L46: Calcium Blockers, Alpha And Beta Blockers

Question 1

Calcium channels

Answer 1

• voltage-gated ion channels —> depolarisation —> channel open

3 types:

• high-voltage activated dihydropyridine-sensitive channel (L-type)
• high-voltage activated dihydropyidine-insensitive
• low-voltage activated channel (T-type)

Question 2

***Role of L-type Ca channel

Answer 2

1. HR regulation (cardiac myocyte)
   - regulate L type Ca channel
   - regulate impulse conduction at SA node and AV node
   - ↑ / ↓ threshold level for pacemaker action potential
2. Force of contraction regulation (cardiac myocyte)
   - regulate Ca-induced Ca release
3. Vasoconstriction by vascular smooth muscle

Question 3

Calcium channel blockers

Answer 3

Preferentially block L-type voltage gated Ca channel
Use:
1. Hypertension:
- short half life —> oscillation in BP (surges of sympathetic reflex) —> sustained-release —> long half life —> constant conc —> ↓ adverse effects
- effective for isolated systolic hypertension (due to ↑ CO)
- effective for low renin hypertension (elderly, African-American)

2. Angina
3. Arrhythmia
   - only cardiac selective ones (Diltiazem, Verapamil)
   - effect on supraventricular sites
   - effective for delayed-afterdepolarisation
   - avoid in ventricular tachycardia —> cardiac arrest, hypotension
   - caution in hepatic dysfunction

• **3 classes:
  1. Dihydropyridine (Nifedipine, Amlodipine) —> Vascular-selective
• Nifedipine: ↓ HR (cardiac Ca blockage), ↑↑ Vasodilation, ↑ coronary flow
• Amlodipine: ↑ HR (reflex tachycardia), ↑↑ Vasodilation, ↑ coronary flow

2. Benzothiazepine (Diltiazem) —> Cardiac-selective
   - ↓ HR, ↓↓ SA conduction, ↓ AV conduction, ↓ contractility
3. Phenylalkylamine (Verapamil) —> Cardiac-selective
   - ↓ HR, ↓ SA conduction, ↓ AV conduction, ↓↓ contractility

ALL causes mild Natriuresis (due to ↑ renal flow)

Adverse effects:

• Hypotension
• Cardiac selective: heart failure
• Vascular selective: peripheral oedema (arterial dilation > venous dilation), gastroesophageal reflex (inhibition of lower oesophageal spincter)
• Amlodipine: reflex tachycardia
• headache, flushing

Question 4

Adrenergic receptors

Answer 4

α1: Vasoconstriction, Smooth muscle contraction
α2: Decreased presynaptic NE release
β1: Increased HR, contractility
β2: Vasodilation, Smooth muscle relaxation

Question 5

α-1 blockers

Answer 5

Prazosin, Doxazosin
- inhibit α-1 receptors in arterioles and venules
—> arterial and venous vasodilation
—> ↓ TPR
—> management of hypertension

However, reflex retention of Na + water (due to reflex activation of renin release)
—> ↓ hypertensive effect —> use in combination with Diuretics, Beta-blockers

Adverse effects

• dizziness, palpitation, headache
• orthostatic hypotension with initial dose/dose increase (due to ↓ venous return in venous dilation)

Question 6

β blockers

Answer 6

Use: Angina, Arrhythmia, Heart failure, Hypertension, MI

1. Heart (β1)
   - ↓ HR, ↓ Force —> ↓ CO
2. Kidney
   - ↓ renin release —> ↓ Na and water reabsoption

(Mild) 3. Peripheral pre-synaptic β receptor
- ↓ NE release —> ↓ sympathetic vasoconstrictor nerve activity —> vasodilation

Adverse effects:

1. Respiratory tract (β2)
   - smooth muscle contraction —> Bronchospasm (CI in obstructive airway disease, less with β1 selective (cardiac selective) β blocker)
2. Liver (β2)
   - risk of Hypoglycaemia (caution in diabetes, less with β1 selective (cardiac selective) β blocker)
3. Vascular smooth muscle (β2)
   - ↓ vasodilation (caution in severe peripheral vascular disease, less with β1 selective (cardiac selective) β blocker)
4. Heart (β1)
   - ↓ HR, ↓ Force —> risk of arrhythmia and heart failure (less with pindolol: intrinsic sympathomimetic activity)
5. CNS
   - CNS disturbance —> sedation, vivid dream, depression (less with low lipid solubility β blockers, discontinuation in psychiatric depression)

Precaution:
1. Withdrawal syndrome (upregulation of β receptor —> rebound hypertension, tachycardia —> gradual dose reduction)

2. Drug interaction (effects reduced by NSAID, risk of severe hypertension with adrenaline administration)
3. Hypoglycaemia (mask warning sign for insulin-induced hypoglycaemia tachycardia)
4. Pheochromocytoma, Clonidine withdrawal

Question 7

Classification of β blocker

Answer 7

1. Non-selective (1st gen, β1 + β2):
   Propranolol
2. Cardiac-selective (2nd gen, β1):
   Metoprolol, Bisoprolol
3. β blocker with vasodilation effect (3rd gen):
   Labetalol (β + α)
   Nebivolol (inhibit β1 + release of nitric oxide from endothelial cells)
4. β blocker with intrinsic sympathomimetic activity (inhibit and slightly activate β receptor - Partial agonist):
   Pindolol