Antihypertensives


BP = (SV x HR) x SVR

Vasodilators

Sodium nitroprusside

Metab to nitric oxide
NO → activates guanylate cyclase → ↑cGMP → ↓ intracellular Ca
Arteries > veins
Can ↑ or ↓ CO depending on position on starling curve
Metabolism

  • Reacts with oxyHb to form NO, cyanide ions and metHb
  • Some cyanide combines with metHB → non toxic
  • Most metab to thiocyanate (less toxic → excreted in urine)
  • Cyanide binds to cytochrome oxidase inhibiting aerobic metabolism
  • Rx is chelation by dicolbalt edetate or sodium thiosulphate which enhances conversion to thiocyanate
Sensitive to light (liberates CN ions)
Onset 30s

GTN
Metab to NO
Veins > arteries
Onset 3 mins
Tachyphylaxis in 48h

Nicorandil
Opens K channels → K efflux down conc gradient → hyperpolarization → Ca channel closure
Also a nitrate

Ca antagonists
Block L-type Ca channels present in heart and vascular smooth muscle
Verapamil and Diltiazem
Heart and vessels
Nifedipine and Nimodipine
Vessels (nimodipine more lipid soluble so crosses BBB)

Hydralazine
↑ cGMP to ↓ Ca
Arteries > veins

Drugs acting on the renin angiotensin system

Angiotensinogen
↓ ← Renin (JGA) (symp, barorecs - aorta, atria, kidney)
AG1
↓ ← ACE
AG2 → vasoconstriction, ↑ symp, ↑ ADH/ACTH
↓
Aldosterone
↓
Na and H2O retention

ACEi
Arteries > veins
Uses – heart failure, ↑BP, DM

AG2 antagonists
↓ effects of AG2 from non ACE pathways

Diuretics

Thiazides
Inhibit Na Cl pump and therefore their reabsorption in DCT
Vasodilate
↑ glucose, ↓K, ↓Na

Loop diuretics
Inhibit Na, k, 2Cl cotransporter in thick ascending limb
Vasodilate
↓Na, ↓K, Mg, Cl
Alkalosis from Cl loss (presumably more Cl lost overall than K or Na - ? one of these reabsorbed later on without Cl)

K sparing
Amiloride blocks Na, K pump in CCD and DCT
Spironolactone – aldosterone antagonist

Osmotic
Mannitol
Freely filtered at Glomerulus but not reabsorbed → osmotic diuresis

Carbonic anhydrase inhibitors
Acetazolomide
Na loss → acidosis (↓SID)
Used in mountain sickness to combat alkalosis from hyperventilating
Also glaucoma (↓ aqueous humour production)

Adrenoceptor antagonists

α antagonists
Phenoxybenzamine
  • Non-competitive irreversible blockade. Non-selective and blocks pre-synaptic a2 recs removing –ve feedback to nor-adrenaline release causing tachycardia. Also central effects (sedation). Persists into postoperative period
Doxazosin and prazosin
  • Competitive and selective α1 blockers so no reflex tachycardia

ß antagonists

Uses
↓ BP, angina, pri and post MI, heart failure, antiarrhythmic , phaeo, ↑thyroid, ↓ sympathetic response to intubation, surgery

Classification
Receptor selectivity
ß1 – Atenolol, esmolol, bosoprolol, metopralol
ß1 + 2 – propranolol, sotalol
ß1 antag + ß2 ag – celiprolol
α and ß antag – labetalol, carvedalol
Partial agonists – pindolol

Mode of action
Heart
G-proteins to
  • ↓cAMP and Ca
  • ↓ Ca and ↑ K perm → hyperpolarization → ↓ rate phase 4 depol → ↓ rate

Effects
BP
↓ CO, ↓ renin, ↑ baroreceptor sensitivity
SEs
Bronchospasm
CNS (lipid sol) – fatigue, depression, nightmares
Hypoglycaemia
Peripheral vascular ischaemia via unopposed α1

Anaesthesia
The study by Poldermans in high-risk patients had to be stopped early because β-blockade proved so beneficial.
Subsequent studies have failed to reproduce these results.
Recent meta-analysis concluded that β-blockade ↓arrhythmias and myocardial ischaemia but had no effect on mortality, MI rate or length of hospital stay.
POISE study (large randomised multicentre trial - metoprolol started a few hours before surgery and continued for 30 days) showed ↓ MI and AF but ↑ mortality and stroke.
Stroke was associated with the hypotension caused by ß-blockade.
May have been better results if patients had been established on them earlier.
The best regimen in terms of patient selection, timing and duration of treatment is uncertain.
Worse outcome if patients on ß-blockers have them stopped.
Risk is minimised by avoiding tachycardia and hypotension – need to achieve both
Patients with IHD should be on ß-blockers already.
Don’t stop them if on and don’t start them shortly before surgery if not on them already.

Centrally acting drugs

Methyldopa
Α2 agonist
→ ↓ norad release → ↓ centrally mediated sympathetic tone
Sedative

Clonidine
Α2 agonist
Spinal cord – augments endogenous opiate release and modulates descending noradrenergic pain pathways
Uses
↓BP, acute and chronic pain, sedation in ITU
↓MAC, stress response, ADH
Does not promote PLT aggregation
100% PO bioavailability
T1/2 – 12h

Others

Ganglion blockers