Pharmacology - Hypertension & Antihypertensives Flashcards
Untreated high BP may lead to - 3
- Endothelial cell damages, causing Atherosclerosis
- Internal organ damage (kidney, eyes, nerves)
- Extra strain on the heart
Left ventricular hypertrophy – Pulmonary oedema
CHF – Peripheral oedema
CVD Risk factors - 11
- Unhealthy lifestyle
- Diabetes
- Dyslipidaemias
- Obesity
- Hypertension
- Age
- Gender
- Genetics
- Myocarditis
- LV or RV dysfunction
- Myocardial Ischaemia
TYPES AND CAUSES OF SYSTEMIC HYPERTENSION - 6
- 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.
- 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. - Pheochromocytoma: A neuroendocrine tumour in the adrenal medulla (chromaffin cells) causing excessive secretion of catecholamines (epinephrine & norepinephrine), which leads to high BP.
- Kidney Diseases: Some affect renal blood flow (BF) & GFR, leading to increased blood volume, salt retention, & elevated BP.
- Drug-Induced Hypertension: Corticosteroids & weight loss pills (e.g., sibutramine) can raise BP.
Birth control pills may also increase BP. - White Coat Hypertension: Increased BP caused by anxiety in clinical setting. Monitoring BP at home can diagnose this.
Hypertension: Diagnosis & Management - Clinic BP
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.
Hypertension: Diagnosis & Management: ABPM or HBPM
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
Choice of antihypertensive drugs, monitoring & treatment:
Hypertension: <55yrs not African or African-Caribbean & without T2D
Or Hypertension with TD2:
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
Choice of antihypertensive drugs, monitoring & treatment:
>55yrs or African or African-Carribbean
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
Monitoring Hypertension Treatment - 4
- Measure standing & sitting BP in people with:
T2D - Symptoms of postural hypotension (faint standing up)
- 80yrs & over.
- Consider ABPM or HBPM, in addition to clinic BP, for people with white-coat effect or masked hypertension.
BP targets
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
Function of Renin: Formation & Breakdown of Angiotensin II
- 4
- Renin: protease released in response to low BP & cleaves angiotensinogen into angiotensin I.
- Angiotensin-converting enzyme (ACE) found in the lungs, activates angiotensin I to angiotensin II
- Angiotensin II acts on AT1 & AT2 receptors (affect vasoconstriction, Na retention & fluid balance)
- Leads to formation of angiotensin III, involved in thirst control & natriuresis.
Function of Renin: Formation & Breakdown of Angiotensin II
Role of ACE2
- 3
- Renin cleaves angiotensinogen to angiotensin I, which is then converted into angiotensin II by ACE.
- Angiotensin II induces vasoconstriction, inflammation, atrophy, & fibrosis by acting on AT1 receptor.
- 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.
THE RAAS: Systemic effects & groups of drugs acting on the RAAS
- 4
- Renin inhibitors (e.g. Aliskiren) inhibit renin, preventing cleaving of angiotensinogen to angiotensin I
- ACEi inhibits ACE converting Angiotensin I to II
- ARBs (AT1 receptor antagonists) prevent angiotensin II binding
- Mineralocorticoids effect salt retention
THE RAAS, ACE INHIBITORS: Examples
CAPTOPRIL is short-acting.
Poor tolerance: taste disturbance (e.g. metallic taste, or loss of taste) and skin rush due to –SH moiety
ACEi S/Es - 5
- Hypotension
- Reflex tachycardia & palpitations
- Hyperkalaemia (due to reduced aldosterone production;
- Taste disturbances (e.g. with captopril)
- Skin rush (with captopril)
THE RAAS: Mechanism based adverse effects of ACEIs - 2
- ACEi inhibition of ACE produces desired result of preventing AT1 decreasing BP
- Inhibiting ACE means Bradykinin increases, resulting in coughs, & B2 increasing vasodilation, causing angioedema.
RAAS: ARB over ACE - 3
ARB Examples:
LOSARTAN
CANDESARTAN
VALSARTAN
Benefits of ARBs over ACEIs:
1. No cough
2. Reduced risk of angioedema
3. Improved tolerance
Normal autoregulation of GFR - 3
- 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
Mechanisms of AKI With ACEI + diuretic + NSAID
- Diuretic decreases blood volume, decreasing GFR & activates the RAAS.
- Efferent arteriole cannot constrict due to of ACEI, hence more decreasing GFR.
- Afferent arteriole cannot relax more due to of NSAID, hence even more decreasing GFR
THE RAAS: Therapeutic uses of drugs that act on the RAAS
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
Mechanism of antihypertensive action:
Calcium Channel Blockers (CCBs)
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)
DIRECT-ACTING VASODILATORS: Calcium Channel Blockers (CCBs): Therapeutic uses
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
Common Adverse Effects of Vascular-Selective CCBs - 7
- Hypotension
- Postural (orthostatic) hypotension (decreased ability of arteries to constrict rapidly when a person suddenly standing up)
- Tachycardia & palpitations (reflex due to increased sympathetic activity)
- Ankle oedema
- Headache & flushes (vasodilation, more frequent with fast-acting CCBs)
- Myocardial ischaemia (on fast withdrawal)
- Constipation (due to block of peristalsis in GIT)
Antihypertensive MoA
Potassium channel activators - 4
- Activation of KATP channels in vascular smooth muscles
- Membrane hyperpolarisation
- Closure of L-type VACCs
- Vasorelaxation
Two Types of KATP Channels - 2
- In Pancreatic Beta Cells: When glucose enters the cell, it is metabolized to produce ATP, closing the KATP channels, leading to cell depolarization, activation of calcium channels, and insulin release.
- In Vascular Smooth Muscle (SM) Cells: These channels are typically closed but can be activated by specific compounds.
DIRECT-ACTING VASODILATORS: Potassium Channel Activators
Therapeutic use & ADRs
Therapeutic use:
MINOXIDIL: In severe resistant hypertension (with diuretic & β-blocker)
Adverse Effects:
1. Reflex tachycardia (reduced with B-blocker)
2. Fluid retention (reduced with diuretic drug)
3. Excessive hair growth
DIRECT-ACTING VASODILATORS: Hydralazine - 3
- Clinical Uses: Prescribed for hypertension during pregnancy (with beta-blockers & diuretics) & heart failure in African-Caribbean patients (with nitrates).
- Mechanism: Unknown
- ADRs: Lupus syndrome, tachycardia, palpitations, hypotension, & peripheral oedema.
ANTIHYPERTENSIVE DRUGS THAT ACT ON THE SYMPATHETIC NS - 6
- β-BLOCKERS
- α1 –ADRENOCEPTOR ANTAGONISTS
CENTRAL-ACTING (brainstem):
3. a2-adrenoceptor agonists: CLONIDINE, METHYLDOPA
4. Imidazoline receptor agonists: MOXONIDINE
5. Ganglion blockers: Trimetaphan
6. Adrenergic neuron blockers: Guanethidine, Reserpine
ANTIHYPERTENSIVE DRUGS THAT ACT ON THE SYMPATHETIC NS:
B-blockers - 3
β-BLOCKERS e.g. ATENOLOL (β1), PROPRANOLOL (non-selective)
1. MoA: Block 1-adrenoceptors in the heart & in the kidney
Benefits as antihypertensive therapy:
2. Reduce reflex tachycardia
3. Reduce renin release and activation of the RAAS
Beta-BLOCKERS with an additional benefits: - 3
- NEBIVOLOL b1-selective, also stimulates NO release in vascular endothelium
Benefit: Vasodilatation with less fatigue, less bradycardia & impotence - PINDOLOL β1-selective & partial agonist at low sympathetic activity
Benefit: Less bradycardia in patients who have cardiac dysrhythmias. - LABETALOL & CARVEDILOL: non-selective beta - blockers with a1-adrenoceptor antagonism
Benefit: Vasodilatation & decrease in TPR with little changes in HR.
β-BLOCKERS: Therapeutic uses 2 & adverse effects
Therapeutic applications:
1. In resistant hypertension (in addition to first-line drugs & diuretics)
2. In severe hypertension in pregnancy (only Labetalol)
Adverse effects:
1. Bronchoconstriction (more frequent with non-selective)
2. Reduced awareness of hypoglycaemia
3. Bradycardia (due to their negative chronotropic effect)
4. Negative inotropic effect in the heart
5. Fatigue
6. Cold extremities
7. Erectile dysfunction
ANTIHYPERTENSIVE DRUGS THAT ACT ON THE SYMPATHETIC NS:
α1 –ADRENOCEPTOR ANTAGONISTS:
MoA & S/Es
Examples: DOXAZOSIN, PRAZOSIN
- 4
- Inhibition of postsynaptic α1-adrenoceptors on vascular smooth muscle cells
Antihypertensive systemic effects: - Arterial dilatation – reduced TPR and cardiac afterload
- Venodilatation – reduced cardiac preload and SV
- Less reflex tachycardia (compare to non-selective alpha-adrenergic receptor blockers like phentolamine)
ANTIHYPERTENSIVE DRUGS THAT ACT ON THE SYMPATHETIC NS:
α1 –ADRENOCEPTOR ANTAGONISTS
Examples: DOXAZOSIN, PRAZOSIN
Therapeutic use & ADR
Therapeutic uses:
1. Resistant hypertension (in addition to first-line drugs & diuretics)
Adverse effects:
2. First-dose hypotension; orthostatic hypotension
3. Reflex tachycardia, palpitations
4. Peripheral oedemas
5. Dizziness
6. Fatigue
7. Sexual dysfunction
CENTRAL-ACTING DRUGS:
α2-Adrenoceptor Agonists & Imidazoline I1 Receptor agonists:
- 3
CENTRAL-ACTING DRUGS:
α2-Adrenoceptor Agonists:
e.g. Clonidine (also has effect on peripheral a2-adrenoceptors)
e.g. α-Methyldopa
Imidazoline I1 Receptor Agonists:
e.g. Moxonidine
CENTRAL-ACTING DRUGS: Central Mechanism:
(e.g. Doxasozin, Clonidine,)
Mechanism of Action - 5
- Act on alpha-2 receptors in the brainstem, particularly in the nucleus of the tractus solitarius, which influences both sympathetic & parasympathetic responses.
- Clonidine activates alpha-2 receptors, while moxonidine is more selective for I1 receptors, which have a more targeted effect on sympathetic outflow.
- Used for managing hypertension, especially when medications like thiazides, beta-blockers, or ACE inhibitors are ineffective or contraindicated.
- Alpha-2 agonists activate alpha-2 receptors, mimicking noradrenaline.
- Inhibits release of norepinephrine from sympathetic nerves, can help lower BP, benefiting antihypertensive patients.
CENTRAL-ACTING DRUGS: Therapeutic applications
Moxonidine
a-Methyldopa
Clonidine
MOXONIDINE
In resistant hypertension (when first-line drugs do not work)
α-METHYLDOPA
In severe hypertension in pregnancy
CLONIDINE
Is rarely used as an antihypertensive drug
Other uses include a treatment of:
Migraine
Insomnia
Opioid detoxification
CENTRAL-ACTING DRUGS: Adverse effects
- 5
- Rebound hypertension upon withdrawal
- Dry mouth
- Sedation & drowsiness 3. Respiratory depression 4. Immune haemolytic reactions
- Liver toxicity
