Drugs used in the treatment of Hypertension I Dr. Asmaa Fady Ph D., MSC., M.B, B.Ch اسم ورقم المقرر – Course Name and No. 8/22/2019

Learning objectives By the end of the lecture, the student should: Explain the mechanism of hypertension List the therapeutic classes for managing the elevated blood pressure Describe the mechanism of action (& therapeutic actions) of each anti-hypertensive class Identify the adverse effects (& their mechanisms) of each antihypertensive class List therapeutic uses, contraindications, pharmacokinetics of each agent in each anti-hypertensive class Differentiate between anti-hypertensive classes in terms of their preferred uses (with other morbidities), therapeutic actions, & adverse effects اسم ورقم المقرر – Course Name and No. 8/22/2019

What is hypertension Systemic Hypertension: Defined as persistent elevation of blood pressure to above 140/90 mmHg in at least two measurements on at least two separate occasions. Hypertensive Urgency: Is a severe form of hypertension with rapid rise of blood pressure to > 180/120 mmHg not associated with target organ damage. Hypertensive Emergency: Is a severe form of hypertension with rapid rise of blood pressure to >180/120 mmHg associated with target organ damage as hypertensive encephalopathy, heart failure and renal failure. If associated with papilledema it is called malignant hypertension اسم ورقم المقرر – Course Name and No. 8/22/2019

Mechanisms for Controlling BP How does the body regulate (or increase) the BP? •The BP due to C.O &/or PR , the body responds by: o +++ Baroreflexes (sympathetic nervous system) o ++Renin–angiotensin–aldosterone system اسم ورقم المقرر – Course Name and No. 8/22/2019

Pathophysiology of Essential Hypertension Arterial blood pressure is directly proportional to cardiac output and peripheral vascular resistance The elevated BP is due to either C.O &/or TPR . afterload A.B.P= COP * TPR. (COP= SV * HR) ABP= arterial blood pressure. COP= cardiac output. TPR= total peripheral resistance. SV= stroke volume. HR= heart rate preload اسم ورقم المقرر – Course Name and No. 8/22/2019

Goals of anti- hypertensive drug therapy A.B.P= COP * TPR. (COP= SV * HR) use Beta blockers (TPR is affected by BV tone (VC TPR, VD TPR) use Arteriodailator Sympathetic +++ use (Sympatholytics: BB, alpha2 agonists, selective alpha 1 blockers) Renin angiotensin aldosterone system (SV depends on venous return which is dependent on blood volume): use (Renin angiotensin system blockers, venodialtors so decreasing VR, or decreasing blood volume: diuretics) Effect of Ca on heart & Bvs: relax heart & Arteriodaialation use (CCBs) اسم ورقم المقرر – Course Name and No. 8/22/2019

Classification of Drugs used in management of hypertension A) First line or primary drugs used alone or in combination: 1. Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blockers (ARBs) & Renin inhibitor (RI) 2. Beta Blockers. 3. Calcium Channel Blockers. 4. Diuretics. B) Second line or Alternative drugs that may be used in selected patients after failure of first line groups or due to adverse effects: 5. Central α2 agonists. 6. Alpha blockers. 7. Vasodilators (vaso, veno & mixed dialators) اسم ورقم المقرر – Course Name and No. 8/22/2019

Drugs used in management of hypertension BB αB BB ACEI RI ARBs AA اسم ورقم المقرر – Course Name and No. 8/22/2019

Medications for Hypertension What’s the effects of the pharmacological interventions on the factors affecting the BP? ACE Inhibitors ARBs Renin Inhibitors α-blockers CCB (both DHP & NDHP) Direct vasodilators Afterload BB CCB (only NDHP) اسم ورقم المقرر – Course Name and No. ACE Inhibitors ARBs Renin Inhibitors Diuretics preload 8/22/2019

1)Renin Angiotensin Aldosteron System (RAAS) Antagonists Veins, arteries اسم ورقم المقرر – Course Name and No. 8/22/2019

Renin Angiotensin Aldosteron System (RAAS) Antagonists (1) ACE inhibitors. (2) ARBs. (3) Renin inhibitors Avoid the routinely combination of these 3 classes together اسم ورقم المقرر – Course Name and No. 8/22/2019

ACE inhibitors: captopril, lisinopril, Fosinopril pharmacokinetics: Absorption: Oral forms. Distribution: pass placental barrier (teratogenic in the 1st trimester, fetal renal hypoplasia if taken during 2nd & 3rd trimester) contraindicate din pregnancy. Metabolism & excretion: All are prodrugs: activated in liver & excreted by the kidneys. except Captopril: (active drug 50% metabolized by liver & 50% excreted unchanged by kidneys). Lisinopril: (active drug totally excreted unchanged by kidneys (adjust dose in renal disease) Fosinopril:(prodrug: excreted in bile: good choice in renal patients) اسم ورقم المقرر – Course Name and No. 8/22/2019

ACE inhibitors: captopril, lisinopril Mechanism of Action: Inhibit Angiotensin Converting Enzyme: a- decrease Conversion of inactive Angio I to active Angio II decrease Synthesis of Angio II: *decrease VC. *decrease Aldosterone. *inhibit Sympathetic. *decrease Hypertrophy & Remodeling of heart & BV. increase Renin & Angio I. b- decrease Inactivation of Bradykinin increase Bradykinin VD (Directly & by increase PGs& NO). اسم ورقم المقرر – Course Name and No. 8/22/2019

ACE inhibitors: pharmacological actions a- Mixed VD Arterial > Venous. b- Art. VD decrease T.P.R. decrease After-load & Bl.p. c- Weak Vein. VD decrease V.R. decrease E.D.V. decrease Pre-load & Bl.p. d- C.O.P. is maintained or even in cases of H.F. e- Increase Renal Blood Flow. f- Advantages: NO decrease of COP, even it may increase COP in HF. NO postural hypotension. NO reflex tachycardia (decrease Baroreceptors reflex & Sympathetic activity). NO abnormality in Glucose or Lipid or Cholesterol or Uric acid metabolism (Better than beat blockers & diuretics). Weak Venodialtors اسم ورقم المقرر – Course Name and No. 8/22/2019

Therapeutic Uses of ACE.I a- Hypertension, especially: - High renin. - Diabetic nephropathy (Very Important). - Heart failure. b- Heart Failure: - Decrease BOTH After & Preload Improve cardiac performance increase COP. اسم ورقم المقرر – Course Name and No. 8/22/2019

ACE inhibitors adverse effects captopril, lisinopril 1- Dry irritant Cough due to increase of Bk & PGs. (how to treat): Treat by NASID or shift to ARBs. 2- First dose hypotension especially in Na+-depleted patients by diuretics. 3- Hyperkalemia, especially if accompanied with K+-retaining diuretics. 4- Allergic manifestations & Angioedema. 8/22/2019 اسم ورقم المقرر – Course Name and No.

ACE inhibitors contraindications & drug interactions captopril, lisinopril *Contraindicated in pregnancy ( Fetal hypotension, renal failure, Oligohydramnios, Malformation or DEATH). *Contraindicated in Bilateral Renal Artery stenosis (Fatal Renal Failure). drug interactions : 1- K+-retaining diuretics e.g. Spironolactone augments the hyperkalemic effect. 2- NASID e.g. aspirin antagonize partially the hypotensive effect by blocking synthesis of PGs. 3- Antacids decreases absorption of ACEIs 8/22/2019 اسم ورقم المقرر – Course Name and No.

Angiotensin II (AT1) - Receptor Blockers: Losartan,Valsartan, Candesartan, Telmisartan Mechanism of action: *Compete with Angio II for AT1-receptors. They are Pure Antagonists. Leading to: decrease V.C. (V.D). decrease Synthesis and release of Aldosterone inhibit Sympathetic : Block of presynaptic AT1-receptors on adrenergic neurons (decrease Noradrenaline release). Prevent hypertrophy & Remodeling of Heart & BV due to hypertension. VD of Renal vessels (decrease Glomerular hypertension (Efferent renal VD). ** Metabolic Actions: Correct side effects of diuretics a- correct Hypokalemia. b- correct Hyperuricemia. اسم ورقم المقرر – Course Name and No. 8/22/2019

Angiotensin II (AT1) - Receptor Blockers: Losartan,Valsartan, Candesartan, Telmisartan Oral forms: Therapeutic Uses: Similar to ACE.I. Side Effects: Similar to ACE.I. BUT NO Dry irritant cough. (no effect on bradykinins). Contraindicated: Pregnancy & bilateral renal artery stenosis. اسم ورقم المقرر – Course Name and No. 8/22/2019

Renin antagonists: A) Drugs Release of Renin: 1- B1-Blockers: Atenolol, Propranolol & Labetalol. 2- α2-agonists: Clonidine & α -Methyl-Dopa B) Drugs attach to the active site of renin enzyme & inhibits its action (Aliskiren) Dosage form: given orally Adverse effects: Similar to ACEI & ARBs adverse effects Diarrhea (especially at high doses) Hyperkalemia Cough & Angioedema (less often than ACE inhibitors) Monitoring Parameters: K+ level & scerum Cr Contraindications: Pregnancy Renin antagonists: اسم ورقم المقرر – Course Name and No. 8/22/2019

2) Beta-blockers (BBs) Mechanism of action (delayed action: 4 weeks) The β-blockers reduce blood pressure primarily by decreasing cardiac output. They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys, thus decreasing the formation of angiotensin II and the secretion of aldosterone. All BBs may consider as treatment option for hypertension Non-selective β blockers propranolol (avoid in asthmatic patient) β1-selective blockers metoprolol & atenolol. Non-selective β blockers with α1- blocking action (labetalol) β blockers with ISA (intrinsic sympathomimetic activity) اسم ورقم المقرر – Course Name and No. 8/22/2019

Beta-blockers (BBs): Mechanism of action & adverse effects اسم ورقم المقرر – Course Name and No. 8/22/2019

Beta-blockers (BBs) Option for hypertensive patients with concomitant heart disease In patients with chronic heart failure and hypertension. Choice in case of hypertension emergency (with stroke). Safe choice for hypertension in pregnancy. β-Blockers should not be used in the treatment of patients with acute heart failure or peripheral vascular disease اسم ورقم المقرر – Course Name and No. 8/22/2019

3) Calcium channel blockers CCBs Nondihydropyridine CBB (NDHP-CBB) Verapamil Diltiazem Dihydropyridine CBB (DHP-CBB) Nifedipine Amlodipine Felodipine Isradipine Nicardipine اسم ورقم المقرر – Course Name and No. 8/22/2019

CCBS (calcium channel blockers) NDHP-CBB: work on both cardiac and vascular smooth muscle cells DHP-CBB: mainly (greater affinity) for vascular smooth muscle cells Mecahnism of action: Ca enters smooth muscle cells (either myocardium or vascular) through special voltage sensitive Ca channels: release of Ca from the sarcoplasmic reticulum and mitochondria: increases the cytosolic level of Ca: vasoconstriction & myocardium contraction اسم ورقم المقرر – Course Name and No. 8/22/2019

CCBS (calcium channel blockers) M.O.A & pharmacological Actions: *NDHP-CBB CCBs block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral arteriolar vasculature: Heart: ↓ contraction (& also ↓ HR, conduction) : used for arrhythmias Coronary and peripheral arteriolar vasculature: vasodilation (↓ PR ↓ BP) DHP-CBB CCBs block the inward movement of calcium by binding to L-type calcium channels in smooth muscle of the coronary and peripheral arteriolar vasculature Coronary and peripheral arteriolar vasculature: dilation (↓ PR ↓ BP Calcium channel blockers do not dilate veins اسم ورقم المقرر – Course Name and No. 8/22/2019

CCBS (calcium channel blockers)- pharmacokinetics NDHP-CCBs Have short half-lives But available as Sustained-release preparations that can be given once-daily dosing NDHP-CCBs Long half-life, Once daily dosing اسم ورقم المقرر – Course Name and No. 8/22/2019

CCBS (calcium channel blockers)- Therapeutic uses NDHP-CCBs 1. Hypertension 2. Angina 3. Atrial fibrillation NDHP-CCBs 1. Hypertension. 2. Angina اسم ورقم المقرر – Course Name and No. 8/22/2019

CCBS (calcium channel blockers) Adverse effects CCBS (calcium channel blockers) NDHP-CCBs 1. Hypotension. 2. AV block (how?) 3. Bradycardia • Verapamil may cause first- degree atrioventricular block and constipation (common) NDHP-CCBs 1. Dizziness 2. Headache 3. Fatigue 4. Peripheral edema Contraindications: Verapamil and diltiazem should be avoided in patients with heart failure or with atrioventricular block due to their negative inotropic and dromotropic effects اسم ورقم المقرر – Course Name and No. 8/22/2019

اسم ورقم المقرر – Course Name and No. 8/22/2019