Viva G5(iv)a

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.

What classes of antihypertensive agents are you aware of?
Classification of Antihypertensive Agents
Class Mechanism Examples

RAAS antagonists

Renin antagonists Inhibits the activity of renin, which reduces the activation of angiotensin , thus prevents RAAS activation Aliskiren

ACE-inhibitors

Interrupts the conversion of Ang-I into Ang-II, thereby interrupting the effects of RAAS activation Perindopril

Angitensin receptor blockers

Interferes with the binding of Ang-II and its AT1 receptor. Irbesartan

Sympatholytic drugs

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
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

Vasodilators

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
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
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.
What agents block the actions of the sympathetic nervous system?

Beta blockers

Selective (β1)
Non-selective
Alpha-1 blockers Reversible
Irreversible
Alpha-2 agonists
Ganglionic blockers
Monoamine transport inhibitors
Catecholamine synthesis inhibitors
How would you classify beta-blockers?
Three Different Classification of Beta-blockers
According to selectivity According to membrane stabilising effects According to intrinsic sympathomimetic activity

Non-selective

  • Propanolol
  • Sotalol

β1-selective

  • Atenolol
  • Metoprolol
  • Bisoprolol
  • Nebivolol
  • Esmolol

Combined α- and β-blocker effect

  • Carvedilol
  • Labetalol

Stabilising

  • Propanolol
  • Sotalol
  • Metoprolol

Non-stabilising

  • Atenolol
  • Bisoprolol
  • Nebivolol
  • Esmolol
  • Carvedilol
  • Labetalol

ISA

  • Labetalol
  • Acebutolol
  • Pindolol

Non-ISA

  • Propanolol
  • Atenolol
  • Metoprolol
  • Bisoprolol
  • Nebivolol
  • Esmolol
  • Sotalol
  • Carvedilol
What are the common  pharmacokinetic properties of beta blockers?

Absorption

All beta-blockers are enterally administered
  • Esmolol
All beta blockers have great GI absopriton
  • Esmolol 
  • Atenolol
Distribution Most of these drugs have a relatively large volume of distribution, and are highly protein-bound
  • Atenolol
Solubility Most of these drugs are hihgly lipid-soluble
  • Esmolol
  • Atenolol
Metabolism All beta blockers ungergo extensive hepatic metabolism, except...
  • Atenolol
  • Esmolol
Clearance None are dependent on renal excretion, except
  • Atenolol
  • Sotalol
What are the mechanisms of the clinical effects of beta blockers?
  • Decrease heart rate:
    • Increase the duration of the action potential of pacemaker cells.
    • by altering the "funny current", If.
  • Increased contractility
    • by decreasing calcium availability, by blocking the β-1 receptors
  • Decreased blood pressure
    • many effects
    • decreased cardiac output, inhibition of renin release, reduction in venous return and plasma volume, resetting of baroreceptor levels, effects on prejunctional β‐receptors (reduction in noradrenaline release)
  • Decreased myocardial oxygen consuption
  • Antiarrhythmic effects:
    • Decrease in the automaticity of ectopic pacemakers (thus, less arrhythmogenesis)
    • Prolonged refractory period for all excitable myocardial tissues. (thus, reduced propagation of malignant arrhythmias)
    • Decrease in ventricular fibrillation threshold
    • Prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects
    • Reversal of ischaemia/reperfusion induced proarrhythmic tendency by their effects on myocardial oxygen supply and demand

Or, in terms of receptors:

  • β1 receptor blockade
    • slows sinoatrial node
    • decelerates ectopic pacemakers
    • decreases contractility of the heart
    • decreases lusitropy
    • decreases renin release by the kidney
  • β2 receptor blockade
    • Opposes the relaxation of vascular smooth muscle in skeletal muscle arterioles, and therefore increases systemic vascular resistance
    • Opposes the relaxation of bronchiolar smooth muscle
    • Contracts gut wall smooth muscle
    • Contracts the bladder wall
    • Contracts the pregnant uterus
    • Decreases gluconeogenesis and glycogenolysis in the liver
    • Decreases insulin release
Compare and contrast metoprolol and esmolol
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.
Describe the pharmacology of clonidine
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
What alpha-1 antagonist agents are you aware of? Describe their pharmacology
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.

References

Biaggioni, Italo. "The sympathetic nervous system and blood volume regulation: lessons from autonomic failure patients." The American journal of the medical sciences 334.1 (2007): 61-64.

Cruickshank, J. M. "Are we misunderstanding beta-blockers." International journal of cardiology 120.1 (2007): 10-27.

López-Sendó, José, et al. "Expert consensus document on β-adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society of Cardiology." European heart journal 25.15 (2004): 1341-1362.

Oliver, Eduardo, Federico Mayor Jr, and Pilar D’Ocon. "Beta-blockers: Historical perspective and mechanisms of action." Revista Española de Cardiología (English Edition) 72.10 (2019): 853-862.

Gorre, Frauke, and Hans Vandekerckhove. "Beta-blockers: focus on mechanism of action Which beta-blocker, when and why?." Acta cardiologica 65.5 (2010): 565-570.

Smits, J. F. M., and H. A. J. Struyker-Boudier. "The mechanisms of antihypertensive action of beta-adrenergic receptor blocking drugs." Clinical and Experimental Hypertension. Part A: Theory and Practice 4.1-2 (1982): 71-86.

Frishman, William H., and Elijah Saunders. "β‐adrenergic blockers." The Journal of Clinical Hypertension 13.9 (2011): 649.

Frishman, William H. "β-Adrenergic blockers." Medical Clinics of North America 72.1 (1988): 37-81.