Antihypertensive drugs

[Ref: SH(H)2:p345]

General principles

Previously effective antihypertensive therapy must be continued during the perioperative period.

Interaction between anaesthetics and anti-HTN drugs

• Attenuation of sympathetic nervous system
  * Orthostatic hypotension
  * Decreased sensitivity to indirect-acting sympathomimetics
  * Increased sensitivity to direct-acting sympthomimetics
  * Exaggerated BP response to acute blood loss, IPPV, position change
• Modified response to sympathomimetics
• Sedation

Side effects of beta-blockers used in treating HTN

• Bradcardia
• Congestive heart failure
• Bronchospasm
• Claudication
• Masking of hypoglycaemia
• Sedation
• Impotence
• Precipitation of angina on abrupt discontinuation

NB

Rebound hypertension on abrupt discontinuation
* Can occur with antihypertensive drugs acting on sympathetic nervous system
* Drugs such as ACE inhibitors are not associated with rebound hypertension

Classes of antihypertensive drugs

Sympatholytics

• Beta blockers
  * e.g. Atenolol, bisoprolol, metoprolol, propranolol, timolol
• Alpha blockers
  * e.g. Prazosin
• Combined alpha blockers
  * e.g. Labetalol
• Centrally acting blockers
  * e.g. clonidine, dexmedetomidine

ACE inhibitors

e.g. Captopril, enalapril, ramipril, perindopril, lisinopril, quinapril,

Angiotensin II receptor inhibitors

e.g. Losartan, candesartan, irbesartan, telmisartan

Calcium channel blockers

e.g. Verapamil, diltiazem, nifedipine, amlodipine, felodipine

Vasodilating drugs

e.g. Hydralazine

Diuretics

• Thiazide
  * e.g. Hydrochlorothiazide, indapamide, chlorothiazide
• Loop diuretics
  * e.g. Furosemide, bumetanide, ethacrynic acid
• Potassium-sparing diuretics
  * e.g. Amiloride, spironolactone

 

Sympatholytics

Labetalol

Blocks alpha1, beta1, and beta2.

Alpha1-blocking action
--> Less bradycardia and negative inotropic effect compared with beta-blocker
* (???) Because in treating HTN, effective dose of labetalol would not have as much beta-blocking activity 

Prazosin

• Selective postsynaptic alpha1 blocker
  --> Vasodilating effect on both arterial and venous vasculature
  * Does not cause reflex-induced tachycardia or increased renin activity
• Lack of increased renin activity could be due to continued activity of alpha2-receptors
• May also be used to increase afterload in CHF
• Substantial first-pass hepatic metabolism
  * <60% bioavailability after oral administration

Side effects of prazosin

• Vertigo
• Fluid retention
• Orthostatic hypotension
• Sudden syncope (acute peripheral vasodilation)
• Interference with antihypertensive effects by NSAID (???)
• Dry mouth
• Exaggerated hypotension during epidural
  * Alpha1-blockade prevents compensatory vasoconstriction in other parts of body

Terazosin and doxazosin

Similar to prazosin

But can be taken once daily

Clonidine

• Centrally acting
• Selective partial alpha2 agonist
  --> alpha2:alpha1 = 220:1
• Elimination half-time = 6-10hrs
  * Longer than dexmedetomidine (2-3hr)

Mechanism

Decreases sympathetic nervous system output from the CNS
* Antihypertensive effect, sedation

Actions on the receptors

• Alpha2A receptor
  --> Sedation, analgesia, sympatholysis (peripheral vasodilation, and decreased BP, HR, and CO)
• Alpha2B receptor
  --> Vasoconstriction, ?anti-shiver effects
• Alpha2C receptor
  --> ?startle response

Use

• Particularly useful in treatment of severe HTN or renin-dependent HTN
• Analgesia
• Preanaesthetic medication (5 microgram/kg PO)
  * Blunt CVS response to sympathetic stimulation
  * Decrease anaesthetic requirement (inhaled AA and opioids)
  * Prolong effect of regional anaesthesia
• Protection against, and treatment for perioperative myocardial ischaemia
• Diagnosis of pheochromocytoma
• Treatment of opioid and alcohol withdrawal syndrome
• Treatment of shivering (75 microgram IV)

Effects

• Greater decrease in SBP than DBP
• Minimal respiratory depressant effects
  * Does not potentiate ventilatory depressant effects of opioids
• Sedation
  * Results from decreased sympathetic activity, and patients are calm but easily aroused
  * Differ from sedation due to increased GABA activity (midazolam or propofol)

Side-effects

• Sedation
• Xerostomia
• Decrease in anaesthetic requirement
• Bradycardia
• Sodium and water retention
• Skin rashes
• Rebound HTN after abrupt discontinuation of clonidine (may occur as soon as 8 hours)

Administration

• Oral dose = 0.2-0.3mg
  * Rapid absorption
• Transdermal patch also available
  * Therapeutic concentration takes 48 hours

Dexmedetomidine

Alpha2 agonist
--> More selective and potent than clonidine
* alpha2:alpha1 = 1620:1

Shorter duration than clonidine
* Elimination half-time = 2-3hrs

Actions

• Similar to clonidine, but stronger
• Causes mild ventilatory depression
• Can also be used for postoperative sedation for critical care patients with ETT
  * 200 to 700 microgram/kg/hour IV

ACE inhibitors

Minimal side effects
* No insomnia, rebound hypertension

Main difference between different ACE inhibitors is in the duration of action

Mechanism of action

Blocks conversion of angiotensin I to angiotensin II

Actions of angiotensin II

The 3 main actions are

• Vasoconstriction
• Increased aldosterone release
  * Aldosterone increases Na+ resorption, and increase urinary loss of K+ and H+
• Increased thirst
  * By stimulating SFO, and maybel OVLT

Side effects of ACE inhibitors

• Cough
  * Due to potentiation of kinin effects
• Upper respiratory congestion
• Rhinorrhoea
• Decreased GFR
  * Caution in renal dysfunction
• Hyperkalaemia
  * Due to decreased production of aldosterone
• Hypotension following induction

Captopril

Well absorbed orally
--> Inhibition of ACE occurs within 15min

No effect in CO or HR

Side effects of captopril

• Rash or pruritus
• Alteration or loss of taste
• Possible antagonism of NSAID
• Hyperkalemia
• Angioedema
  * Due to drug-induced inhibition of bradykinin metabolism

Enalapril

Similar to captopril

But a prodrug
* Metabolised by liver (and in kidney???) into active metabolite, enalaprilat

Ramipril

Also a prodrug

Longer duration of effect (24-60hr) than:
* Captopril (6-10hr)
* Enalapril (18-30hr)
* Lisinopril (18-30hr)

Angiotensin II receptor inhibitors

Produces antihypertensive effect by directly blocking angiotensin II receptors (AT1 receptors) without affecting ACE activity

Side effects

• Less cough
  * Due to the lack of bradykinin accumulation
• Hyperkalaemia
• Hypotension following induction

Calcium channel blockers

Discussed elsewhere (To be done)

Vasodilating drugs

Hydralazine

• Phthalazine derivative
  * Activates guanylate cyclase to produce vascular relaxation
• Dilation effect is greater on arteriole than on veins
  --> Smaller incidence of orthostatic hypotension
• Use of beta-blockers limits reflex increase in sympathetic nervous system induced by hydralazine
• Used to treat hypertensive crisis
  * 2.5 to 10mg
  * Effects begin within 10 to 20min, last for 3 to 6 hrs

Metabolism

• Extensive hepatic first-pass
• Main route of metabolism
  --> Acetylation

After oral administration

• Rapid acetylators have lower bioavailability (30%)
• Slow acetylators have higher bioavailability (50%)

Side-effects

• Sodium and water retention
• Vertigo
• Nausea
• Tachycardia
• Angina pectoris (due to myocardial stimulation)
• Drug fever
• Polyneuritis
• Anaemia
• Systemic lupus erythematosus-like syndrome
  * In chronically treated patients, 10-20%

Minoxidil

Direct relaxation of arteriolar smooth muscle.

Almost no effect on venous capacitance vessels

ACE inhibitors and calcium channel blockers may be as effective with less side effects

Extensive metabolism

Side effects of minoxidil

• Fluid retention
• Pulmonary hypertension
• Pericardial effusion and cardiac temponade
• Abnormal ECG
  * Flattening or inversion of T wave
  * High voltage of QRS
• Hypertrichosis
• Marked reflex increase in HR and CO
• Marked orthostatic hypotension