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Memy H. Hassan, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Dina S. El-Agamy, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Lecture ILOs • To outline the basic scientific terms of hypertension and

different management options

• To understand the action of drugs on cardiac and vascular

smooth muscle

• Topics covered in this lecture 1. Snapshot overview about hypertension

2. Characters of ideal antihypertensive drugs

3. Pharmacological principles in the treatment of hypertension

4. Classes of antihypertensive drugs.

5. Mode of action and beneficial effects of different antihypertensive drugs

6. Main uses, main adverse effects and main drug interactions of antihypertensive

drugs

7. Choice of antihypertensive drug in different disease conditions

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Remember

Snapshots about hypertension

Def.: HTN is a sustained elevation of blood pressure: – Systolic BP 140 mm Hg

– Diastolic BP 90 mm Hg.

When drug therapy is indicated?

• If the diastolic pressure 90 mm Hg.

HTN Risk Factors A) Influenceable factors: Cigarette smoking; Elevated LDL; Stress;

Obesity; Increased Na intake.

B) Non- Influenceable factors: Family history; Insulin resistance (DM); Age

Signs & Symptoms – Usually NO SYMPTOMS!

– “The Silent Killer”

– May have: Headache; Blurry vision; Chest Pain; Frequent urination at night

• Confirmed by Blood Pressure Measurement

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Category

• Normal

• High normal (Prehypertension)

Hypertension (old classes))

• Stage 1 (mild)

• Stage 2 (moderate)

• Stage 3*** (severe)

• Stage 4*** (Malignant)*

Systolic** Diastolic

<130 <85

139 89

140-159 90-99

160-179 100-109

180-209 110-119

>210 >120

Remember

Classification of HTN

1. According to the degree of rise in BP

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Hypertension

Essential (primary) HTN - in 90-95 % & of unknown cause.

- Predisposing factors are risk

factors.

Secondary HTN (in 5-10 %)

due to: a) Pathological defect: e.g., Renal

artery stenosis & Coarctation of

the aorta.

b) Hormonal defects: Cushing´s

syndrome, phaeochromocytoma.

c) Physiological defects: e.g.,

HTN with pregnancy

d) Drug-induced HTN:

(sympatomimetics,

glucocorticoids)

Remember

2. Classification of HTN According to Etiology

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THERAPY OF HYPERTENSION

A) Non-pharmacological Approaches

1. Salt intake:

2. Body weight:

3. Cessation of smoking or alcohol drinking.

4. Regular physical activity and relaxation.

6. Stress avoidance (both physical & mental).

7. Intake K+:

8. Coffee restriction:

B) Pharmacotherapy using antihypertensive drugs which are classified

according to the mode of action

1. Diuretics.

2. Sympatholytics.

3. Direct Vasodilators.

4. Calcium channel blockers.

5. Drugs that interfere with Renin Angiotensin System (RAS).

Characters of ideal antihypertensive drug

1) Effectively reduce BP

2) Taken once daily

3) No serous side effects or at least acceptable profile

4) Produce 24 h control

5) Reduce HTN- induced complications

6) Shows predictable dose-effect relationship

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Mode of hypotensive action: • Diuretic effects (Depletion of the sodium and water) blood

volume and cardiac output.

• Vasodilator effects PR (with thiazides)

i- Thiazides and related drugs Chlortalidone, Hydrochlorothizide & Indapamide, etc. Most frequently used diuretics in HTN. More effective as hypotensive drugs than loop diuretics. In severe HTN, used in combination with other drugs (ACEIs or ARBs). Not useful in HTN patients with renal impairment. Mechanism of hypotensive action of thiazides

a) Initially: blood volume by diuretic effects CO. b) Later on: VD effect PVR

Side effects:

HYPO: tension, kalaemic metabolic alkalosis , magnesaemia, natraemia,

erection………………. HYPER: glycaemia , uricaemia, calcaemia

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ii- LOOP DIURETICS

e.g., Furosemid, ethacrynic acid, bumetanide & torsemide.

Used in: - Severe HTN.

- HTN patients with renal impairment.

- HTN Patients with left sided HF &/or pulmonary oedema.

- HTN not responded to thiazide diuretics

- HTN emergency. Rapid onset & short duration (4 hours) .

- Less antihypertensive efficacy than thiazides (due to short duration).

Mechanism of hypotensive action:

a) Diuretic effect blood volume CO.

b) Venodilation venous return CO.

Side effects

similar to thiazide except it produces hypocalcemia,

ototoxicity and Idiosyncratic allergic reactions

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iii- K-sparing Diuretics

1. Spironolactone (Aldactone):

– Lower BP by its diuretic effect ( plasma

volume).

– Aldosterone receptor blocker

– Used in:

• HTN due to hyperaldosteronism.

• Combination with K-depleting drugs

• Combination with digitalis & thiazides in HF.

2. Amiloride & triamterene: • Useful in combination with K-depleting drugs.

• Blocking lumenal sodium channels

Drugs interfering with Renin-angiotensin System

Beta-blocker -

--

A- Angiotensin converting enzyme inhibitors (ACEIs)

Types of ACEIs

1. Active molecules: Captopril, Lisinopril, Enalaprilat

2. Prodrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril.

Mechanism of Action: Inhibition of angiotensin II formation leading to:

a- Beneficial effect

1-Reduction in systemic arteriolar resistance, systolic, diastolic and mean

arterial pressure.

2- Regional hemodynamic effects:

– Increased regional blood flow & large artery compliance

3- Decreased aldosterone secretion

B- Bad effect: accumulation of bradykinin causing dry cough sometimes

accompanied by wheezing, and angioedema

Effect of ACEIs on blood pressure

i- Favorable side effects: tolerated by most patient.

ii- Beneficial for diabetics : renoprotective in diabetic nephropathy.

iii- Beneficial in HTN with heart failure: 1st choice.

iv- Beneficial if used Post MI: morbidity& improve ventricular function.

v- Do not cause sexual dysfunction: (unlike diuretics & sympatholytics).

vi- Do not cause postural hypotension. (unlike α blocker &direct vasodilators)

vii- Do not produce serious metabolic alterations: no hypokalemia, no

hyperglycemia, no hyperlipidemia.

Advantages of ACEIs

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Uses of ACEIs

1. Hypertension: stages 1- 4 HTN

2. Heart failure: 1st choice.

3. Acute MI:

– Started immediately during the acute phase

of MI.

– Administered along with thrombolytics,

aspirin, and BBs).

1. Diabetic & non-diabetic nephropathy:

– Renoprotective: because of intrrenal

hypertension or growth factor formation.

ADRs of ACEIs 1. S-H related adverse effect:

– Allergic reactions: edema, rash and neutropenia ( # Use other ACEIs).

– Dysgeusia: temporary loss of taste. (# Use other ACEIs).

– Drug (e.g., antacids) and food interactions (reduce absorption of captopril # by giving before meal

2. Class adverse effects: – Hypotension : after 1st dose in Na+ depleted patients by diuretics # stop diuretics before

administration.

– Dry cough and loss of smell: due to accumulation of bradykinin & PGs

– Hyperkalemia: (due to aldosteron) # by HTZ (e.g., capozid).

– Fetopathic Potential: fetal hypotension , fetal growth retardation & fetal death if given during 2nd or 3rd trimesters.

– Acute renal failure: In patients with bilateral renal artery stenosis # C/I in bilateral artery stenosis

– Angioedema: rapid swelling in the nose, throat, mouth, glottis, larynx, lips, and/or tongue

due to change in bradykinin metabolism

– Proteinuria……..in patients with compromised renal function.

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B) BLOCKERS OF AT1 RECEPTOR

Members:

Losartan , Candesartan, Irbesartan, Valsartan, Telmisartan, Eprosartan

Thiazide-combinations: Losartan + HTZ, Candesartan + HTZ & Valsartan

+ HTZ

Mode of action

Competitive antagonists of angiotensin II :

• Relax smooth muscle VD

• renal salt and water excretion

• Reduce plasma volume

• Decrease cellular hypertrophy antiremodeling

BP

Advantages of AIIRBs over ACEIs

• Prevent accumulation of bradykinin and PGs.

• Free from dry cough caused by ACEIs

Uses: as ACEIs:

Mild-severe HTN; Post MI; HF

Diabetic nephropathy.

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Sympatholytics

a) -Adrenergic blockers: e.g., propranolol,

metoprolol, etc.

b) - Adrenergic blockers: e.g., prazosin,

phenoxybenzamine, etc.

c) Mixed adrenergic antagonists: e.g., labetalol &

carvedilol.

d) Adrenergic neuron blockers: e.g., reserpine,

guanethidine & guanadrel.

e) Ganglion blockers: e.g., trimethaphan.

f) Centrally acting: e.g., clonidine, -methylopa.

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1. - Adrenergic Receptor Antagonists

• First generation (non-selective β blockers): e.g., Propranolol, Nadolol, Sotalol and Timolol

• Second gereation ( β1-Selective β blockers): e.g., e.g., Acebutolol, Atenolol, Bisoprolol, Esmolol & Metoprolol

Mechanism of Hypotensive Action of -Blockers

1. Decreased cardiac output.

2. Inhibition of renin secretion from the kidneys.

3. Decreased central sympathetic outflow.

4. Blocking presynaptic 2-receptors → NEP release.

Therapeutic Uses of - blockers in HTN

1. Used for all grades of HTN.

2. All are preferred in HTN concomitant with:

– SVT, previous MI, IHD, chronic HF, and migraine headache.

3. β1-Selective β blockers are preferred in asthmatics & diabetics-why?

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2. 1 - Adrenergic Antagonists

e.g. Prazosin; doxazosin; Terazosin

produce a competitive block of ɑ1-adrenoceptors.

– VD of artery & arterioles PVR diastolic BP.

– VD of veins & venules venous return CO systolic

BP (not significant).

Tamsulosin, an ɑ1a- blocker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia.

Therapeutic Uses of 1 -blockers

• Attractive drugs for HTN patients with BPH–why?

– improve both urinary & BP symptoms.

ADRs of 1 - Adrenergic Antagonists

1. First-dose Phenomena. Orthostatic hypotension (given at bed time); Syncopal

attacks and fall

2. Palpitation & tachycardia

3. GI upset

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3. Mixed 1 and - receptor antagonists

1. Labetalol (TRANDATE) • Used in hypertensive emergencies; I.V. labetalol

BP sufficiently & rapidly.

• Blocking 1-adrenergic receptors & -receptors.

2. Carvedilol (COREG):

• Used in HTN with symptomatic HF:

– It reduces mortality in patients with HF why?

Because of VD & anti-remodeling effect.

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4. Central sympatholytics

a) - Methyldopa (ALDOMET): – Commonly used in HTN with pregnancy- why?

• Due to its efficacy and safety for both mother and fetus.

– Centrally acting antihypertensive agent- How?

- Methyldopa (prodrug) active metabolite -methylnorepinephrine :

• Central 2-agonist central sympathetic outflow.

• Peripherally released as false transmitter.

ADRs of -Methydopa 1. Central ADRs related to pharmacological actions:

Sedation; Psychic depression: due to depletion of catecholamines in CNS; Dryness of the mouth; Reduction in libido & impotence: due to sympatholytic action in the CNS; Parkinsonian signs: due to dopamine depletion in basal ganglia; Hyperprolactinemia gynecomastia and galactorrhea.

ii) Rare ADRs; immunological reactions:

1) Hepatotoxicity associated with fever. 2) Hemolytic anemia.

3) leukopenia, thrombocytopenia, red cell aplasia,

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b) Direct central 2-agonist:

Members:

• Clonidine (CATAPRES); Guanabenz (WYTENSIN); Guanfacine (TENEX)

Mechanism of action:

• Central 2 (2A) receptor agonists (in brainstem) sympathetic

outflow from the CNS BP (both CO & PVR).

• High doses peripherally stimulate postsynaptic 2 receptor VC

BP.

Uses of Clonidine (2006) Not commonly used in TTT of HTN.

• Clonidine is used in hypertensive patients for the diagnosis of

pheochromocytoma

• Clonidine is used in management of opioid withdrawal

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CALCIUM CHANNEL-BLOCKERS

1. Dihydropyridine derivatives: 1. Nifedipine

2. Amlodipine 3. Isradipine

4. Nicardipine

5. Felodipine

– VD with reflex tachycardia.

2. Non-dihydropyridine: Diltiazem (DILZIUM)

Verapamil (ISOPTIN)

– VD with –ve chronotropic & -ve inotropic effects.

Blocking Ca2+ channels (L-type voltage-sensitive type) Ca2+

intracellularly

Relaxation of the arterial smooth muscle but not much effect on venous

smooth muscle → Significant reduction in afterload but not preload.

Myocardial depressant effect by only verapamil and diltiazem CO.

Inhibiting phosphodiesterase enzymes cAMP VD PVR.

Cardiovascular Uses of CCBs

Angina pectoris

Hypertension

Supraventricular arrhythmias (verapamil & Diltiazem only)

- Atrial Flutter

- Atrial Fibrillation

- Paroxysmal SVT

CCBs – Mechanisms of Action ( COP and TPR)

According to route of administration

Oral Vasodilators Hydralazine & Minoxidil

Parenteral Vasodilators Diazoxide & Sodium nitroprusside

(Used in emergency(

Direct Vasodilators

Direct Vasodilators according to site of action

Arteriodilators Hydralazine & Minoxidil and

Diazoxide

Mixed Vasodilators Sodium nitroprusside

Vasodilators

• They dilate blood vessels by acting directly on

smooth muscle cells through non-autonomic

• Major mechanisms for direct vasodilators

– Release of nitric oxide e.g. sodium nitroproside

– Opening of potassium channels e.g. Minoxidil,

Diazoxide

– Fall of intracellular calcium in BV e.g. Hydralazine

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Hydralazine Action:

VD is usually associated with:

REFLEX TACHYCARDIA # by - blockers

WATER RETENTION # Diuretics.

No Postural hypotension: Because of preferential arteriodilation.

Uses

Severe hypertension (stage 3).

Congestive heart failure. (Hydralazine + nitrates + BB + HTZ)

Hypertensive emergencies (pregnant women especially preeclampsia).

Side effects

Headache

Tachycardia and marked sodium and water retention

Diarrhea

A lupus-like syndrome may occur

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K+ ATP Channel Openers: Minoxidil

Mechanism of hypotensive action:

• Minoxidil is a prodrug

• Therapeutic Uses of Minoxedil:

1. TTT of severe hypertension in male patients:

2. Resistant Heart failure (due to VD effect).

3. Topically in Alopecia “male pattern baldness” Adverse Effects and Precautions:

1. Fluid and salt retention # diuretics.

2. Reflex tachycardia & palpitation # BB.

3. Hypertrichosis: in face, back, arms, and legs (offensive to women) # avoided in females.

4. Hyperglycemia # avoided in DM.

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Diazoxide (HYPERSTAT IV)

• It is long-acting arteriodilator

• insulin secretion hyperglycemia.

Uses:

1. I.V. in hypertensive emergencies if:

– Non-availability of sodium nitroprusside.

– Non-availability of infusion pump.

– Non feasible close monitoring of BP.

2. Orally in hypoglycemia associated with hyperinsulinoma.

Adverse Effects of Diazoxide:

Palpitations & tachycardia; Fluid retention; Hyperglycemia;

Gastrointestinal intolerance

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Sodium nitroprusside (mixed dilator)

Locus and Mechanism of Action:

• It acts by releasing NO NO activates the guanylyl

cyclase cGMP VD in both arterioles & venules

both PVR & venous return BP.

• Therapeutic Uses • Short-acting agent (few minutes) thus it must be

infused continuously

1. Hypertensive emergencies (first choice).

because it has rapid onset of action, very effective and has an acceptable toxicity that can be monitored

1. Acute aortic dissection: to BP during the surgery.

2. HTN patients with cardiac asthma: to improve CO.

3. Post MI: to decrease myocardial oxygen demand.

4. To induce controlled hypotension during anesthesia.

Sodium nitroprusside (cont.) • Side effects

– Hypotension (most frequent adverse effect)

– Nausea & vomiting

– Headache

– Palpitation

– Release of cyanide ions in certain cases.

APPENDIX

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Steps of Drug Therapy for

Hypertension

1st Step → Monotherapy

Diuretics ACEI

Ca Channel Blockers β-blocker

• The drugs therapy is changed if:

(a) NO response

(b) They are poorly tolerated

(c) There is contraindication e.g. asthma

(d) There is concurrent disease that might benefit from

another class of antihypertensive drugs

If BP decreased BUT not to the recommended

level

• 2nd Step → Two Drugs

β-blockers + diuretic OR Ca antagonist

OR

ACEI + diuretic OR Ca antagonist

• If failed → 3 drugs

• If failed → Resistant hypertension (give 4 or 5

drugs including vasodilators)

Pregnant Women

Pre-existing chronic hypertension

Give only methyl dopa, Nifedipine OR Labetalol

Other drugs are teratogenic

Diuretics, β-blockers & ACEI retard fetal growth in the 2nd trimester

Pre-eclampsia After 20 weeks of gestation

Hypertension, edema, protein urea & hyperuricemia

Fetal death or growth retardation

Bed rest

In severe case, give iv bolus injection of hydralzine

Then methyl dopa, Nifedipine OR labetalol

Treatment of Hypertensive Emergencies

• Hypertensive emergencies (with end organ damag) include

hypertension associated with vascular damage (termed malignant

hypertension) and hypertension associated with hemodynamic

complications such as heart failure, stroke, or dissecting aortic aneurysm

• The goal of treatment in the first few hours or days is to lower BP by

about 25%, maintaining diastolic blood pressure at no less than 100 mm

Hg. Subsequently, blood pressure can be reduced to normal levels using

oral medications over several weeks.

• Complete normalization of blood pressure at first is contraindicated

because rapid normalization of blood pressure may lead to cerebral

hypoperfusion and brain injury.

Treatment of Hypertensive Emergencies

• Sodium nitroprusside (most common FIRST CHOICE).

• Other parenteral drugs e.g. fenoldopam, nitroglycerin,

labetalol, calcium channel blockers, diazoxide, and

hydralazine.

• Esmolol is often used to manage intraoperative and

postoperative hypertension.

• Diuretics such as furosemide are administered during

administration of powerful vasodilators

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TTT of hypertensive urgency

HTN urgency: HTN crisis without end organ damage

• Need prompt medical attention BUT lowering BP

can be achieved within 24-48 h.

• Use vigorous oral therapy in outpatient clinic.

• e.g., Captopril & clonidine Can be used for

treatment of HTN urgency.

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Choice of Antihypertensive Drugs

1. Uncomplicated stage 1 HTN.

2. Uncomplicated stage 2 HTN.

3. HTN with heart failure.

4. HTN + pregnancy

5. Isolated syst HTN

6. HTN emergency

1. HTZ Diuretics or Bs, ACEIs / AIIRBs, CCBs (or combination)

2. HTZ Diuretics + another drugs from any class.

3. ACEIs / AIIRBs + Diuretic, Bs,

4. -methydopa or Hydralazine

5. CCBs (Amlodipine).

6. I.V. Na nitroprusside,

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Summary of most important contraindications of

antihypertensive drugs

• CCBs (verapamil & diltiazem) in HTN with HF or

heart block.

• BBs in HTN with peripheral vascular disease.

• BBs and ACEIs in HTN with BA or COPD.

• Diuretics, BBs, ACEIs or AIIRBs in HTN with

pregnancy.

• BBs, Diuretics & diazoxide in HTN with diabetes.

• Thiazides, BBs and sympatholytics in HTN with

impotence.

LETURE RESOURCES: • Harvey R. A. (2015). Lippincott's Illustrated Reviews:

Pharmacology. 5th ed., Philadelphia, PA, USA,

Lippincott Williams& Wilkins. Unite IV; chapter 19.

• Katzung B.G. (2015), Basic and Clinical

Pharmacology, 13 th ed., New York, USA, McGraw-

Hill Medical. Section III; chapter 11.

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