1. HYPERTENSION Control of normal blood pressure 1-When there is an increase in blood pressure, the baroreceptors fire and send signals to the medulla. 1-When there is an increase in blood pressure, the baroreceptors fire and send signals to the medulla. 2-In the medulla, these signals reduce the sympathetic outflow to the heart and other BV. 3- While when there is low blood pressure the baroreceptors signal the medulla to increase sympathetic outflow to the heart and also to the blood vessels. This results in 2 things: a. Increased force and rate of contraction (to increase cardiac output) a. Increased force and rate of contraction (to increase cardiac output) b. Increased peripheral resistance b. Increased peripheral resistance 4-The kidney is also able to regulate blood pressure: When there is a drop in blood pressure, the kidney detects that as being a drop in perfusion. The juxtaglomerular cells sense this fall in perfusion and so cause the release of rennin.Rennin can also be released via β1 sympathetic activation. 5-R A A S causes increased fluid retention (aldosteron increase blood volume and hence cardiac output) and increased peripheral resistance 5-R A A S causes increased fluid retention (aldosteron increase blood volume and hence cardiac output) and increased peripheral resistance ( via the VC actions of angiotensin II). ( via the VC actions of angiotensin II).

2. B.P.=C.O x P.R. B.P.=C.O x P.R. S.V. H.R. S.V. H.R. Neurohumoral Neurohumoral blood volume Neurohumoral blood volumeNeurohumoral blood volumeNeurohumoral activation activation Kidney disease activation activation V.C. of Bl.V. Excretion +v chronotropic Urine output Blood volume H.R. S.V. S.V. C.O. C.O. B.P. B.P.

3. Some causes of hypertension Renal artery stenosis Renal artery stenosis Chronic renal disease Chronic renal disease Primary hyperaldosteronism (in aldosteron secretion due to a tumor in adrenal cortex) Primary hyperaldosteronism (in aldosteron secretion due to a tumor in adrenal cortex) Stress Stress Hyperthyroidism (Thyrotoxicosis) Hyperthyroidism (Thyrotoxicosis) Pheochromocytoma (increase in NE) Pheochromocytoma (increase in NE) Smoking Smoking Atherosclerosis Atherosclerosis

4. Hypertension Definition of hypertension hypertension is a sustained elevation in blood pressure over 120/80 mm Hg hypertension is a sustained elevation in blood pressure over 120/80 mm Hg The diagnosis of hypertension needs to be done on more than one visit to the doctor The diagnosis of hypertension needs to be done on more than one visit to the doctor

5. Treatment of hypertension In patients with mild elevation in blood pressure, non pharmacological treatment methods may be applicable. These treatment methods may include: · Stop smoking · Stop smoking · Lose weight · Lose weight · Moderate alcohol consumption · Moderate alcohol consumption · Exercise · Exercise · Reduce salt intake · Reduce salt intake

6. Con: Treatment of hypertension For more serious increases in blood pressure, the current drug treatment involves: 1. Diuretics 1. Diuretics 2.sympatholytic agents : include adrenergic neuron blockers, β blockers and α blockers 2.sympatholytic agents : include adrenergic neuron blockers, β blockers and α blockers 3. Vasodilators : include Ca2+ channel blockers and d irectly acting vasodilators 3. Vasodilators : include Ca2+ channel blockers and d irectly acting vasodilators 4. Angiotensin converting enzyme inhibitors 4. Angiotensin converting enzyme inhibitors 5. ACE antagonist. 5. ACE antagonist. 6. Centrally acting agents :to reduce sympathetic outflow 6. Centrally acting agents :to reduce sympathetic outflow

7. Begin Lifestyle Modifications Begin Lifestyle Modifications Í If Inadequate Response Initiate Drug Therapy Í Initial Drug Choices (Unless Contraindicated) Diuretics, beta-blockers Diuretics, beta-blockers Specific indications Diabetes mellitus: use ACE inhibitors Heart failure : use ACE inhibitors, Diuretics Myocardial infarction & angina: use beta-blockers, ACE I Í If No Response or If Troublesome Side Effects Í Substitute Another Drug from Different Class Substitute Another Drug from Different Class Í If Inadequate Response, But Drug Is Well-Tolerated Í Add Second Drug from A Different Class Í If Inadequate Response If Inadequate Response Í Continue Adding Agents from Other Classes

8. I- Diuretics 1-They are called water piles, they decrease blood volume thus Venous return (preload) CO BP thus Venous return (preload) CO BP Loop diuretics: (furosemide, bumetanide, torsemide) are the most effective diuretics mainly used in emergency as in hypertensive crisis. Loop diuretics: (furosemide, bumetanide, torsemide) are the most effective diuretics mainly used in emergency as in hypertensive crisis. Thiazide diuretics (chlorothiazid) act on the distal loop and are less effective than loop diuretics. Thiazide diuretics (chlorothiazid) act on the distal loop and are less effective than loop diuretics. Potassium sparing diuretics: not effective antihypertensive drugs because they have weak diuretic effect. However they are used with other diuretics to decrease their hypokalemic effect (which is dangerous on heart). Potassium sparing diuretics: not effective antihypertensive drugs because they have weak diuretic effect. However they are used with other diuretics to decrease their hypokalemic effect (which is dangerous on heart).

9. II-sympatholytic agents i-Adrenergic neuron blockers 1- Guanethidine;(inhibits NA release) Highly polar, therefore does not get into the CNS, acts peripherally Highly polar, therefore does not get into the CNS, acts peripherally Taken into secretory vesicles (by the same uptake mechanism as NA) and displace NA from its storage granules. Taken into secretory vesicles (by the same uptake mechanism as NA) and displace NA from its storage granules. Then, it prevents NA release from the presynaptic terminal (stabilize the nerve membrane)- hence no NA release with gradual depletion of NA stores Then, it prevents NA release from the presynaptic terminal (stabilize the nerve membrane)- hence no NA release with gradual depletion of NA stores Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence reducing cardiac output Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence reducing cardiac output Side effects: Side effects: Postural hypotension Postural hypotension Weakness Weakness Impotence & Diarrhea Impotence & Diarrhea 2- Reserpine(inhibits NA storage) Blocks NA transport into synaptic vesicles. May also interfere with NA uptake mechanisms ( but it enters the CNS). Blocks NA transport into synaptic vesicles. May also interfere with NA uptake mechanisms ( but it enters the CNS). Blocks dopamine transport into storage vesicles, so decrease synthesis of NA Blocks dopamine transport into storage vesicles, so decrease synthesis of NA Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence reducing cardiac output Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence reducing cardiac output Side effects: Postural hypotension Sedation& Depression Sedation& Depression Parkinsonism Parkinsonism Peptic ulcer Peptic ulcer

10. ii -Adrenergic receptor blockers 1-β blockers 1. Blocking of the β 1 receptors of the heart: Reducing contractility. Causing bradycardia(-ve inotropic,-ve chronotropic ) 1. Blocking of the β 1 receptors of the heart: Reducing contractility. Causing bradycardia(-ve inotropic,-ve chronotropic ) 2. Blocking β receptors in the kidney: decrease the release of rennin 2. Blocking β receptors in the kidney: decrease the release of rennin Non selective β1 & β2 blocker: Propranolol. Non selective β1 & β2 blocker: Propranolol. β1 selective: Atenolol,Metoprolol,nadolol & timolol β1 selective: Atenolol,Metoprolol,nadolol & timolol Non selective beta antagonists should be avoided since they can cause extra cardiac effects, most notably bronchoconstriction. Even the relatively cardio selective antagonists may be capable of blocking β2 receptors, thus causing bronchoconstriction. Therefore, blockers are contraindicated in asthmatics Non selective beta antagonists should be avoided since they can cause extra cardiac effects, most notably bronchoconstriction. Even the relatively cardio selective antagonists may be capable of blocking β2 receptors, thus causing bronchoconstriction. Therefore, blockers are contraindicated in asthmatics Other adverse effects: Other adverse effects: Cold extremities (NA effect on BV. Will be on α1 receptors) so NOT taken by patients with PVD. Cold extremities (NA effect on BV. Will be on α1 receptors) so NOT taken by patients with PVD. Bronchospasm (prevent dilation of the bronchi by circulating adrenaline) Bronchospasm (prevent dilation of the bronchi by circulating adrenaline) CNS effects if the drug penetrates the BBB cause insomnia CNS effects if the drug penetrates the BBB cause insomnia Increased triglycerides since β receptors are also present in the liver to increase fat metabolism Increased triglycerides since β receptors are also present in the liver to increase fat metabolism Also they inhibit glycogenolysis (so can cause hypoglycemia) Also they inhibit glycogenolysis (so can cause hypoglycemia) They are contraindicated in diabetic patients because they mask symptoms of hypoglycemia (tachycardia)& also can themselves produce hypoglycemia by inhibiting glycogenolysis & gluconogenesis). They are contraindicated in diabetic patients because they mask symptoms of hypoglycemia (tachycardia)& also can themselves produce hypoglycemia by inhibiting glycogenolysis & gluconogenesis). Withdrawal syndrome e.g. Propranolol may result in tachycardia if it is removed suddenly. Withdrawal syndrome e.g. Propranolol may result in tachycardia if it is removed suddenly. Bradycardia Bradycardia

11. 2-α blockers α1 stimulation by NA or adrenaline causes vasoconstriction (and hence increased PR), α1 stimulation by NA or adrenaline causes vasoconstriction (and hence increased PR), α1 blockers block this effect, and so dilate blood vessels · α1 blockers block this effect, and so dilate blood vessels · They reduce plasma triglyceride and reduce LDL & cholesterol. They reduce plasma triglyceride and reduce LDL & cholesterol. Ex.: Prazosin & Terazosin Adverse effects: Postural hypotension (occurs on the first dose) Postural hypotension (occurs on the first dose) Explanation: Sympathetic stimulation of α receptors is important to constrict blood vessels of the legs to pump blood back to the heart upon standing. As α1 receptors are blocked, when changing from a supine position to a standing position, the blood will be pooled to the legs quickly, causing hypotension (may cause some people to get dizzy and faint) Failure to ejaculate Failure to ejaculate Reflex tachycardia & Na and water retention. Reflex tachycardia & Na and water retention. 3-A combined α and β blocker 3-A combined α and β blocker Ex. labetalol Ex. labetalol It is not used widely It is a logical choice for emergencies (hypertensive crisis) where you want to reduce blood pressure quickly (by reducing CO and TPR at the same time) Useful in pre ecclampsia of pregnancy Useful in pre ecclampsia of pregnancy In treatmeant of pheochromocytoma before surgery. In treatmeant of pheochromocytoma before surgery.

12. III-Vasodilator agents a-Directly acting vasodilators 1-Hydralazine 1-Hydralazine Mechanism of action The mechanism is unknown. It dilates arterioles· It is not used much because it can cause reflex stimulation of the sympathetic nervous system. since the vasodilatation causes sever transient drop in blood pressure. This reflex stimulation causes increased heart rate and contractility, and also rennin release (causes marked fluid retention and edema). The mechanism is unknown. It dilates arterioles· It is not used much because it can cause reflex stimulation of the sympathetic nervous system. since the vasodilatation causes sever transient drop in blood pressure. This reflex stimulation causes increased heart rate and contractility, and also rennin release (causes marked fluid retention and edema). In order for hydralazine to be useful, it needs to be combined with a β blocker (to prevent the cardiac effects) and a diuretic (to overcome the fluid retention). In order for hydralazine to be useful, it needs to be combined with a β blocker (to prevent the cardiac effects) and a diuretic (to overcome the fluid retention). Side effects: Side effects: · Headache (due to vasodilatation) · Headache (due to vasodilatation) · Nausea · Nausea · Tachycardia & edema (reflex stimulation of sympathetic) · Tachycardia & edema (reflex stimulation of sympathetic) SO; Need to be used in conjunction with β blockers and diuretics · Caution in the elderly and those with coronary artery diseases. The reflex stimulation of the heart (due to drope in BP ) may precipitate an ischemic attack due to excessive demands on the heart. · Caution in the elderly and those with coronary artery diseases. The reflex stimulation of the heart (due to drope in BP ) may precipitate an ischemic attack due to excessive demands on the heart. · A systemic lupus like condition may develop in some people · A systemic lupus like condition may develop in some people

13. Con: a-Directly acting vasodilators 2-Minoxidil 2-Minoxidil Relaxes blood vessels by opening K+ channels· This causes K+ to rush out of the cell, hyperpolarizing the smooth muscle and so making it less excitable Relaxes blood vessels by opening K+ channels· This causes K+ to rush out of the cell, hyperpolarizing the smooth muscle and so making it less excitable Adverse effects: ·Water & Salt retention ·Water & Salt retention Reflex stimulation of sympathetic NS. Reflex stimulation of sympathetic NS. · Tachycardia · Tachycardia SO: Need to be used in conjunction with β blockers and diuretics · Causes hair growth (hirsiutism)· Another therapeutic use of this drug is in the treatment of baldness · Causes hair growth (hirsiutism)· Another therapeutic use of this drug is in the treatment of baldness 3-Sodium nitroprusside 3-Sodium nitroprusside A nitrovasodilator (Releases NO which directly relaxes smooth muscle in blood vessels)· A nitrovasodilator (Releases NO which directly relaxes smooth muscle in blood vessels)· Only route of administration is intravenously· Only route of administration is intravenously· Reserved for acute use only Reserved for acute use only (i.e.) It is used in emergency situations where a rapid drop in blood pressure is required· Since the drug contains cyanide, cyanide poisoning may develop (i.e.) It is used in emergency situations where a rapid drop in blood pressure is required· Since the drug contains cyanide, cyanide poisoning may develop

14. b-Calcium channel blockers The depolarization of vascular smooth muscle relies on the influx of Ca2+ (rather than Na+· )These drugs relax (VD) arteriolar smooth muscle by reducing calcium entry via L type calcium channels (which are also present in the heart)· There are various types of Ca2+ channels blockers: The depolarization of vascular smooth muscle relies on the influx of Ca2+ (rather than Na+· )These drugs relax (VD) arteriolar smooth muscle by reducing calcium entry via L type calcium channels (which are also present in the heart)· There are various types of Ca2+ channels blockers: · Nifedipine: arterioselective · Nifedipine: arterioselective · Amlodipine: arterioselective · Amlodipine: arterioselective · Diltiazem: cardioselective · Diltiazem: cardioselective · Verapamil: cardioselective · Verapamil: cardioselective Adverse effects: · Flushing · Flushing · Edema · Edema · Dizziness · Dizziness Bradycardia,AV blockade (with cardioselective agents)· Bradycardia,AV blockade (with cardioselective agents)· Verapamil must not be given to patients with a heart problem because it can slow down the heart sufficiently to cause cardiac failure. Verapamil must also never be used in conjunction with a βblocker because of their additive effects on depressing the heart…………complete heart block Verapamil must not be given to patients with a heart problem because it can slow down the heart sufficiently to cause cardiac failure. Verapamil must also never be used in conjunction with a βblocker because of their additive effects on depressing the heart…………complete heart block

15. IV-Angiotensin converting enzyme inhibitors ACEI Angiotensin converting enzyme is found widespread throughout the body. It acts mostly in the lungs, but is also found in the brain, kidney and on endothelium· ACE inhibitors prevent the conversion of angiotensin I to angiontensin II· ACE is also responsible for the inactivation of bradykinin, so that inhibition of this enzyme also leads to increased bradykinin levels· Bradykinin can act as a local vasodilator agent. However, the adverse effects of bradykinin (mainly cough) are what limits the usefulness of ACE inhibitors Angiotensin converting enzyme is found widespread throughout the body. It acts mostly in the lungs, but is also found in the brain, kidney and on endothelium· ACE inhibitors prevent the conversion of angiotensin I to angiontensin II· ACE is also responsible for the inactivation of bradykinin, so that inhibition of this enzyme also leads to increased bradykinin levels· Bradykinin can act as a local vasodilator agent. However, the adverse effects of bradykinin (mainly cough) are what limits the usefulness of ACE inhibitors Ex.: Captopril & Enalapril Ex.: Captopril & Enalapril Adverse effects: · Dry cough (due to bradykinin) · Dry cough (due to bradykinin) · Loss of taste · Loss of taste · Severe hypotension · Severe hypotension · Rash · Rash · Angioedema (due to bradykinin) · Angioedema (due to bradykinin) Hyperkalemia (due to decreased aldosterone) Hyperkalemia (due to decreased aldosterone)

16. Con: Angiotensin converting enzyme inhibitors Advantages of ACE inhibitors over other therapies: Advantages of ACE inhibitors over other therapies: There is no reflex sympathetic (NO tachycardia or edema) There is no reflex sympathetic (NO tachycardia or edema) Less adverse effects on lipid profile and glucose than diuretics and β blockers Less adverse effects on lipid profile and glucose than diuretics and β blockers The most beneficial effect is its inhibition of cardiovascular remodeling due to effect of Ang II on heart. The most beneficial effect is its inhibition of cardiovascular remodeling due to effect of Ang II on heart. (i.e )Evidence has shown that cardiac hypertrophy and vascular changes are the result of angiotensin II having a trophic effect. Therefore, reduction in the amount of angiotensin helps prevent the cardiac enlargement. (i.e )Evidence has shown that cardiac hypertrophy and vascular changes are the result of angiotensin II having a trophic effect. Therefore, reduction in the amount of angiotensin helps prevent the cardiac enlargement.

17. V-Angiotensin II receptor antagonists Ex. Lorsatan & valsartan Angiotensin II binds to 2 receptors: AT1 and AT2 receptors· AT1 receptor is the one we are interested in because most of the known actions of angiotensin II is mediated by AT1 AT1 and AT2 receptors· AT1 receptor is the one we are interested in because most of the known actions of angiotensin II is mediated by AT1 The AT1 receptors are distributed widely: Vascular smooth muscle Adrenal cortex Kidney KidneyBrain · It is selective for AT1 receptors · It is selective for AT1 receptors · It inhibits the cardiovascular effects of angiotensin II · It inhibits the cardiovascular effects of angiotensin II · Similar efficacy to ACE inhibitors but without the bradykinin associated side is no cough and no chance of angioedema · Similar efficacy to ACE inhibitors but without the bradykinin associated side effects: There is no cough and no chance of angioedema However, other side effects may be: · Pathological effects on the fetus · Pathological effects on the fetus · GI adverse effects · GI adverse effects · Hyperkalemia (due to decreased aldosterone) · Hyperkalemia (due to decreased aldosterone)

18. VI-Centrally acting antihypertensive -The 2 drugs which are used are both α2 agonists · As α2 receptors are located presynaptically and centrally, once stimulated they will inhibit the release of NA from the sympathetic nerve terminal & reduce sympathetic outflow from CNS. -The 2 drugs which are used are both α2 agonists · As α2 receptors are located presynaptically and centrally, once stimulated they will inhibit the release of NA from the sympathetic nerve terminal & reduce sympathetic outflow from CNS. α-methyldopa α-methyldopa Enters the CNS via active transport into the brain· Converted to a methyl NA by the same enzymes (dopadecarboxylase) which are involved in NA synthesis & form α- methyl NA which is a false transmitter. Enters the CNS via active transport into the brain· Converted to a methyl NA by the same enzymes (dopadecarboxylase) which are involved in NA synthesis & form α- methyl NA which is a false transmitter. Selective α2 agonist causes reduced sympathetic outflow to the blood vessels and heart Selective α2 agonist causes reduced sympathetic outflow to the blood vessels and heart Adverse effects: Sedation, depression Sedation, depression Dry mouth (due to inhibition of the medullary areas controlling salivation) Dry mouth (due to inhibition of the medullary areas controlling salivation) Postural hypotension Postural hypotension Clonidine Clonidine Selective α2 agonist,it causes reduced sympathetic outflow to the blood vessels and heart· Selective α2 agonist,it causes reduced sympathetic outflow to the blood vessels and heart· It can cause rebound hypertension on cessation, therefore the patient needs to be titrated off the drug slowly It can cause rebound hypertension on cessation, therefore the patient needs to be titrated off the drug slowly Both drugs have weak postural hypertensive effect Both drugs have weak postural hypertensive effect