Pharmacology - Hypertension & Antihypertensives

Question 1

Untreated high BP may lead to - 3

Answer 1

1. Endothelial cell damages, causing Atherosclerosis
2. Internal organ damage (kidney, eyes, nerves)
3. Extra strain on the heart
   Left ventricular hypertrophy – Pulmonary oedema
   CHF – Peripheral oedema

Question 2

CVD Risk factors - 11

Answer 2

1. Unhealthy lifestyle
2. Diabetes
3. Dyslipidaemias
4. Obesity
5. Hypertension
6. Age
7. Gender
8. Genetics
9. Myocarditis
10. LV or RV dysfunction
11. Myocardial Ischaemia

Question 3

TYPES AND CAUSES OF SYSTEMIC HYPERTENSION - 6

Answer 3

1. Cushing’s Syndrome: Excessive cortisol production due to a pituitary adenoma (Cushing’s disease) or adrenal tumours. Symptoms: obesity, moon face, skin bruising, anxiety, & depression.
2. Primary Hyperaldosteronism (Conn’s Syndrome): Caused by an adrenal cortical adenoma.
   Leads to high BP, muscle cramps, muscle weakness, headaches, & metabolic alkalosis due to potassium imbalances & increased kidney secretion of H+ ions.
3. Pheochromocytoma: A neuroendocrine tumour in the adrenal medulla (chromaffin cells) causing excessive secretion of catecholamines (epinephrine & norepinephrine), which leads to high BP.
4. Kidney Diseases: Some affect renal blood flow (BF) & GFR, leading to increased blood volume, salt retention, & elevated BP.
5. Drug-Induced Hypertension: Corticosteroids & weight loss pills (e.g., sibutramine) can raise BP.
   Birth control pills may also increase BP.
6. White Coat Hypertension: Increased BP caused by anxiety in clinical setting. Monitoring BP at home can diagnose this.

Question 4

Hypertension: Diagnosis & Management - Clinic BP

Answer 4

Hypertension: Diagnosis & Management
Clinic BP >140/90mmHg: Check BP every 5yrs
Clinic BP 140/90-179/119mmHg: Offer home BP monitor. Assess CV risk
180/120mmHg or more: Refer to specialist same day.

Question 5

Hypertension: Diagnosis & Management: ABPM or HBPM

Answer 5

ABPM or HBPM >135/85mmHg: Check BP every 5yrs
ABPM or HBPM 135/85-149/94mmHg: Offer lifestyle advice.
A) >80yrs Offer lifestyle & drug treatment
B) <80 with target organ damage, CVD, renal disease, diabetes or Qrisk >10%: Discuss starting drug treatment
C) <60yrs, Qrisk <10%: Offer lifestyle & drug treatment
D) <40yrs: Consider specialist evaluation
ABPM or HBPM >150/95mmHg: Lifestyle advice & drug treatment
A) <40yrs: Consider specialist evaluation

Question 6

Choice of antihypertensive drugs, monitoring & treatment:
Hypertension: <55yrs not African or African-Caribbean & without T2D
Or Hypertension with TD2:

Answer 6

Step 1: ACEi or ARB Step 2: (ACEi or ARB) + CCB or thiazide-like diuretic
Step 3: (ACEi or ARB) + CCB + thiazide-like diuretic
Step 4: Discuss adherence, confirm resistant hypertension with ABPM or HBPM, then consider expert advice or add:
Low-dose spironolactone4 if blood potassium level is ≤4.5 mmol/l
Alpha-blocker or beta-blocker if blood potassium level is >4.5 mmol/l

Seek expert advice if BP is uncontrolled on optimal tolerated doses of 4 drugs

Question 7

Choice of antihypertensive drugs, monitoring & treatment:
>55yrs or African or African-Carribbean

Answer 7

Step 1: CCB Step 2: CCB + (ACEi or ARB or thiazide-like diuretic)
Step 3: ACEi or ARB + CCB + thiazide-like diuretic
Step 4: Discuss adherence, confirm resistant hypertension with ABPM or HBPM, then consider expert advice or add:
Low-dose spironolactone4 if blood potassium level is ≤4.5 mmol/l
Alpha-blocker or beta-blocker if blood potassium level is >4.5 mmol/l

Seek expert advice if BP is uncontrolled on optimal tolerated doses of 4 drugs

Question 8

Monitoring Hypertension Treatment - 4

Answer 8

1. Measure standing & sitting BP in people with:
   T2D
2. Symptoms of postural hypotension (faint standing up)
3. 80yrs & over.
4. Consider ABPM or HBPM, in addition to clinic BP, for people with white-coat effect or masked hypertension.

Question 9

BP targets

Answer 9

Age <80
Clinic BP <140/90mmHh
ABOM/HBPM <135/85mmHg
Age ≥80 years:
Clinic BP <150/90mmHG
ABPM/HBPM<145/85mmHg
Frailty or multimorbidity: Use clinical judgement

Question 10

Function of Renin: Formation & Breakdown of Angiotensin II
- 4

Answer 10

1. Renin: protease released in response to low BP & cleaves angiotensinogen into angiotensin I.
2. Angiotensin-converting enzyme (ACE) found in the lungs, activates angiotensin I to angiotensin II
3. Angiotensin II acts on AT1 & AT2 receptors (affect vasoconstriction, Na retention & fluid balance)
4. Leads to formation of angiotensin III, involved in thirst control & natriuresis.

Question 11

Function of Renin: Formation & Breakdown of Angiotensin II
Role of ACE2
- 3

Answer 11

1. Renin cleaves angiotensinogen to angiotensin I, which is then converted into angiotensin II by ACE.
2. Angiotensin II induces vasoconstriction, inflammation, atrophy, & fibrosis by acting on AT1 receptor.
3. ACE2 acts as a counter‐regulator of ACE by hydrolysing angiotensin II to angiotensin (1‐7), which acts via the Mas receptor to promote vasodilation, hypotension, & apoptosis.

Question 12

THE RAAS: Systemic effects & groups of drugs acting on the RAAS
- 4

Answer 12

1. Renin inhibitors (e.g. Aliskiren) inhibit renin, preventing cleaving of angiotensinogen to angiotensin I
2. ACEi inhibits ACE converting Angiotensin I to II
3. ARBs (AT1 receptor antagonists) prevent angiotensin II binding
4. Mineralocorticoids effect salt retention

Question 13

THE RAAS, ACE INHIBITORS: Examples

Answer 13

CAPTOPRIL is short-acting.

Poor tolerance: taste disturbance (e.g. metallic taste, or loss of taste) and skin rush due to –SH moiety

Question 14

ACEi S/Es - 5

Answer 14

1. Hypotension
2. Reflex tachycardia & palpitations
3. Hyperkalaemia (due to reduced aldosterone production;
4. Taste disturbances (e.g. with captopril)
5. Skin rush (with captopril)

Question 15

THE RAAS: Mechanism based adverse effects of ACEIs - 2

Answer 15

1. ACEi inhibition of ACE produces desired result of preventing AT1 decreasing BP
2. Inhibiting ACE means Bradykinin increases, resulting in coughs, & B2 increasing vasodilation, causing angioedema.

Question 16

RAAS: ARB over ACE - 3

Answer 16

ARB Examples:
LOSARTAN
CANDESARTAN
VALSARTAN

Benefits of ARBs over ACEIs:
1. No cough
2. Reduced risk of angioedema
3. Improved tolerance

Question 17

Normal autoregulation of GFR - 3

Answer 17

1. Reduction in RBF through glomerulus due to decrease in plasma volume activates the RAAS to compensate for reduction in the GFR. It does that via two main mechanisms:

A). Angiotensin II constricts more the efferent arteriole that regulates renal blood flow out of the glomerulus than the afferent arteriole, leading to increase glomerular pressure & GFR.

B). Reduction in plasma volume & reduced delivery of NaCl to distal tubule, stimulates macula densa cells activating COX-2 & release of PGE2 (part of the tubuloglomerular feedback mechanism) that selectively relaxes the afferent arteriole, hence increasing RBF into the glomerular & increases GFR.
The effect is enhanced by local release of PGI2 in the afferent arteriole

Question 18

Mechanisms of AKI With ACEI + diuretic + NSAID

Answer 18

1. Diuretic decreases blood volume, decreasing GFR & activates the RAAS.
2. Efferent arteriole cannot constrict due to of ACEI, hence more decreasing GFR.
3. Afferent arteriole cannot relax more due to of NSAID, hence even more decreasing GFR

Question 19

THE RAAS: Therapeutic uses of drugs that act on the RAAS

Answer 19

Patients with:
1. Systemic hypertension
2. Ischaemic heart disease & myocardial infarction
3. Heart failure
4. Diabetic nephropathy
5. Progressive renal insufficiency

CONTRAINDICATIONS: In pregnancy (teratogenic effect)
NOT the first choice of therapy (Due to low activity of RAAS) in
>55yrs
Patients of African-American or Caribbean origin

Question 20

Mechanism of antihypertensive action:
Calcium Channel Blockers (CCBs)

Answer 20

BLOCK OF THE L-TYPE VOLTAGE-ACTIVATED CALCIUM INFLUX IN VASCULAR SMOOTH MUSCLE CELLS

RATIONALE: vascular selectivity, antihypertensive action is additive to ACEI/ARBs or adrenoceptor antagonists)
Systemic effects:
Main: arterial dilatation (decrease in TPR & cardiac afterload)
Venodilatation (decrease in central venous pressure & cardiac preload)

Question 21

DIRECT-ACTING VASODILATORS: Calcium Channel Blockers (CCBs): Therapeutic uses

Answer 21

Therapeutic uses as antihypertensive drugs:
First-line treatment in:
the elderly (over 55 years of age);
patients of African-American or Caribbean family origin of any age;
severe hypertension in pregnancy (nifedipine)

Vascular selective DIHYDROPYRIDINES are preferred:
NIFEDIPINE, a fast-acting (modified release preparations are available)
AMLODIPINE, a slow-acting

Question 22

Common Adverse Effects of Vascular-Selective CCBs - 7

Answer 22

1. Hypotension
2. Postural (orthostatic) hypotension (decreased ability of arteries to constrict rapidly when a person suddenly standing up)
3. Tachycardia & palpitations (reflex due to increased sympathetic activity)
4. Ankle oedema
5. Headache & flushes (vasodilation, more frequent with fast-acting CCBs)
6. Myocardial ischaemia (on fast withdrawal)
7. Constipation (due to block of peristalsis in GIT)