. Selective A2 b. Ergot Alkaloids c. Selective A1 d. Non selective Alpha

C. Identification (ANS 3 and 4) _______________11. An example of Quinazoline. _______________12. An example of Imidazoline. _______________13. An example of Haloalkylamines. _______________14. Myocardial contractility is mainly an effect of this receptor. _______________15. Formula of Stroke Volume. _______________16. A Beta blocker which undergoes extensive first pass metabolism in the liver. _______________17. A Beta blocker with extensive metabolism in the liver by oxidation and Glucuronidation. _______________18. A Beta blocker in which the presence of food or alcohol in the stomach does not affect absorption. _______________19. Give one drug with Membrane Stabilizing Action. _______________20. A drug which decreases the rate of synthesis of aqueous humor.

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