Flashcards in Pharmacology 9: Hypertension and heart failure drugs Deck (49):
Verapamil- a Ca2+ channel blocker for hypertension, should not be given with a beta blocker- used in hypertension and HF, WHY?
severe bradycardia and/or hypotension can occur
what is the threshold for drug tment for hypertension?
> or =160mmHg systolic and > or =100mmHg diastolic
tment threshold for hypertension in diabetic patient, and target level on tment?
140mm systolic or 90mm diastolic
and target is <130/80mmHg
most common cause of secondary hypertension?
chronic kidney disease
BHS classification of hypertension?
Grade 1 (mild) 140-159 systolic, 90-99 diastolic
Grade 2 (moderate) 160-179, 100-109
Grade 3 (severe) >=180, >=110
lifestyle therapy for patients with hypertension?
Maintain normal body weight (BMI 20-25 kg/m2
Reduce salt intake to 30
Consume >5 portions of fresh fruit/vegetables daily
Reduce intake of total and saturated fat
step 1 hypertensive tment in patient <55yrs?
ACEI, or AngII receptor blocker if ACEI not tolerated
if both CI or not tolerated, can use a beta blocker
ACEIs also preferred therapy in hypertensive diabetic as delay onset and progression of diabetic glomerular disease
how do ACEIs reduce BP?
competitive inhibitors of ACE, causing...
decrease AngII: so cause areteriolar vasodilation, which decreases systemic resistance.
reduces salt and water retention by PCT at kidney, and by decreasing aldosterone, promote a natriuresis to reduce intravascular volume.
reduce ADH release
reduce SNS activation
increase bradykinin, which causes vasodilation
can also cause venodilation
examples of ACEIs?
ADRs of ACEIs?
persistent dry cough
action of angiotensin II receptor antagonsits (AT1 antagonists)
E.g. Losartan, Valsartan
Bind to angiotensin AT1 receptor
Inhbit vasoconstriction and aldosterone stimulation
caused by angiotensin II
Well tolerated, few side effects
ADRs of AngII receptor antagonists (AT1 antagonists)?
hypotension e.g. dizziness
don't get dry cough- as don't interfere with ACE responsible for bradykinin degradation
step 2 hypertensive tment in patient aged <55yrs?
combine step 1 ACEI/AngII receptor blocker with Ca2+ channel blocker, or thiazide-related diuretic if Ca2+ blocker not tolerated or high risk of HF.
3 main groups of Ca2+ channel blockers?
Dihydropyridines (Nifedipine, Amlodipine)
where do Ca2+ channel blockers act in hypertension?
bind to specific alpha subunit of L-type calcium channel, reducing cellular calcium entry.
oral agents used in LT tment of hypertension
how do the dihydropyridine agents e.g. amlodipine primarily act to decrease BP?
vasodilators- peripheral, coronary and pulmonary arteries
block Ca2+ induced smooth muscle contraction, hence cause vasodilation
how do verapamil and diltiazem primarily act to decrease BP?
-ve inotropes and chrontropes, decreasing myocardial contractility and HR, and impulse conduction.
Verapamil depresses SA node, prolongs effective refractory period, and is used as an anti-arrhythmic drug.
diltiazem has less inotropic effect than verapamil, and is used to treat angina.
PK properties of dihydropyridine Ca2+ channel blockers?
Good oral absorption
Protein bound > 90%
Metabolised by the liver- CYP450?
Few have active metabolite
ADRs of dihydropyridine Ca2+ channel blockers?
Sympathetic nervous system activation – tachycardia
Flushing, sweating, throbbing headache
Gingival hyperplasia (rare)
ADRs of phenylalklyamines e.g. verapamil?
Risk of bradycardia
Reduce myocardial contractility (negative inotrope) –
can worsen heart failure
Verapamil injection should not be given to patients recently treated with beta-blockers because of the risk of hypotension and asystole.
action of verapamil?
Impedes calcium transport across the myocardial
and vascular smooth muscle cell membrane
Class IV anti-arrhythmic agent/prolongs the action
potential/effective refractory period- decreases slope of phase 0 depolarisation of pacemaker cell AP
Peripheral vasodilatation and a reduction in cardiac
preload and myocardial contractility
Diltiazem acts similarly
ADRs of diltiazem?
bradycardia, sino-atrial block, AV block, palpitations, dizziness, hypotension
less -ve inotropic effect than verapamil
step 3 tment of hypertension in patient <55yrs?
thiazide-like diuretic and ACEI/AngII-receptor antagonist combined with Ca2+ channel blocker
action of thiazides/thiazide like diuretics in hypertension?
e.g. chlortalidone= thiazide like, and bendroflumethiazide= thiazide?
produce maximal effect at low doses= flat dose-BP response curve
reduce distal tubular Na+ reabsorption, so increase renal excretion of Na+ and H20, reducing intravascular volume= initial antihypertensive effect, so part. effective in those with volume-based hypertension e.g. primary renal disease patients, decrease volume lowers CO to decrease BP.
Later, TPR falls, thiazides must have a vasodilatory effect, and this combats the RAAS activation that occurs with volume depletion, and drugs achieve maximal antihypertensive effect at doses lower than that needed for max diuretic effect so must reduce BP by decreasing CO and TPR.
ADRS of thiazides/thiazdie-like diuretics?
hyperuricaemia, gout- inflammatory arthritis due to build up of urate in blood, causes very painful, red and swollen joints.
impaired glucose tolerance, espec. with beta blockers
increased cholesterol and triglyceride levels
step 4 tment of hypertension in those aged <55yrs?
Consider seeking specialist advice
Add low-dose spironolactone (K+ sparing diuretic) or use high-dose thiazide-related diuretic if plasma-potassium concentration above 4.5 mmol/litre
Monitor renal function and electrolytes
If additional diuretic therapy is contra-indicated, ineffective, or not tolerated, consider an alpha-blocker or a beta-blocker
step 1 tment of hypertension in those aged 55 or over, or any age and of african or caribbean family origin?
Calcium-channel blocker; if not tolerated or if there is evidence of, or a high risk of, heart failure, give a thiazide-related diuretic (e.g. chlortalidone or indapamide)
step 2 tment of hypertension in those aged 55 or over, or any age and of african or caribbean family origin?
Calcium-channel blocker or thiazide-related diuretic in combination with an ACE inhibitor or angiotensin-II receptor antagonist (an angiotensin-II receptor antagonist in combination with a calcium-channel blocker is preferred in patients of African or Caribbean family origin)
steps 3 and 4 same as for patient <55yrs
CIs to Ca2+ blockers verapamil and diltiazem?
CIs to ACEIs?
CIs to beta blockers?
how do alpha blockers e.g. doxazosin act in hypertension?
Selective antagonism at post-synaptic a-1 adrenoceptors
and antagonise the contractile effects of noradrenaline on vascular smooth muscle
Reduce peripheral vascular resistance
More effect in upright position
Benign effect on plasma lipids / glucose
Safe in renal disease
ADRs of alpha blockers used in step 4 antihypertensive therapy?
headache and fatigue
oedema- especially if combined with dihydropyridines e.g. amlodipine
effects of beta blockers used in step 4 antihypertensive therapy?
e.g. atenolol, bisoprolol
Developed for angina but found to lower blood pressure
Reduce heart rate- decrease slope of phase 4 depolarisation of pacemaker potential mediated by SNS and prolong AV node repolarisation, and cardiac output
Inhibit renin release
Initially TPR increases later falls to normal
ADRs of beta blockers?
bronchospasm- CI in asthma
impaired glucose tolerance
reduced exercise tolerance
lethargy and impaired concentration
cold hands- Raynaud's
what is aliskiren?
direct renin inhibitor- binds to pocket in renin molecule, inhibiting cleavage of angiotensinogen produced by liver to Ang I
how do beta blockers act at the kidney?
bind to beta 1 adrenoceptors (Gs) on granular cells in juxtaglomerular apparatus to inhibit renin release mediated by SNS.
PKs of aliskiren?
t1/2= 40 hrs- can do once daily dosing
steady state takes 5-8 days
mainly eliminated in faeces
caution in those at risk of hyperkalaemia or severe renal impairment and stenosis.
CI in pregnancy
interacts with furosemide (loop)
how does decision to treat hypertension at levels of 140-159 systolic and 90-99 diastolic come about?
depends on overall CVS risk profile= is there a more than 15% risk of CVS event in next 10 yrs?, and presence or absence of end organ damage in heart, eye or kidney.
at borderline, optimum body weight, regular physical activity, and moderation of alcohol and salt intake can avoid need for drug tment. should also advise smoking cessation- help CVD risk factors.
examples of centrally acting agents used in treating hypertension?
Methydopa: converted to a-methyl-noradrenaline –
a potent a2-adrenoceptor agonist (Gi)
Clonidine: direct pre-synaptic a2-adrenoceptor
agonist, used to control vasomotor effects in post-menopausal women e.g. flushing and night sweats*
Moxonidine: imidazoline I1 receptor agonist and
some a2 agonist effect
Reduce sympathetic outflow
• Side effects restrict use:
*a-Methyldopa can be used to treat hypertension in pregnancy- no know effects on fetus.
drugs that can improve prognosis of heart failure?
problem with aldosterone concentration when using ACEI or Ang II receptor antagonist in heart failure?
concentration returns to normal, and it causes endothelial dysfunction producing myocardial fibrosis which along with K+/Mg2+ loss produces arrhythmias that can lead to sudden cardiac death, as does endothelial dysfunction increasing risk of acute coronary events.
physiological effects of beta blockers in heart failure?
reduce HR and BP- reduces CO (inhibit renin release to decrease BP?), so reduce myocardial O2 demand
also reduce mobilisation of glycogen and negate unwanted effects of catecholamines- would try and increase HR- reduce slope of phase 4 depolarisation of pacemaker potential.
why must beta blockers be initiated at a low dose in HF?
failing heart is dependent on HR for cardiac output
why might an aldosterone antagonist e.g. spironolactone be added on to an ACEI and beta blocker in heart failure tment?
in patients who continue to remain symptomatic (particularly in those with moderate to severe heart failure); low doses of spironolactone reduce symptoms and mortality in these patients
secondary causes of hypertension?
tment for hypertensive emergencies?
sodium nitroprusside= Mimics the action of endogenous
nitric oxide on vascular smooth muscle, acting as a potent
vasodilator-decrease TPR, and preload and CO?
what is the usefulness of ACEIs in heart failure?
reverse aldosterone mediated volume retention, so decrease preload on heart to reduce workload
cause vasodilation which reduces TPR, and afterload on heart so reduce impedence to LV ejection and so increase LV stroke volume.
can also increase venous capacitance by decreasing breakdown of bradykinin, so decrease preload.