Pharmacology 9: Hypertension and heart failure drugs

Question 1

Verapamil- a Ca2+ channel blocker for hypertension, should not be given with a beta blocker- used in hypertension and HF, WHY?

Answer 1

severe bradycardia and/or hypotension can occur

Question 2

what is the threshold for drug tment for hypertension?

Answer 2

> or =160mmHg systolic and > or =100mmHg diastolic

Question 3

tment threshold for hypertension in diabetic patient, and target level on tment?

Answer 3

140mm systolic or 90mm diastolic

and target is <130/80mmHg

Question 4

most common cause of secondary hypertension?

Answer 4

chronic kidney disease

Question 5

BHS classification of hypertension?

Answer 5

Grade 1 (mild) 140-159 systolic, 90-99 diastolic
Grade 2 (moderate) 160-179, 100-109
Grade 3 (severe) >=180, >=110

Question 6

lifestyle therapy for patients with hypertension?

Answer 6

Patient education
Maintain normal body weight (BMI 20-25 kg/m2
)
Reduce salt intake to 30 
minutes/day
Consume >5 portions of fresh fruit/vegetables daily
Reduce intake of total and saturated fat
(Smoking cessation)
(Relaxation therapies)

Question 7

step 1 hypertensive tment in patient <55yrs?

Answer 7

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

Question 8

how do ACEIs reduce BP?

Answer 8

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

Question 9

examples of ACEIs?

Answer 9

ramipril

lisinopril

Question 10

ADRs of ACEIs?

Answer 10

persistent dry cough
renal failure
hyperkalaemia
angio-oedema
hypotension

Question 11

action of angiotensin II receptor antagonsits (AT1 antagonists)

Answer 11

E.g. Losartan, Valsartan
Bind to angiotensin AT1 receptor
Inhbit vasoconstriction and aldosterone stimulation 
caused by angiotensin II
Well tolerated, few side effects

Question 12

ADRs of AngII receptor antagonists (AT1 antagonists)?

Answer 12

renal failure
hyperkalaemia
hypotension e.g. dizziness
don’t get dry cough- as don’t interfere with ACE responsible for bradykinin degradation

Question 13

step 2 hypertensive tment in patient aged <55yrs?

Answer 13

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.

Question 14

3 main groups of Ca2+ channel blockers?

Answer 14

Dihydropyridines (Nifedipine, Amlodipine)
Benzothiazepines (Diltiazem)
Phenylalkylamines (Verapamil)

Question 15

where do Ca2+ channel blockers act in hypertension?

Answer 15

bind to specific alpha subunit of L-type calcium channel, reducing cellular calcium entry.
oral agents used in LT tment of hypertension

Question 16

how do the dihydropyridine agents e.g. amlodipine primarily act to decrease BP?

Answer 16

vasodilators- peripheral, coronary and pulmonary arteries

block Ca2+ induced smooth muscle contraction, hence cause vasodilation

Question 17

how do verapamil and diltiazem primarily act to decrease BP?

Answer 17

-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.

Question 18

PK properties of dihydropyridine Ca2+ channel blockers?

Answer 18

Good oral absorption
Protein bound > 90%
Metabolised by the liver- CYP450?
Few have active metabolite

Question 19

ADRs of dihydropyridine Ca2+ channel blockers?

Answer 19

Sympathetic nervous system activation – tachycardia 
and palpitations
Flushing, sweating, throbbing headache
Oedema
Gingival hyperplasia (rare)

Question 20

ADRs of phenylalklyamines e.g. verapamil?

Answer 20

Constipation
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.

Question 21

action of verapamil?

Answer 21

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

Question 22

ADRs of diltiazem?

Answer 22

bradycardia, sino-atrial block, AV block, palpitations, dizziness, hypotension
less -ve inotropic effect than verapamil

Question 23

step 3 tment of hypertension in patient <55yrs?

Answer 23

thiazide-like diuretic and ACEI/AngII-receptor antagonist combined with Ca2+ channel blocker

Question 24

action of thiazides/thiazide like diuretics in hypertension?

Answer 24

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.

Question 25

ADRS of thiazides/thiazdie-like diuretics?

Answer 25

hypotension
hypokalaemia
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
activates RAAS

Question 26

step 4 tment of hypertension in those aged <55yrs?

Answer 26

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

Question 27

step 1 tment of hypertension in those aged 55 or over, or any age and of african or caribbean family origin?

Answer 27

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)

Question 28

step 2 tment of hypertension in those aged 55 or over, or any age and of african or caribbean family origin?

Answer 28

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

Question 29

CIs to Ca2+ blockers verapamil and diltiazem?

Answer 29

heart failure

heart block

Question 30

CIs to ACEIs?

Answer 30

renovascular hypertension

pregnancy

Question 31

CIs to beta blockers?

Answer 31

asthma
COPD
heart block

Question 32

how do alpha blockers e.g. doxazosin act in hypertension?

Answer 32

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

Question 33

ADRs of alpha blockers used in step 4 antihypertensive therapy?

Answer 33

postural hypotension
dizziness
headache and fatigue
oedema- especially if combined with dihydropyridines e.g. amlodipine

Question 34

effects of beta blockers used in step 4 antihypertensive therapy?

Answer 34

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

Question 35

ADRs of beta blockers?

Answer 35

bronchospasm- CI in asthma
bradycardia
impaired glucose tolerance
reduced exercise tolerance
lethargy and impaired concentration
cold hands- Raynaud's

Question 36

what is aliskiren?

Answer 36

direct renin inhibitor- binds to pocket in renin molecule, inhibiting cleavage of angiotensinogen produced by liver to Ang I

Question 37

how do beta blockers act at the kidney?

Answer 37

bind to beta 1 adrenoceptors (Gs) on granular cells in juxtaglomerular apparatus to inhibit renin release mediated by SNS.

Question 38

PKs of aliskiren?

Answer 38

t1/2= 40 hrs- can do once daily dosing
low bioavailability
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)

Question 39

how does decision to treat hypertension at levels of 140-159 systolic and 90-99 diastolic come about?

Answer 39

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.

Question 40

examples of centrally acting agents used in treating hypertension?

Answer 40

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:
– Tiredness/lethargy
– Depression
*a-Methyldopa can be used to treat hypertension in pregnancy- no know effects on fetus.

Question 41

drugs that can improve prognosis of heart failure?

Answer 41

ACEI/ARB
aldosterone blockage
beta blocker

Question 42

problem with aldosterone concentration when using ACEI or Ang II receptor antagonist in heart failure?

Answer 42

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.

Question 43

physiological effects of beta blockers in heart failure?

Answer 43

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.

Question 44

why must beta blockers be initiated at a low dose in HF?

Answer 44

failing heart is dependent on HR for cardiac output

Question 45

why might an aldosterone antagonist e.g. spironolactone be added on to an ACEI and beta blocker in heart failure tment?

Answer 45

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

Question 46

secondary causes of hypertension?

Answer 46

CKD
renovascular hypertension
Conn's syndrome
pheochromocytoma
Cushing's syndrome
Acromegaly
Liddle's syndrome

Question 47

tment for hypertensive emergencies?

Answer 47

sodium nitroprusside= Mimics the action of endogenous
nitric oxide on vascular smooth muscle, acting as a potent
vasodilator-decrease TPR, and preload and CO?

Question 48

what is the usefulness of ACEIs in heart failure?

Answer 48

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.

Question 49

how is drug tment initiated for chronic heart failure?

Answer 49

Tment aims to relieve symptoms, improve exercise tolerance, reduce the incidence of acute exacerbations, and reduce mortality. An ACE inhibitor, titrated to a ‘target dose’ together with a beta-blocker, form the basis of treatment for all patients with heart failure due to left ventricular systolic dysfunction.
An ACE inhibitor is generally advised for patients with asymptomatic left ventricular systolic dysfunction or symptomatic heart failure. An angiotensin-II receptor antagonist may be a useful alternative for patients who, because of side-effects such as cough, cannot tolerate ACE inhibitors; a relatively high dose of the angiotensin-II receptor antagonist may be required to produce benefit. Candesartan or valsartan may be given under specialist supervision as adjuncts to an ACE inhibitor in the treatment of heart failure when other treatments are unsuitable.