This viva tests Section G8(iii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "understand the pharmacology of anti-hypertensive drugs". Specifically, this section covers the classification of antihypertensives, beta blockers and sympatholytic agents.
| Class | Mechanism | Examples | |
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RAAS antagonists |
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| Renin antagonists | Inhibits the activity of renin, which reduces the activation of angiotensin , thus prevents RAAS activation | Aliskiren | |
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ACE-inhibitors |
Interrupts the conversion of Ang-I into Ang-II, thereby interrupting the effects of RAAS activation | Perindopril | |
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Angitensin receptor blockers |
Interferes with the binding of Ang-II and its AT1 receptor. | Irbesartan | |
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Sympatholytic drugs |
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Beta blockers |
Selective (β1) |
By binding to Gs-protein coupled β1 and β2 receptors, blocks cAMP synthesis |
Metoprolol |
| Non-selective | Propanolol | ||
| Alpha-1 blockers | Reversible | By inding to the Gq-protein-coupled alpha-1 receptor, this drug decreases the activation of phospholipase C, resulting in a decreased concentration of the secondary messengers IP3 and DAG. The result is decreased intracellular calcium availability, which in turn leads to decreased smooth muscle contraction tone. | Prazocin |
| Irreversible | Phenoxybenzamine | ||
| Alpha-2 agonists | Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release. | Clonidine α-methyldopa |
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| Ganglionic blockers | Blocks ganglionic autonomic neurotransmission by inhibiting the nicotinic Ach receptors, therefore decreasing both sympathetic tone and vagal neurotransmission. | Hexamethonium | |
| Monoamine transport inhibitors | Blocks VMAT-2 in the adrenergic neurotransmission pathway, causing the depletion of catecholamine and serotonin stores in central and peripheral nerve terminals | Reserpine | |
| Catecholamine synthesis inhibitors | By inhibiting the conversion of tyrosine into dopa, blocks the synthesis of catecholamines | α-methyltyrosine | |
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Vasodilators |
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| Calcium channel blockers | Dihydropyridine | Modulates the opening of voltage-gated calcium channels, which prevents intracellular calcium influx during depolarisation. This decreases the availability of intracellular calcium for vascular smooth muscle cells, decreasing their resting tone. In cardiac myocytes, this decreases contractility as well as the automaticity of pacemaker cells. | Amlodipine Nimodipine |
| Non-dihidropyridine | Verapamil Diltiazem |
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| Nitrate vasodilators (nitric oxide donors) |
Acts as donor of nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of cyclic GMP in vascular smooth muscle. This hyperpolarises the membrane by increasing potassium channel conductivity and decreases the availability of inracellular calcium, thereby decreasing the resting tone and contractility of vascular smooth muscle | GTN Nitroprusside |
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| Potassium channel activators | Activates ATP-sensitive potassium channels which inhibits the opening of voltage-dependent calcium channels indirectly, by hyperpolarising the membrane. | Hydralazine | |
| Phosphodiesterase inhibitors | Increases cyclic AMP by inhibiting phosphodiesterase (with maximum selectivity for PDE10), which is responsible for cAMP catabolism. Selective for vascular smooth muscle. | ||
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Beta blockers |
Selective (β1) |
| Non-selective | |
| Alpha-1 blockers | Reversible |
| Irreversible | |
| Alpha-2 agonists | |
| Ganglionic blockers | |
| Monoamine transport inhibitors | |
| Catecholamine synthesis inhibitors | |
| According to selectivity | According to membrane stabilising effects | According to intrinsic sympathomimetic activity |
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Non-selective
β1-selective
Combined α- and β-blocker effect
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Stabilising
Non-stabilising
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ISA
Non-ISA
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Absorption |
All beta-blockers are enterally administered |
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| All beta blockers have great GI absopriton |
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| Distribution | Most of these drugs have a relatively large volume of distribution, and are highly protein-bound |
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| Solubility | Most of these drugs are hihgly lipid-soluble |
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| Metabolism | All beta blockers ungergo extensive hepatic metabolism, except... |
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| Clearance | None are dependent on renal excretion, except |
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Or, in terms of receptors:
| Name | Metoprolol | Esmolol |
| Class | Beta blocker | Beta blocker |
| Chemistry | aryloxypropanolamine | aryloxypropanolamine |
| Routes of administration | Oral or IV | IV |
| Absorption | 50% oral bioavailability | 0% oral bioavailability |
| Solubility | pKa 9.7, poor lipid solubility | pKa 9.5, minimal lipid solubility |
| Distribution | VOD 2.8-4.8 L/kg; only 12% protein bound | VOD 3.4 L/kg; 60% protein bound |
| Target receptor | Selective β1 receptor blocker | Highly selective β1 receptor blocker |
| Metabolism | Mainly hepatic clearance | Rapidly metabolised in blood by hydrolysis of methyl ester linkage |
| Elimination | minimal renal excretion; half-life 3-4 hrs | minimal renal excretion; half-life 9 min |
| Time course of action | 12-24 hrs | Rapid onset and offset of effect |
| Mechanism of action | By binding to Gs-protein coupled β1 receptors, blocks cAMP synthesis | By binding to Gs-protein coupled β1 receptors, blocks cAMP synthesis |
| Clinical effects | β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary filling, and decreased arrhythmogenicity. | β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary filling, and decreased arrhythmogenicity. |
| Class | Alpha-2 agonist |
| Chemistry | Imidazoline derivative |
| Routes of administration | IV and oral |
| Absorption | Well absorbed orally, and has minimal first-pass metabolism. Bioavailability is 70-80% |
| Solubility | Reasonably amphoteric: dissolves quite well in both water and fat. pKa is 8.0 |
| Distribution | 30-40% protein-bound; VOD is 2.1 L/kg |
| Target receptor | Presynaptic alpha-2 receptors, as well as imidazoline receptors., where it acts as an agonist (which account for a lot of its non-antihypertensive effects) |
| Metabolism | About 30% is metabolised in the liver into numerous metabolites, and the rest is excreted unchanged in the kidney. |
| Elimination | Mainly renally eliminated; half-life is biphasic: by distribution is about 20min, and by elimination 5-7 hrs |
| Time course of action | Duration of the effect is ~ 6 hrs |
| Mechanism of action | Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release. |
| Clinical effects | Class effects (bradycardia, decreased blood pressure), as well as sensitisation of opiate receptors, sedation, analgesia, and an initial hypertensive phase following IV administration |
| Name | Prazocin | Phentolamine | Phenoxybenzamine |
| Class | Alpha antagonist | Alpha antagonist | Alpha antagonist |
| Chemistry | Quinazoline derivative | Imidazoline | Haloalkylamine |
| Routes of administration | Oral only | IV only | Oral only |
| Absorption | Oral bioavailability is 43-69%; high first-pass metabolism. | Bioavailability is variably reported as 30% or 100% | Bioavailability is about 20-30%, mainly because of incomplete and variable gut absorption |
| Solubility | pKa 8.42; slightly water-soluble; also only slightly lipid-soluble, but enough that it can cross the blood-brain barrier. | pKa = 9.78; highly lipid-soluble | Highly lipid-soluble, but poorly water-soluble. pKa = 7.97 |
| Distribution | Highly protein bound (92-97%). VOD ~ 42L/kg | 54% protein bound; VOD is large, about 6L/kg | The VOD is massive because of the high lipid solubility and protein binding, but nobody seems to have a number for it in the literature |
| Target receptor | Alpha-1 adrenoceptor | Fairly unselective alpha-1 and alpha-2 receptor blocker; as well as an agonist of beta-receptors | Slightly more selective for alpha-1 adrenoceptors, vs. alpha-2 receptors |
| Metabolism | Hepatic metabolism, primarily by demethylation and conjugation. Of the metabolites, basically everything is excreted in the bile. | Extensive hepatic metabolism, 80% renal excretion (10% to 13% excreted as unchanged drug) and 20% faecal excretion. | Hepatic metabolism into inactive metabolites (very slow, as little free drug is available in the circulation) |
| Elimination | Half-life is about 2.5 hrs | Half-life is 19 minutes | Inactive metabolites are eliminated in the bile and urine. Half-life is about 24 hrs. |
| Time course of action | Relatively slow onset, 1-3 hrs after oral administration. Duration of effect is 6-8hrs | After IV administration, the onset and offset of effect are rapid. | Onset of effect is about 1-2 hrs; however the duration of effect is 3-4 days, as this is roughly how long it takes you to synthesise new alpha-receptors |
| Mechanism of action | Competitive alpha-1 adrenergic receptor blocker: by binding to this Gq-protein-coupled receptor, this drug decreases the activation of phospholipase C, resulting in a decreased concentration of the secondary messengers IP3 and DAG. The result is decreased intracellular calcium availability, which in turn leads to decreased smooth muscle contraction tone. | The antihypertensive effect is as a NON-competitive (irreversible) alpha-1 adrenergic receptor blocker. By covalently binding to this Gq-protein-coupled receptor, this drug decreases the activation of phospholipase C, resulting in a decreased concentration of the secondary messengers IP3 and DAG. The result is decreased intracellular calcium availability, which in turn leads to decreased smooth muscle contraction tone. | |
| Clinical effects | Produces systemic vasodilation without affecting heart rate and cardiac output; also produces venodilation; acts as a smooth muscle relaxant at the level of the urethral sphincter, decreasing symptoms of prastatic hypertrophy. Also decreases risk of PTSD. Has been used to manage Rayhaud's phenomenon. Postural hypotension is one of the possible side effects. | Systemic vasodilation; because of its non-selective blockade of all alpha receptors, there is usually some reflex tachycardia and increased cardiac output. | Postural hypotension, tachycardia, arrhythmias, drowsiness, fatigue, inhibition of ejaculation, nasal congestion, miosis, and dry mouth. Also penetrates the CNS, causing stimulation, nausea, vomiting, motor excitation, and occasionally seizures. |
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