CVS 3 - Hypertension Flashcards
Arbitrary definition
sustained b.p. (systemic or diastolic) > 140/90 mm Hg
MAP =
MAP = CO x TPR
MAP – mean arterial pressure
CO – cardiac output (bpm x vol)
TPR – total peripheral resistance
Hypertension: diuretics
• Thiazides/”thiazide like”
– bendroflumethiazide, indapamide, chlortalidone, metolazone
– generally preferred –effective & well tolerated
– relatively long half-life helpful
– Simple model water excretion →↓ plasma vol →↓ b.p. an inadequate explanation on its own!
» potent loop diuretics aren’t the most potent anti-hypertensive agents
» diuresis is rapid, ↓b.p. but may take weeks
» low doses are antihypertensive without significant diuresis and without permanent volume reduction
– mechanism not fully clear:
» decrease total body sodium →↓ vascular stiffness?
» direct arterial dilation? (how?)
– particularly useful in elderly
• K+
– avoid hypokalaemia
– spirinolactone, eplerenone –useful if hypertension due to hyperaldosteronism
• Loop diuretics
– diuresis > anti-hypertensive less effective in hypertension
– not usually first choice except certain circumstances eg volume-driven hypertension sparing diuretics “treating the problem” in chronic kidney disease
Hypertension: b receptor antagonists
• Hypertension: b receptor antagonists Not preferred first option except in cases of angina or M.I.
• b1 antagonists
– reduce heart rate/contractility see diagram
– reduce renal renin secretion (Ang II!) – a key effect in reducing bp?
– α1 vasocontrictor response intact – helpful (eg patient standing up)
– inhibit reflex tachycardia caused by vasodilators (eg dihydropyridine)
– contraindication in heart block & asthma (even b1 “selective” such as atenolol, bisoprolol)
• Partial agonists “b1 blockers with intrinsic sympathomimetic activity” eg pindolol
– reduce bp, less bradycardia (Partial agonists inhibit action of agonist (Noradrenalin) but in absence of agonist can partially stimulate the receptor.)
• dual a1 and b1 antagonists
– carvedilol, labetalol
– additional a1 vasodilation allows ↓b.p. without bradycardia ADR
• withdrawal
– rebound sympathetic stimulation of heart
– potential problem in angina, M.I.
– hence gradual discontinuation recommended
a1 cause
a1 cause vasocontriction
Effects of β adrenoceptor antagonists
b1 heart rate, heart contractility: ↓cardiac output - promotes ↓ BP
b1 Renin release (JG cells): ↓RAAS - promotes ↓ BP
b2 vasodilation in some peripheral beds: vasoconstriction - promotes ↑ BP
b2 glycogenolysis in liver: ↓glucose
b2 bronchial smooth muscle relaxation: ↑airway resistance
β2 aqueous humour production: ↓ocular pressure
OVERALL effect is ↓ B.P
Hypertension: selective a1 adrenoceptor antagonists
• Mechanism
– relax arteriolar resistance vessels & dilate venous capacitance (reduced return)
– minimal effect on cardiac output
– need antagonism of a1 not a2 (a2 agonism)
• Drugs
– doxazosin – terazosin – prazosin
• Indications
– hypertension –especially if resistant to other treatment – benign prostatic hyperplasia
• PK
– well absorbed and extensive first pass metabolism – major distinction is t1/2 ( duration of action)
» prazosin t1/2 =3 h b.d.
» doxazosin, terazosin t1/2 = 9-12 h o.d.
• ADR
– postural hypotension (venous pooling) – reflex tachycardia→palpitations
– lethargy, dizziness, headache
• Cautions
– avoid in pregnancy
– can precipitate/worsen heart failure
• Contra-indication – incontinence
• Drug interactions
– the hypotensive effect is accentuated by diuretics & β antagonists
Hypertension: Centrally acting agents
• a2 adrenergic agonists (work in CNS)
– selectivity for a2 avoids sympathomimetic effects
– inhibit sympathetic output from CNS by inhibiting NE release
– methyldopa
» pro-drug metabolized to methylnorepinephrine in CNS
» no effect on renal blood flow – useful for patients with renal disease
» used for hypertension in pregnancy–no fetal ADR reported
» otherwise rarely used due to hepatictoxicity
– clonidine
» long t1/2 and good absorption » withdrawal tachycardia,↑b.p.
• Imidazoline receptor agonists
– moxonidine
– inhibits sympathetic output
– More frequently loosed for hair loss!
Hypertension: Calcium channel antagonists
• Particularly useful in elderly patients if thiazide inadequate, persons of African descent may respond less well
• 1,4 dihydropyridines – more “vascular selective”
– arterial vasodilation
– amlodipine, nifedipine, nicardipine
– nifedipine may increase mortality (M.I.)
• Verapamil, diltiazem
– less vascular selective – also have cardiac effects
» negative chronotropic: reduced firing of SA node and AV block (slower conduction through AV node)
» negative inotropic: reduced Ca2+ influx inhibits contractility
– contraindication in patients with previous cardiac failure – because of negative inotropic effects
– useful for treating hypertension in patients with angina (educed cardiac output reduces O2 requirement!)
Hypertension: ACE inhibitors
• ACE inhibitors
– Reduce:
» AngII →vasoconstriction
» AngII → aldosterone release also reduced so naturesis also helps – reduced metabolism of bradykinin
• Drugs
– captopril - prototypic drug, now less common
– ramipril,
» pro-drug, active metabolite is ramiprilat (water soluble poor absorption).
– enalapril (pro-drug) and enalaprilat (active)
– lisinopril
» not pro-drug – adequately absorbed
– perindopril
• Indications
– Hypertension (Can be combined with diuretics),
– heart failure, after MI,
– diabetic nephropathy
» high glc → kidney damage
» high bp exacerbates this
Hypertension: ACE inhibitors - pk, adr, caution, contraindication, interaction
ACE inhibitors prevent potassium secretion and reduce GFR
• PK
– enalapril –absorption reduced by food
– lisinopril –poorly absorbed
– generally have long t1/2 because bind to ACE (promotes stability)
• ADR
– generally well tolerated
– hypotension – especially if hypovolemic (low fluid vol)
– Hyperkalemia if patient has impaired renal function already (further ↓ excretion)
– persistent dry cough in 10-30% (due to ↑BK ? - so can avoid this with AngII Rec antagonists) – rash
-because the pro-drug is converted in the liver to the
• Cautions active drug – Pro-drugs (activated in liver) may be less effective in patients with hepatic insufficiency
• Contraindications
– contraindicated in patients with already reduced renal perfusion (vasodilation further reduces blood supply to kidney)
– contraindicated in pregnancy –potential foetal toxicity
• Drug interactions
– potentiate the action of other drugs that lower bp, esp if volume low due to diuretics
– additive hyperkalaemia if given with K+ sparing diuretic
– with NSAIDS reduce glomerular pressure and filtration.
NSAID- ACE inhibitor interaction
ACE inhibitors work preferentially on efferent rather than afferent arteriole. Hence lowers glomerular pressure and filtration rate
Hypertension: Angiotensin II receptor antagonists
• AT1 receptor antagonists
– similar action to ACE inhibitors but no effect on BK metabolism
• Drugs
– losartan
» first Ang II antagonist used therapeutically
– candesartan cilexetil
» prodrug, active drug (candesartan, t1/2= 9 h) from liver metabolism
» low Foral ~15% & 99% bound to plasma protein
– irbesartan
» better Foral ~70% and 90% bound to plasma protein
– valsartan
» poor absorption (& reduced by food) and short t1/2 (5h)
– olmesartan
– telmisartan
– eprosartan • Indications
– Hypertension, prevention of diabetic nephropathy
• ADR
– well tolerated & low incidence of cough (no effect BK metabolism)
– hypotension →headache, dizziness, fatigue but <1% patients candesartan cilexetil
• Cautions
– avoid in patients with renal insufficiency- can cause renal impairment (kidney perfusion requires local action of AngII to create sufficient pressure –ARB causes efferent dilation →↓ pressure )
• Contrainidications – pregnancy
• Drug Interactions
– potentiate the action of other drugs that lower bp, esp if volume low due to diuretics
– hyperkalemia with a K+ sparing diuretic
– NSAIDS antagonise hypotensive effects of Ang II receptor antagonists
Hypertension: combination therapy
• Drug synergy/additivity – can use lower dose of individual drugs so may avoid ADR
• Dose of individual agent increased to maximum recommended dose (or ADR become limiting) before try combination
• b receptor antagonists & dihydropyridine Ca channel antagonists
– but not with verapamil – potential for severe bradycardia (because verapamil is not vascular selective, dihydropyridines are) - Avoid!
• Diuretics & ACE inhibitor
• ACE inhibitor & Ca antagonist
• Choice is often logical
– patient with angina b blocker or Ca2+ channel would be appropriate but not in a patient with cardiac failure
– diuretic avoided in patients with diabetes or gout
Pregnant woman has HT with asthma - recommend?
- methydopa as labetalol should not be used asthmatic patients
- nifedipine can delay labour so can’t give that either
