1. Therapy of hypertensionBy
Dr. Mohamed Abd Almoneim Attia

2. Calcium channel blockers (CCBs)
These are drugs that block voltage-gated Ca2+ channels.
Classification of CCBs according to therapeutic effect:
CCB with mainly cardiac effects: verapamil, diltiazem.
CCB with mainly vascular effects: nifedipine, amlodipine, isradipine.
CCB with mainly tissue protection: flunarizin, cinnarizine
N.B : Voltage-dependent Ca2+ channels: they are of 3 main types:
L-type (Large in conductance or Long lasting).
T-type (Transient in duration).
N-type (Neuronal in distribution).
L-type channel is the dominant type in cardiac and vascular sm ms.
They open in response to cell depolarization and could be blocked by calcium channel blockers.
Calcium channel blockers block the L-type more than other types.

3. Pharmacokinetics: Oral absorption is nearly complete
Pharmacokinetics: Oral absorption is nearly complete. Plasma protein binding is 70-98% Metabolism: verapamil and diltiazem are metabolized into active metabolites. In older patients and in patients with liver cirrhosis the dose should be decreased. Pharmacological effects:

4. Verapamil
Diltiazem
Nifedipine
+++
↓↓↓ ↓↓ ++ ↓ -
↑ (reflex)
Heart:
–ve inotropic effect
A-V conduction HR +
Blood vessels:
Coronary and arterial dilatation BP

5. Other effects:
1-Smooth muscles: they relax bronchial, GIT, and uterine smooth ms.
2-Platelets: they ↓ platelet aggregation.
3-Insulin release: verapamil ↓ insulin release (in high dose).
4-CNS: they ↓ seizure (convulsions) activity.

6. A. Cardio-selective CCBs (verapamil and diltiazem):
Therapeutic uses:
A. Cardio-selective CCBs (verapamil and diltiazem):
1-Ischemic heart disease: see IHD
They ↓ myocardial contractility and myocardial O2 demand.
They ↓ coronary vascular resistance and increase coronary blood flow.
They dilate epicardial coronary vessels.
They improve myocardial relaxation and ↓ myocardial cell necrosis.
N.B.
Although nifedipine is coronary dilator, it has some disadvantages in angina:
It may cause hypotension and reflex tachycardia.
It may cause “steal phenomenon” .

7. 2-Cardiac arrhythmias: supraventricular tachycardia (SVT):
Because they ↓ SAN activity and slow A-V conduction.
N.B.
Nifedipine is contraindicated because it cause hypotension and reflex tachycardia.

8. 3-Hypertrophic obstructive cardiomyopathy (IHSS):
In hypertrophic obstructive cardiomyopathy, the wall of the left ventricle and interventricular septum is much thickened leading to narrowing of the aortic outlet and obstruction of blood flow. This obstruction is increased by increasing contractility while decreasing contractility leads to decrease resistance to blood flow through the aortic outlet.
N.B.
Nifedipine is contraindicated because it produces reflex tachycardia → worsening of the outflow obstruction.

9. 4-Arterial hypertension:
They cause VD due to ↓ Ca2+ influx in the vascular sm ms.
They ↓ myocardial contractility and COP.
They ↓ platelet aggregation.
B. Vasculo-selective CCBs (Nifedipine and amlodipine):
1-Arterial hypertension.
2-Senile cerebral ischemia (nimodipine).
3-Peripheral vascular disease: to improve peripheral microcirculation.
4-Chronic renal failure: to minimize renal ischemia.
5-Re-perfusion injury: to minimize tissue damage.
6-Prophylaxis of migraine: by unknown mechanism.

10. Adverse effects:
1-Verapamil and diltiazem:
*Bradycardia and heart block.
*Worsening of CHF (due to their –ve inotropic effect).
*↓ insulin release and worsening of DM.
*Constipation and reversible hepatotoxicity.
*Ankle edema (less common than with nifedipine).

11. 2-Nifedipine:
*Hypotension and reflex tachycardia.
*Steal phenomenon and aggravation of angina.
*Gingival hyperplasia.
*Ankle edema (due to VD).
How to treat ankle edema if occurred from CCBs?
Minimize sodium intake.
Avoid prolonged standing.
Mild diuretics.
Stop CCBs if the above measures failed.

12. Contraindications and precautions:
1-Verapamil:
Heart failure.
Bradycardia, heart block, or sick sinus syndrome (SSS).
With β-blockers: because both β-blockers and verapamil have –ve inotropic and chronotropic effects, this will cause severe cardiac depression (nifedipine is the drug of choice if β-blockers are used with CCBs because it doesn't cause bradycardia).
With digitalis: because digitalis also ↓ A-V conduction and HR.

13. 2-Nifedipine:
Severe heart failure.
Hypotension.
Hypertrophic obstructive cardiomyopathy (IHSS)
Unstable angina (for fear of reflex tachycardia and steal phenomenon).

14. RENNIN ANGIOTENSIN ALDESTERON SYSTEM
RENIN: It is a proteolytic enzyme secreted by the kidney into the blood stream.Stimuli that increase renin secretion: Sodium depletion, diuretics, hypotension, hemorrhage, upright posture, dehydration, constriction of renal artery, heart failure and Cirrhosis

15. Actions of Angiotensins
Angiotensin I (precursor of angiotensin II): It has no pharmacological action.
Angiotensin II: It acts on two receptors; AT1 and AT2 receptors
(1) Its action on AT1 receptor produces the following:
CVS:
Arteriolar constriction leading to increased systolic and diastolic blood pressure (40 times as active as norepinephrine).
Angiotensin II produces positive inotropic and chronotropic effects which are primarily due to central and peripheral sympathetic stimulation.
Endocrine:
Increase secretion and synthesis of aldosterone which causes Na and water retension.
Facilitate catecholamine synthesis and release.
Increase pituitary vasopressin and ACTH.

16. Renal:
Suppress renin release
V.C of renal efferent arterioles, increases proximal tubular Na+ reabsorption
C.N.S
Increase H2O intake and vasopressin secretion.
Stimulate central sympathetic discharge.
(2)Its action on AT2 receptor produces the following:
Antiproliferation.
Apoptosis (normal cell death).
Vasodilatation and increase local bradykinin.

17. Stimulators of renin-Ang system:
 Renal ischemia of any cause.
Hypovolemia and hypotension.
β1 agonists.
Vasodilators.
Inhibitors of the renin-Ang system:
 Inhibitors of renin release: β-blockers, α-methyldopa, clonidine.
Inhibitors of plasma renin activity: aliskrine.
Inhibitors of Ang-2 formation: angiotensin-converting enzyme inhibitors (ACEIs)(pril)
Blockers of AT receptors: saralasin, losartan, valsartan

18. Angiotensin-converting enzyme inhibitors (ACEIs):
 Classification:
A-SH-Containing:
Captopril
Zofinopril
The sulfhydryl group (-SH) present in captopril may be responsible for the immunological side effects e.g. angioedema, taste changes, skin rash, leukopenia
B-Non SH-Containing:
  Enalapril
Fosinopril
Lisinopril
Benazepril

19. Mechanism of action: They inhibit Ang-converting enzyme (ACE) leading to:
Inhibition of Ang-2 formation in the heart, blood vessels, and tissues.
Prevent degradation of bradykinin which is a potent VD.
Inhibition of aldosterone release.
ACEIs have direct VD action to both arteries and veins.

20. Pharmacological effects:
CVS:
1-They ↓ BP mainly by decreasing peripheral resistance but no reflex tachycardia or changes in the COP can occur due to:
Resetting of baroreceptors downwards.
Venodilatation
Enhanced parasympathetic activity.
2-They ↑ COP only in congestive heart failure (not in normal conditions) due to reduction of systemic BP and peripheral VD.
3-They ↓ the left ventricular mass and wall thickening after myocardial infarction because they prevent myocyte cell proliferation and collagen synthesis (i.e. prevent cardiac remodeling).
4-They maintain cerebral and coronary blood flow.

21. Kidney: They ↓ proteinuria in mild renal impairment and diabetic patients. They ↑ RBF. Cell growth and proliferation: They ↓ cell apoptosis They ↓ cell proliferation and collagen synthesis.

22. 2-Congestive heart failure (CHF):
Therapeutic uses:
1-Hypertension:
2-Congestive heart failure (CHF):
To ↓ arterial BP → ↓ afterload.
To ↓ aldosterone → ↓ Na and H2O retention → ↓ preload.
To prevent myocardial hypertrophy and degeneration.
3-Post-infarction ventricular remodeling:
To ↓ mass and wall thickness of the left ventricle through:
↓ arterial BP.
↓ myocyte cell proliferation and collagen synthesis.
↓ apoptosis.
4-Diabetic nephropathy and microalbuminuria:
To ↓ apoptosis, cell proliferation, and collagen synthesis.
5-Possible other uses:
Insulin resistance - Atherosclerosis - Rheumatoid arthritis

23. Side effects: CAPTOPRIL
C Cough and bronchospasm: inhibition of ACE leads to accumulation of bradykinin, which cause bronchial irritation and constriction.
 Prevention: by administration of NSAIDs (e.g. aspirin) to ↓ bradykinin synthesis
A Angioedema (edema of the face and throat): due to accumulation of bradykinin or due to autoimmune reaction. It may be fatal.
P :Proteinuria in patients with compromised renal function.
T Taste changes: temporary loss of taste (ageusia and dysgeusia).
O Orthostatic (First dose) hypotension: especially in sodium depleted patients.
Prevention: the first dose must be small and at bedtime then increase gradually.
 P Pregnancy: teratogenesis (fetal pulmonary hypoplasia and growth retardation)
R skin Rash
I Increased K+ (hyperkalemia).
L Leukopenia (neutropenia): especially in patients with impaired renal function.

24. Contraindications:
1-Hypotension.
2-Severe renal failure (serum creatinine > 3 mg/dl).
3-Bilateral renal artery stenosis or stenosis in a solitary kidney.
In these conditions, the use of ACEIs is dangerous because of aggravation of renal failure in both kidneys.
4-Pregnancy and lactation: they may cause fetal pulmonary hypoplasia and growth retardation.
5-Hyperkalemia.
6-Neutropenia or thrombocytopenia.
7-Severe anemia: as they may cause bone marrow depression.
8-Immune problems: e.g. autoimmune diseases and with immunosuppressive drugs.

25. Precautions: 1-Initial dose should be small and at bedtime to avoid 1st dose hypotension. 2-Frequent monitoring of kidney functions (serum creatinine) one week after treatment and then every 3 months. 3-Frequent monitoring of serum K+. 4-Avoid use with K+ sparing diuretics to avoid severe hyperkalemia. 5-Mention other contraindications…….

26. Angiotensin II receptor blockers (ARBs)
(Losartan, valsartan, candesartan, eprosartan, telmisartan)
They selectively block AT1 receptors.
They have no effect on bradykinin metabolism.
They have the potential for more complete inhibition of Ang-2 action compared with ACE inhibitors because there are non-ACE enzymes (cathepsin and chymase) that can convert Ang-1 into Ang-2.
The adverse effects and contraindications are similar to those described for ACE inhibitors but cough and angioedema are less common than with ACE inhibitors.

27. Vasodilators
Classification
1-Arterio-dilators: e.g. nifedipine, hydralazine, minoxidil, diazoxide.
They directly dilate arteries and reduce blood pressure (↓ afterload) so they are used in systemic hypertension and congestive heart failure.
2-Venodilators: e.g. nitrates.
They dilate veins (↓ preload) so they are used in acute pulmonary edema.
3-Mixed dilators: sodium nitroprusside, prazosin, ACEIs, trimetaphan.
They are used in congestive heart failure because they ↓ preload and afterload.

28. General considerations:
They usually cause reflex sympathetic stimulation (e.g. reflex tachycardia and ↑ plasma renin) so they can be combined with beta-blockers.
They usually cause salt and water retention so they should be combined with diuretics.
They don't cause CNS side effects or orthostatic hypotension.
They preserve renal and cerebral blood flow.

29. Mechanism: direct vasodilator for small arteries and arterioles.
Hydralazine
Mechanism: direct vasodilator for small arteries and arterioles.
Therapeutic uses:
Severe systemic hypertension.
Primary pulmonary hypertension.
Hypertension in pregnancy (2nd choice after α-methyldopa).
Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Systemic lupus erythematosis (SLE)-like syndrome in slow acetylators.

30. Minoxidil
Mechanism: direct arteriolodilator by opening K+ channels → hyperpolarization → relaxation of the vascular sm ms.
Therapeutic uses:
Severe hypertension in combination therapy.
Hypertension in (renal) patients.
Topical minoxidil is used to stimulate hair growth in male baldness.
Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Hypertrichosis= hirsutism (undesirable hair growth in the face and body).

31. Diazoxide
Mechanism: direct arteriolodilator by opening K+ channels → hyperpolarization → relaxation of the vascular sm ms.
Therapeutic uses:
Hypertensive emergencies e.g. hypertensive encephalopathy. (rapid i.v. injection to avoid rapid and extensive binding with plasma proteins).
Hypoglycemia due to hyperinsulinism to decrease insulin secretion from the pancreatic β-cells through opening of its K+ channels.

32. Side effects:
Hypotension and reflex tachycardia.
Salt and water retention.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Hyperglycemia due to inhibition of insulin release.
Hyperuricemia.

33. Sodium nitroprusside
Mechanism: It liberates nitric oxide (NO) → ↑ cGMP → ↓ Ca2+ entry in the vascular sm ms → dilatation of both arteries and veins.
It is rapidly metabolized in RBCs into cyanide then to thiocyanate before excretion.
Therapeutic uses:
Hypertensive encephalopathy: It must be given by i.v. infusion .
Congestive heart failure: to ↓ both preload (venodilatation) and afterload (arteriolodilatation).

34. Side effects:
Hypotension and reflex tachycardia.
Headache, Anginal pain, Nausea, Dizziness (HAND).
Prolonged therapy can lead to cyanide toxicity (death can occur from metabolic acidosis and arrhythmia) or thiocyanate toxicity (delirium and psychosis).
►Precautions:
Avoid exposure to light because the drug is sensitive to light.
Stop infusion gradually to avoid rebound hypertension.
Too much infusion may lead to cyanide toxicity.
In liver disease cyanide ions are not converted into thiocyanate and become more toxic.

35. Hypertensive emergencies:
Defined as diastolic blood pressure more than 130 mmHg associated with progressive end organ damage e.g papilledema , hypertensive encephalopathy, pulmonary edema or acute renal failure.
The patient should be hospitalized for rapid but (careful and controlled) reduction of blood pressure.
Avoid excessive rapid lowering of blood pressure since it can result in stroke or myocardial infarction.

36. Management of hypertensive emergencies
 They include: hypertensive encephalopathy, acute left ventricular failure, cerebral stroke, and aortic dissection.
 Management:
 Hospitalization
Rapid reduction of BP in hours not in minutes by one or more of the following drugs:
 Sublingual drugs: nifedipine and captopril
 Parenteral drugs:
Furosemide i.v.
Hydralazine i.v. slowly .
Diazoxide (rapid i.v. injection).
Sodium nitroprusside 5 μg/kg/min i.v. infusion.
Nitroglycerine i.v. infusion.
Nifedipine i.v. slowly .
Beta-blockers (propranolol) 1-2 mg i.v. slowly.
α-methyldopa i.v.

37. Investigations:
A)Basic studies for all cases:
1-Renal function tests: (urine examination-serum createnine-blood urea).
2-Plasm electrolyte level :
*As a base line before diuretics therapy.
*As screen for mineralocorticoids induced hypertension.
3-Blood glucose:
* To diagnose other conditions associated with increased blood glucose + hypertension as pheocromocytoma…..etc
4-Serum uric acid:
*As a risk factor for hypertension ……….(metabolic syndrome).

38. 5-Serum cholesterol:. As a base line before diuretics therapy
5-Serum cholesterol: *As a base line before diuretics therapy. *As a risk factor for hypertension ……….(metabolic syndrome). 6-Measurment of plasma rennin: 7-ECG: to assess LVH and cardiac status.

39. B) To detect secondary cause in selected cases:
*Pheocromocytoma (sweating, palpitation,headache…..)
*renal arteriography in renal artery stenosis (abdominal bruit)
C) To detect occurrence of complications:
*Fundus examination.
*Renal function tests.
*ECG- CXR- angiography.
*EEG

40. Choice of drugs in therapy of hypertension:
A) Mild or moderate hypertension:
1-Start with a single drug (monotherapy) using one of the following: (A-B-C-D). Here D refers to thiazide type diuretics.
Choice of first line therapy should be based on (type of patient and presence of concomitant diseases ).

41. However, the preferred drug for initial therapy of mild or moderate hypertension are thiazide diuretics or beta blockers which shown to reduce cardiovascular morbidity and mortality in large clinical trials. 2) The started drug should be started at a low dose to avoid side effects. If blood pressure remains uncontrolled, the dose is increased. 3) If blood pressure is not controlled either change to a single drug of a different group or ADD a second drug with a different site of action e.g (thiazide +BB) or (thiazide +ACEI). 4) If hypertension is not controlled by the (two drug regimen), ADD a third drug e.g thiazide +BB+ vasodilator (ACEI or CCB or hydralazine or prazocin).

42. B-Severe hypertension: Start by (triple therapy) using a combination of 3 drugs e.g thiazide +B B +vasodilator?????? N.B: In patients with renal impairment, thiazides are contraindicated so, loop diuretics as frusemide are recommended. Beta blockers can be replaced with a central α2 agonist as (clonidine and α methyl dopa) if beta blockers are contraindicted.

43. C-Hypertension resistant to triple therapy:
Patients resistant to triple therapy described above may respond to:
Minoxidil + beta blocker + loop diuretics (frusemide).
ACEI + loop diuretics (frusemide) +CCB.

44. Causes of failure of treatment of hypertension: 1-Non compliance with drug therapy. 2- Inadequate drug dosage. 3- Incorrect choice of drug e.g thiazide in advanced renal insufficiency. 4-Excess salt intake. 5-Concomitant use of antagonistic drugs e.g NSAIDs ,cold remedies, oral contraceptives ….etc 6-Failue to recognize the cause of hypertension e.g pheochromocytoma or renal artery stenosis.

45. Choice of antihypertensive drugs in special situations:
Preferred drug
Clinical situation
α Methyl dopa,hydralazine,labetalol and nifedipine
Hypertension in pregnancy
ACEI ,α Methyl dopa
Hypertension and diabetes
CCB
Hypertension and bronchial asthma
,CCB
clonidine,α Methyl dopa, Loop diuretics (frusemide)
Hypertension and renal failure
Diuretics and ACEI
Hypertension and heart failure

47. Case I
A 47 old male presents to your office for a yearly checkup. He smokes 40 cigarette/day, and examination detect wheezy chest and bronchospasm. His blood pressure is 175/105 mm Hg. (measured more than once). His fundoscopic examination is normal.
1-Mention the stage of hypertension in this case?
2-Mention the investigations of a patient with hypertension?
3-What is the goal of hypertension therapy ?
4-What are the most common drug classes in therapy of hypertension now ?

48. 5-What are other drug classes used for treatment of hypertension ?
 Can you start with thiazide in this case?
6-What is the mechanism of action of the thiazide in this case ?
7-Mention the adverse effects of the thiazide ?
8-After 2 weeks of therapy the patient bl.pr. became 150/95 do you recommend adding a new drug?
9- What, and why?
10-What is the mechanism of action of this drug As antihypertensive ?
11-What is the possible side effects in this patient ?
12-If the patient develop bradycardia ( 60 beats/min ) , how to deal with ?

49. Case II
A male patient is presented to you by moderate degree of hypertension and chronic renal impairment ( serum creatinine 4 mg /dl ).
Can you give diuretic in this case ? what and why ?
Can you give ACE inhibitors in this case? When? and Why?
What are other safe drugs used for treatment of hypertension in presence renal insufficiency?
Mention antihypertensive drug/s contraindicated in treatment of hypertension with renal failure?

50. Case III
A 35 old obese pregnant lady with moderate degree of hypertension and What is your advice as regard to diet in this case?
What is /are the antihypertensive drugs/s of choice?
Mention mechanism of action of methyldopa as antihypertensive?
What are antihypertensive drugs absolutely contraindicated in pregnancy and why?

51. Case IV
A 45 old diabetic female presented in your office with headache and dizziness, her blood pressure 170/100 and fasting blood glucose level 130 mg/dl and postprandial blood glucose 160 mg/ dl , she is controlled by glimpride drug .
Mention antihypertensive drug/s used in this case?
What are antihypertensive drugs contraindicated in this case? Why?

52. Case V
If you are faced with a male patient with hypertension and left sided congestive heart failure, what are the antihypertensive of choice in this case and what is/are the drug/s contraindicated and why?

53. Case VI
Patient with hypertension and elevated cholesterol and triglyceride
What are antihypertensives that can be used ?
What are antihypertensives that are contraindicated ?

54. Case VII How can you treat a patient in a state of hypertensive emergency?

55. Case : A 56 year old obese male lawyer was found to have a blood pressure of 180/110mmHg during routine checkup, otherwise he was clinically free. The same BP was noted on three subsequent visits. He smoked at least 30 cigarettes a day for 20 years. How would you proceed to manage this case? A 58 year old professor complained of headache. His blood pressure was found to be 220/115 mmHg and there was no evidence of cardiac failure or renal impairment. How would you treat this patient? Case: A 47 year old man presented with a history of attacks of chest pain provoked by exertion and relieved by rest. Exercise stress test was performed and the patient was diagnosed as (exertional angina pectoris) .How would you proceed to manage this man taking in consideration that his blood pressure was 170/100 mmHg and that he is a heavy smoker?