Anti-hypertensive agents:

What classes of antihypertensives are you aware of ? (x4).

ACE inhibitors – reduce angiotensin 2 –> reduced peripheral resistance and decreased blood volume (preload)
B Blockers – reduce HR and cause peripheral vasodilation ( venodilation leading to decreased pre load too)
Ca Channel blockers – reduce peripheral resistance
Diuretics – reduce preload
Nitrates – venodilate (to reduce pre load) and dilate arteries – drop peripheral resistance.

Malignant HTN
- SBP> 200 and DBP>120 with end organ failure eg encephalopathy, nephropathy/AKI, severe headache, confusion, apprehension, blurred vision, nausea, vomiting, focal neurology. Untreated can progress –> convulsions, coma, death.
HTN with haemodynamic compromise –> CCF, stroke, dissecting aortic aneurysm
Treatment
- Parenteral antihypertensives then convert to oral once BP stabilised
- Needs art line and strict fluid balance
- Goal is to reduce BP by 25% and DBP shouldn’t drop below 110-100. Normal BP should be aimed in several weeks not acutely.
- Sodium Nitroprusside – commonest
- Labetalol, GTN, fenoldopam, Ca channel blockers, hydralazine – also used.
- Concurrent diuretics used to prevent volume expansion in reaction to the vasodilators.
- Periop – esmolol is often used to control BP.

Centrally acting sympathoplegic – reduce sympathetic outflow from vasomotor centres in the brain but retain baroreceptor control so are less likely to cause postural hypotension. Reduces renal vascular resistance.
Used in pregnancy induced HTN, pre eclampsia
Analog of L-dopa, paralells NA pathway of production.
PD – Released from adrenergic nerves –> replaces NA–> peripherally this doesn’t make a difference cos it still causes vasoconstriction at alpha receptors, but centrally it can cause antihypertensive effects.
PK – max effect 4-6hrs post, action persists after parent drug gone, t1/2 2hrs, bioavail 25%, start 1g/d, no reduction required in renal imp
Toxicity – sedation esp at onset of treatment, lactation, positive coombs test (reversible)

Another central sympathoplegic
Partial agonist at alpha adrenoceptors
PD – IV injection –> immediate hypertension due to agonist action at alpha adrenoceptors in arterioles –> more sustained hypotension cos it stops other agonists acting there.
It also exerts hypotensive effect via alpha receptors in medulla –> hypotension + bradycardia (more than methyldopa). Reduces renal vascular resistance. Not much postural hypotension.
PK – lipid soluble, increasing increases effect, t1/2 8-12hrs, bioavail – 95%, dose reduce in renal imp
SE – dry mouth, sedation, depression(should be withdrawn), withdrawal after long term use can result in lifethreatening HTN,

PD – powerful parenteral antihypertensive used in hypertensive crisis and severe heart failure. Dilates arteries and veins –> decrease TPR and venous return. Acts like nitrates –> activate guanyl cyclase –> increase cGMP –> relax vascular smooth muscle.
In normal ppl BP decreases but in ppl with heart failure the drop in afterload is so significant that BP increases
PK – complex of nitrate, iron and cyanide. Cyanide metabolised by mitochondria and distributed to ECF and slowly renally cleared.
Effect dissapears within 1-10mins after ceasing meds. So Given as IV infusion. Needs art line to monitor during infusion.
Photosensitive so made up fresh each time and covered.
SE – hypotension, cyanide accumulation(disorientation, weakness, psychosis, muscle spasm, convulsions), metabolic acidosis, arrhythmias, death. Can combat cyanide build up with injection of sodium thiosulfate.

PD – opens K channel –> hyperpolarises/stabilises membrane potential so prevents vascular smooth muscle from contracting –> reflex tachycardia and increased CO.

PD – dilates arterioles not veins, useful in heartfailure and severe HTN, can be combined with nitrates.
PK – rapidly metabolised by liver(low bioavail), t1/2 1.5-3hrs,
SE – rapidly develops tachyphylaxis, headaches, nausea, anorexia, palpitations, sweating, flushing. Reflex tachycardia–> may worsen angina or cause tachyarrhythmias.
Toxicity – esp in slow acetylaters – arthralgia, myalgia, skin rashes, fever – SLE like syndrome. Reversible by stopping drug.

Normal physiology : Reduced renal arterial pressure, increased sympathetic tone, increased sodium concentration/decreased sodium abount at distal renal tubule –> renin release –> activate angiotensinogen –> Angiotensin to angiotensin 1 –> ACE in endothelium converts ACE1 to ACE 2 –> vasocontrictor, sodium retainer and stimulate aldosterone that further increase Na retention.
PD – ACEI stop peripheral conversion of Angiotensin 1 to 2. More bradykinin(vasodilator). Anti hypertensive by reducing TPR. CO and HR not changed much. No reflex tachycardia so safe in angina patients.
Good in CKD cos reduces proteinuria and stabilises renal function.
Captopril – the original
Enalapril, perindopril, ramipril are all predrugs converted in liver by hydrolysis.
SE – severe hypotension if started in volume depleted patient. Acute renal imp(esp in bilateral renal artery stenosis), hyper K, dry cough(bradykinin), angio-oedema. CI in 2nd and 3rd trimester of pregnancy.
PK

Drug	T1/2 (Hrs)	Oral Bioavailablity	Dose reduc in renal imp
Captopril	2	65%	Yes
Lisinopril	12	25%	Yes
Losartan (ARB)	1-2	36%	No

Losartan/telmisartan/candesartan/valsartan
Angiotensin 2 receptor blocker. No effect on bradykinin so less cough and angio oedema.