1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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

9. 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

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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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.

17. 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.

18. 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

19. 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

20. 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

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

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