CARDIOVASCULAR SYSTEM DRUGS-1

CARDIOVASCULAR SYSTEM DRUGS

A-adrenoceptor antagonists (blockers) 

EXAMPLES 

Doxazosin, prazosin, tamsulosin, alfuzosin

MECHANISM OF ACTION 

Inhibits a1-adrenoceptors in arterioles, thereby reducing the tone of vascular smooth muscle and reducing total peripheral resistance. Inhibition of a1-adrenoceptors in periurethral prostatic stroma results in relaxation of the internal urethral sphincter and some relief of obstructive urinary symptoms in males.

INDICATIONS

• Hypertension (i.e. doxazosin, particularly in resistant cases as part of polytherapy) 
• Benign prostatic hyperplasia

CAUTIONS AND CONTRA-INDICATIONS

Caution in patients with a susceptibility to heart failure

SIDE-EFFECTS

• Postural hypotension.
• Dizziness.
• Weakness and fatigue. 
• Reflex tachycardia. 
• Headache. 
• Dry mouth. 
• Ejaculatory failure 

METABOLISM AND HALF-LIFE 

Variable – e.g. doxazosin (t½ 22h) extensively metabolised by the liver; alfuzosin (t½ 3–5h) partially metabolised. 

MONITORING 

May cause severe first-dose hypotension, therefore, need to start at a low dose and warn the patient of side-effects.

DRUG INTERACTIONS

Enhanced hypotensive effect with antihypertensives and alcohol

IMPORTANT POINTS

• Centrally acting a2-adrenoceptor agonists (e.g. clonidine, methyldopa) also have an antihypertensive effect (mediated via suppression of the vasomotor centre in the brain). 
• These agents are rarely used due to infrequent but potentially severe adverse effects (methyldopa may cause hepatitis). Methyldopa continues to be used for hypertension in pregnancy

Adenosine 

MECHANISM OF ACTION 

Stimulates specific A1 receptors on the surface of cardiac cells thus influencing adenosine-sensitive Kþ channel and cAMP production. This leads to prolonged conduction through the AV node, often with a high degree AV block.

INDICATIONS

• Rapid reversal of SVT to sinus rhythm. SVT with aberrant conduction (specialist use only). 
• Aiding diagnosis of narrow or broad complex tachycardias

CAUTIONS AND CONTRA-INDICATIONS 

• Second and third-degree AV block. Sick sinus syndrome. 
• Prolonged QT syndrome. 
• Severe hypotension. 
• Decompensated heart failure. Asthma

SIDE-EFFECTS

• Chest pain
• Dyspnea
• Bronchospasm
• Nausea
• Severe bradycardia
• Choking sensation
• Light-headedness 

METABOLISM AND HALF-LIFE

 t½ <2s. Metabolised by uptake into red blood cells and deaminated in plasma.

MONITORING 

Cardiac monitoring required.

DRUG INTERACTIONS. 

Effects of adenosine are potentiated by dipyridamole

IMPORTANT POINTS. 

• Ensure the patient is linked to a cardiac monitor or defibrillator. 
• Attempt vasovagal manoeuvres prior to administration unless contra-indicated 
• If no response to the above, start with 6mg IV rapid bolus given through a large vein and flush with 20ml of normal saline. 
• Repeat with 12mg after 1–2 minutes if no response. A further 12mg can be given. 
• Early specialist cardiology advice is warranted if no response to 12mg of adenosine or if adverse signs are present at any stage e.g. heart failure. 
• Patients should be informed prior to adenosine administration of possible chest pain and the sensation of the heart ceasing to beat

Aldosterone antagonists 

EXAMPLES Spironolactone, eplerenone

MECHANISM OF ACTION 

Competitive antagonist at intracellular aldosterone receptors in renal tubules causing a reduced production of aldosterone-induced proteins. This indirectly reduces the activity of Naþ/Kþ ATPase in the collecting ducts, increasing excretion of Naþ and decreasing Kþ loss. Spironolactone, in particular, also acts on receptors in other tissues, including androgen receptors.

INDICATIONS

• Congestive cardiac failure (spironolactone) 
• Oedema and ascites in liver disease (spironolactone)
• Post-MI heart failure (eplerenone)
• Nephrotic syndrome (spironolactone) 
• Primary hyperaldosteronism (including Conn’s syndrome) (spironolactone)

CAUTIONS AND CONTRA-INDICATIONS

• Electrolyte disturbances (including hyperkalaemia and hyponatraemia) 
• Caution in renal impairment

SIDE-EFFECTS 

• Hyperkalaemia (Kþ sparing effect)
• GI disturbance
• Anti-androgenic effects (spironolactone – menstrual irregularities in females, gynecomastia and hypogonadism in males)

METABOLISM AND HALF-LIFE 

Metabolised to active metabolites. t½ of drug is 60–90min but t½ of active metabolites is longer (up to 11h)

MONITORING 

Monitor plasma electrolytes for adverse effects as above.

DRUG INTERACTIONS

• Enhanced hypotensive effect with other antihypertensives. 
• Increased risk of hyperkalaemia with ACEIs/ARBs and amiloride.
• Increased risk of nephrotoxicity with NSAIDs

IMPORTANT POINTS

• Eplerenoneismoreselectivethanspironolactoneandthereforecausesfewersexhormonerelated adverse effects. 
• Spironolactone may also be used in hypertension (unlicensed indication).

Amiodarone 

MECHANISM OF ACTION InhibitsNaþ/KþATPasesinmyocardium.Prolongsactionpotential duration and refractory period slow AV conduction and SA node function.

INDICATIONS 

• Paroxysmal SVT
• Nodal and ventricular tachycardias
• Atrial fibrillation and flutter
• VF
• Tachyarrhythmias associated with Wolff–Parkinson–White syndrome

CAUTIONS AND CONTRA-INDICATIONS 

• Sinus bradycardia
• SA node block 
• Thyroid dysfunction

SIDE-EFFECTS

• Photosensitive rash
• Slate-grey skin discolouration
• Bradycardia
• Hypothyroidism or hyperthyroidism
• Corneal microdeposits (dazzling at night)
• Pulmonary fibrosis/pneumonitis 

METABOLISM AND HALF-LIFE 

Plasma t½ is long 50 days (ranges from 10–100 days)

MONITORING 

LFTs, TFTs and chest x-ray prior to commencing treatment. LFTs and TFTs every 6 months while on treatment.

DRUG INTERACTIONS

• Increases plasma levels of warfarin, digoxin and phenytoin (reduce doses accordingly) leading to toxicity.
• Drugs that prolong QT interval

IMPORTANT POINTS

• Should only be initiated under specialist supervision . 
• ECG monitoring required when given intravenously. 
• Should be administered through a central line or large IV cannula.
• Can cause torsades de pointes, particularly in individuals with prolonged QT interval (congenital or acquired)

Angiotensin-converting enzyme inhibitors (ACEIs)

EXAMPLES 

Ramipril, lisinopril, perindopril

MECHANISM OF ACTION 

Inhibit angiotensin-converting enzyme, preventing the conversion of angiotensin I to angiotensin ii. This prevents angiotensin-mediated effects(arteriolar constriction and aldosterone release) resulting in reduced afterload and reduced circulating volume, thereby reducing BP.

INDICATIONS

• Hypertension
• Heart failure (result in improved survival in LV dysfunction) 
• Prophylaxis of further cardiovascular events post-MI
• Diabetic nephropathy (lisinopril - results in reduced progression of the disease) Patients at high cardiovascular risk (ramipril)

CAUTIONS AND CONTRA-INDICATIONS

• Hypersensitivity to ACEIs. 
• Pregnancy 
• Renal artery stenosis (reversal of angiotensin II-mediated constriction of efferent arteriole results in reduced GFR)
• Caution in peripheral vascular disease as this may be associated with undiagnosed renal artery stenosis

SIDE-EFFECTS

• Persistent dry cough. Hypotension (may get severe first-dose hypotension)
• Renal impairment
• Hyperkalaemia
• Angioedema (rare)

METABOLISMANDHALF

LIFE Variable–e.g.ramipril(t½13–17h)has an active metabolite; lisinopril (t½ 12h) does not undergo metabolism. 

MONITORING 

• Monitor U&Es for renal impairment prior to and 1–2 weeks after commencing treatment.OncestableontherapyU&Esmustbecheckedatleastannually.
• Careful clinical monitoring is required when used in severe heart failure.

DRUG INTERACTIONS

• Risk of profound first-dose hypotension with loop diuretics and enhanced hypotensive effect with other antihypertensive agents
• Increased risk of renal impairment with NSAIDs
• Enhanced hypoglycaemic effect of insulin, metformin and sulfonylureas
• Effects are antagonised by corticosteroids

IMPORTANT POINTS 

• Clinical effects of the different agents are similar; choice determined by t½(e.g.lisinoprilhas longer t½, therefore suitable for once-daily dosing) and by side-effect profile
• ACEIs/ARBs are less effective in African–Caribbean patients due to ACE polymorphisms

Angiotensin II receptor blockers (ARBs)

EXAMPLES 

Candesartan, losartan, valsartan, irbesartan

MECHANISM OF ACTION 

Act as antagonists at angiotensin II (type 1) receptors. This prevents angiotensin II-mediated effects (arteriolar constriction and aldosterone release) resulting in reduced afterload and reduced circulating volume, thereby reducing BP.

INDICATIONS 

• Hypertension
• Heart failure (result in improved survival in LV dysfunction)
• Diabetic nephropathy in type 2 diabetes

CAUTIONS AND CONTRA-INDICATIONS

• Pregnancy
• Renal artery stenosis (reversal of angiotensin II-mediated constriction of efferent arteriole results in reduced GFR)
• Caution in peripheral vascular disease as this may be associated with undiagnosed renal artery stenosis

SIDE-EFFECTS

• Hypotension (may get severe first-dose hypotension)
• Renal impairment
• Hyperkalaemia
• Angioedema (rare)
• METABOLISM AND HALF-LIFE 
• Variable – e.g. valsartan (t½ 6h) is excreted largely unchanged via the biliary route; losartan (t½ of the active metabolite is 6–9h) is excreted via biliary and urinary routes.

MONITORING 

• Monitor U&Es for renal impairment prior to and 1–2 weeks after commencing treatment.
• Once table on therapy U&Es must be checked at least annually.
• Careful clinical monitoring is required when used in severe heart failure.

DRUG INTERACTIONS

• Risk of profound first-dose hypotension with loop diuretics and enhanced hypotensive effect with other antihypertensive agents. 
• Increased risk of renal impairment with NSAIDs. 
• Enhanced hypoglycaemic effect of insulin, metformin and sulfonylureas. 
• Effects are antagonised by corticosteroids

IMPORTANT POINTS

• ACEIsinhibitACE-mediated breakdown of bradykinin; bradykinin instimulates vagal afferent nervefibresandproducesarefractorydrycough.
• This side-effectdoesnotoccurwithARBs as they do not act directly on ACE. ACEIs/ARBs are less effective in African/Caribbean patients due to ACE polymorphisms

Antimuscarinics 

EXAMPLES 

Atropine, hyoscine, procyclidine

MECHANISM OF ACTION

Antimuscarinics act as competitive antagonists of A Choneffector cells by blocking specific muscarinic receptors (e.g. atropine blocks cardiac M2 receptors). 

Their therapeutic action stems mainly from inhibition of smooth muscle contraction and glandular tissue innervated by postganglionic cholinergic neurones.

INDICATIONS

• Bradycardia (atropine)
• Mydriasis and cycloplegia
• Parkinsonism (procyclidine)
• Symptomatic relief of GI or GU muscle spasm (hyoscine)
• Urinary incontinence 

CAUTIONS AND CONTRA-INDICATIONS

• Myasthenia gravis
• Paralytic ileus
• Pyloric stenosis
• Prostatic enlargement

SIDE-EFFECTS 

• Constipation
• Urinary retention
• Dry mouth
• Blurred vision
• Drowsiness

METABOLISM AND HALF

Live Highly variable–t½foratropineis2–4 hands metabolised by the liver to inactive metabolites; t½ for hyoscine is 5h;t½ for procyclidine is 12h. 

MONITORING 

Administration of atropine requires cardiac and blood pressure monitoring.

DRUG INTERACTIONS

The increased sedative effect when hyoscine gave with alcohol

IMPORTANT POINTS

• Hyoscine may be used for GI colic and excessive respiratory secretions in end-of-life care.
• It is also used to reduce respiratory secretions during anaesthesia. 
• Atropine is used as part of the Resuscitation Council UK guidelines for symptomatic bradycardia and in cardiac arrests when pulseless electrical activity is below 60 complexes per min

Aspirin

MECHANISM OF ACTION 

• Irreversibly inhibits cyclo-oxygenase, resulting in reduced platelet aggregation via impaired thromboxane A2 and prostacyclin production within platelets. 
• Inhibition of thromboxane A2 persists for the lifespan of the platelet(7–10days). Inhibition of prostacyclin is temporary as production by endothelial cells is continuous.

INDICATIONS 

• Prophylaxis of MI
• Prophylaxis of cerebrovascular disease 
• AF (if warfarin is not indicated) 
• Mild to moderate pain. Pyrexia

CAUTIONS AND CONTRA-INDICATIONS.

• Active peptic ulcer
• Haemophilia
• Bleeding diathesis
• Hypersensitivity

SIDE-EFFECTS

• Bronchospasm. 
• GI and another haemorrhage
• GI disturbance 

METABOLISM AND HALF

LIFE Metabolised by the liver; t½ 4h

MONITORING 

No specific drug monitoring required

DRUG INTERACTIONS

• Use of aspirin and anticoagulants increases the risk of bleeding 
• Increased risk of GI side-effects with corticosteroids

IMPORTANT POINTS

• Low dose aspirin (75mg) used for long-term prophylaxis. High dose (300mg) is given if an ischaemic event is suspected. 
• If at high risk of upper GI bleed, give a proton pump inhibitor in conjunction with aspirin. 
• Can cause Reye’s syndrome (hepatic and CNS disorder) in children under 16 years old. 
• An overdose may cause a respiratory alkalosis (adults) due to hyperventilation and  metabolic acidosis (children) due to salicylate load and accumulation of lactic, pyruvic and aceto-acetic acid

b-adrenoceptor antagonists (b blockers) 

EXAMPLES 

Atenolol, propranolol, bisoprolol, carvedilol, sotalol, labetalol, nebivolol

MECHANISM OF ACTION

Block activation of b-adrenoceptors (predominantly mediated through b1 antagonism) thereby reducing the exceptionally-induced rise in heart rate and reducing cardiac contractility. This reduces systolic BP and myocardial O2 demand.

INDICATIONS 

• Angina 
• Arrhythmias
• Hypertension
• Heart failure (bisoprolol and carvedilol only)
•  Prophylaxis post-MI
•  Migraine prophylaxis
•  Thyrotoxicosis 
•  Anxiety

CAUTIONS AND CONTRA-INDICATIONS. 

• Asthma
• Uncontrolled heart failure
• Bradycardia, sick sinus syndrome, second or third-degree heart block
• Hypotension/cardiogenic shock 
• Severe peripheral arterial disease

SIDE-EFFECTS 

• Bronchospasm
• Fatigue
• Cold peripheries
• Bradycardia and hypotension
• Sleep disturbances
• Reduced glucose tolerance
• Hyperkalaemia
• Sexual dysfunction in males
• Dizziness and headache
• Heart block 

METABOLISM AND HALF-LIFE 

Variable – e.g. atenolol (t½ 6h) is excreted largely unchanged in the urine; propranolol (t½ 4h) is metabolised by the liver. 

MONITORING 

Monitor clinically for adverse effects.

DRUG INTERACTIONS 

• Enhanced hypotensive effects with antihypertensives and alcohol . 
• Hypotensive effect antagonised by NSAIDs, steroids and oestrogens. 
• May mask warning signs of hypoglycaemia in diabetics.
• Increased risk of AV block and heart failure with verapamil and diltiazem

IMPORTANT POINTS

• Cardioselectivity: atenolol, bisoprolol and nebivolol have less effect on b2 receptors and therefore reduced bronchospasm. 
• Lipid solubility: atenolol and sotalol are most water-soluble therefore less able to cross blood-brain barrier resulting in less sleep disturbance. 
• Half-life: atenolol, bisoprolol and carvedilol have a longer duration of action hence only need to be taken once daily
• Additional effects: sotalol is a mixed class II/III antiarrhythmic (requires monitoring of QT interval due to risk of torsades de pointes). 
• Nebivolol causes peripheral vasodilatation (mediated by nitric oxide). Intravenous labetalol can be used as a treatment for hypertensive emergencies, particularly those associated with pregnancy

Calcium channel blockers (CCBs) 

EXAMPLES 

Dihydropyridines (nifedipine, amlodipine, felodipine), diltiazem, verapamil 

MECHANISM OF ACTION

Block L type Ca2þ channel store duce in fluxof Ca2þ into cells and thereby reduce contraction of myocytes. Dihydropyridines are highly vascular selective and cause peripheral and coronary vasodilatation. Verapamil and diltiazem are less selective and act directly on cardiac tissue to reduce cardiac contractility and slow conduction at the AV node

INDICATIONS 

• Hypertension
• SVT (verapamil and diltiazem)
• Prophylaxis of angina
• Raynaud’s phenomenon (dihydropyridines only)
• Cluster headache prophylaxis (verapamil)

CAUTIONS AND CONTRA-INDICATIONS

•  Cardiogenic shock or hypotension
•  LVF (verapamil and diltiazem)
• Second or third-degree heart block (verapamil and diltiazem) 
• Bradycardia (verapamil and diltiazem)
• Unstable angina (dihydropyridines)

SIDE-EFFECTS 

• Bradycardia (verapamil and diltiazem) 
• Reflex tachycardia (dihydropyridines)
• Hypotension
• Vasodilatory effects (flushing, headache, ankle swelling, palpitations)
• Constipation (verapamil)
• Heart failure (verapamil)

METABOLISMANDHALF-LIFE

All extensively metabolised in the liver. t½ for diltiazem is 3–5h; t½ for verapamil is 6 hours; t½ for dihydropyridines is highly variable. 

MONITORING 

No specific drug monitoring required

DRUG INTERACTIONS

• Enhanced hypotensive effects with antihypertensives and alcohol . 
• Increased risk of AV block, bradycardia, severe hypotension and heart failure if verapamil or diltiazem are given with b blockers. 
• Plasma concentration of some CCBs are increased by grapefruit juice

IMPORTANT POINTS

• Verapamil and diltiazem are Vaughan Williams class IV antiarrhythmics . Vascularselectivity of different CCBs is explained by voltage dependence; dihydropyridines are inactive at the hyperpolarised membrane potentials of the myocardium during diastole. 
• Verapamil and diltiazem are less voltage dependent and hence less selective

Cardiac glycosides 

EXAMPLE 

Digoxin 

MECHANISM OF ACTION 

• Inhibits Naþ/Kþ ATPase in the myocardium and thereby reduces extrusion ofCa2þ.This prolongsphases4and0ofthecardiac action potential resulting in an increaseinenddiastolicfillingandforceofcontraction(inaccordancewiththeFrank–Starling law of the heart).
• IndirectlyslowsconductionatSAnodeandAVnodeandcentrallystimulates the vagus nerve, resulting in a negative chronotropic effect.

INDICATIONS 

• Supraventricular arrhythmias (atrial fibrillation and atrial flutter)
• Heart failure

CAUTIONS AND CONTRA-INDICATIONS. 

• Complete heart block and second-degree block
• Tachyarrhythmias associated with Wolff–Parkinson–White syndrome
• Ventricular tachycardia/fibrillation
• Myocarditis/constrictive pericarditis
• Hypertrophic cardiomyopathy

SIDE-EFFECTS 

• GI disturbance
• Dizziness
• Blurred or yellow vision (xanthopsia suggests toxicity)
• Arrhythmias/conduction defects
• Rash
• Abdominal pain (suggests toxicity) 

METABOLISM AND HALF-LIFE 

PLASMA t½ is36h. Exclusively eliminated by the kidneys, hence need to reduce maintenance dose in elderly patients and in renal impairment.

MONITORING 

• Check U&Es prior to initiation of treatment. 
• Digoxin levels should be taken 6h post-dose.

DRUG INTERACTIONS

• Increased risk of AV block and symptomatic bradycardia with b blockers. 
• Risk of cardiac toxicity secondary to hypokalaemia with diuretics. 
• Plasma concentrations increased by verapamil and diltiazem. 
• Plasma concentration increased by amiodarone and reduced by St John’s wort

IMPORTANT POINTS. 

• Hypokalaemia and hypercalcaemia predispose to digoxin toxicity. 
• Narrow therapeutic index hence risks of toxicity. 
• Requires loading dose at initiation of treatment

Clopidogrel 

MECHANISM OF ACTION

The active metabolite selectively inhibits the binding of ADP to its platelet receptor and the subsequent activation of GPIIb/IIIa complex, inhibiting platelet aggregation.

INDICATIONS

• Acute coronary syndrome. 
• Acute ST-elevation MI. 
• Aspirin intolerance/hypersensitivity. 
• Prophylaxis of atherosclerotic events in patients with coronary, cerebral or peripheral vascular disease

CAUTIONS AND CONTRA-INDICATIONS

Active bleeding (e.g. peptic ulcer, intracranial haemorrhage)

SIDE-EFFECTS . Bleeding. 

• GI disturbance. 
• Gastric and duodenal ulcers

METABOLISMANDHALF-LIFE 

Clopidogrelisaprodrug, extensively metabolised in the liver to produce the active metabolite. t½ of the main metabolite is 8h.

MONITORING 

No specific drug monitoring required.

DRUG INTERACTIONS

Caution is given in combination with other antiplatelet, anticoagulant or fibrinolytics due to risk of bleeding

IMPORTANT POINTS

• Can be given in combination with low-dose aspirin in ACS and acute MI.
• Given as loading dose (300–600mg) at the initiation of treatment. 
• Usually stopped 7 days pre-operatively, to reduce the risk of perioperative bleeding. 
• Combination with warfarin (e.g. in patients with AF presenting with ACS) significantly increases the risk of bleeding

Dipyridamole 

MECHANISM OF ACTION 

• Inhibits adenosine deaminase and phosphodiesterase, preventing thedegradationofcAMP.
• This reduces the production of thromboxaneA2andplateletactivation and aggregation.

INDICATIONS 

Ischaemic stroke and TIA

Adjunct to warfarin for prophylaxis of thromboembolism with prosthetic heart valves

CAUTIONS AND CONTRA-INDICATIONS

Hypersensitivity

SIDE-EFFECTS 

• GI disturbance 
• Worsening coronary heart disease
• Bleeding

METABOLISM AND HALF-LIFE 

Plasma t½ is 9–12h; predominantly excreted in bile.

MONITORING No specific drug monitoring required.

DRUG INTERACTIONS

• Enhances cardiovascular effects of adenosine.
• Caution is given in combination of other antiplatelets, anticoagulants or fibrinolytics due to risk of bleeding

IMPORTANT POINTS

• Used in combination with anticoagulation in patients with prosthetic heart valves, and low dose aspirin in patients with ischaemic stroke/TIA. 
• Only the modified release the formulation is licensed for these indications

Fibrates 

EXAMPLES 

Fenofibrate, bezafibrate, gemfibrozil

MECHANISM OF ACTION 

Increase the activity of lipoprotein lipase to facilitate catabolism of VLDL (by promoting entry of triglycerides from VLDL and chylomicrons into target tissues). Fibrates also increase the cholesterol content of HDL particles.

INDICATIONS 

• Primary hyperlipidaemia
• Serum triglycerides >10mmol/l 
• Intolerance to statins

CAUTIONS AND CONTRA-INDICATIONS

• Severe hepatic or renal impairment (resulting in low albumin e.g. nephrotic syndrome
• Primary biliary cirrhosis
• Gallbladder disease
• SIDE-EFFECTS 
• GI disturbance
• Myositis-like syndrome (uncommon)
• Cholestasis and increased risk of cholelithiasis 

METABOLISM AND HALF-LIFE 

Variable – e.g. fenofibrate (t½ 20h) is excreted largely unchanged in the urine; gemfibrozil (t½ 1½h) is eliminated mainly by metabolism. 

MONITORING 

Monitor LFTs (especially if concomitant statin use); only measure creatine kinase if clinically indicated.

DRUG INTERACTIONS

• Increased risk of rhabdomyolysis with statins (especially gemfibrozil). 
• The enhanced anticoagulant effect of warfarin. 
• Increased risk of hypoglycaemia with oral antidiabetic agents
• IMPORTANT POINTS. Fibrates may be required in combination with statins in diabetic patients to achieve target lipid-lowering