CARDIOVASCULAR SYSTEM DRUGS-2

CARDIOVASCULAR SYSTEM DRUGS-2

LVF = Left ventricular failure
U&Es = Urea and electrolytes 
GFR = Glomerular filtration rate
t½ = Half-life
VTE = Venous thromboembolism

cGMP =Cyclic guanosine monophosphate

HMG CoA =3-hydroxy-3-methylglutaryl coenzyme A

MAO = Monoamine oxidas

DVT = Deep vein thrombosis

COMT = Catechol-O-methyl transferase

PE = Pulmonary embolism

VTE = Venous thromboembolism

OCP = Oral contraceptive pil

Fibrinolytics 

EXAMPLES 
Streptokinase, alteplase, reteplase, tenecteplase

MECHANISM OF ACTION
Activation of plasminogen to form plasmin, a proteolytic enzyme that promotes the breakdown of fibrin clots into fibrin degrading products leading to clot dissolution and reperfusion.

INDICATIONS 

• Acute MI
• Massive pulmonary embolus (alteplase)
• Acute ischaemic stroke (under specialist supervision by stroke physician)

CAUTIONS AND CONTRA-INDICATIONS

• Aortic dissection. 
• Active bleeding. 
• Active peptic ulcer disease. 
• Previous haemorrhagic stroke or recent ischaemic stroke. 
• Coagulation defects. 
• Recent surgery/trauma. 
• Active intracranial neoplasm. 
• Uncontrolled hypertension (relative contraindication)

SIDE-EFFECTS

• Bleeding (including cerebral haemorrhage). 
• Nausea and vomiting.
• Reperfusion cardiac arrhythmias and ischaemia.
• Cerebral and pulmonary oedema. 
• Anaphylaxis.
• Severe hypotension

METABOLISMANDHALF-LIFE 
Variable–t½ for streptokinase is18–23min;t½ for alteplase is 4–5min. Metabolised predominantly by the liver.

MONITORING 
Monitor for signs of bleeding, anaphylaxis and intracranial haemorrhage.

DRUG INTERACTIONS

• Risk of haemorrhage is increased with oral anticoagulants. 
• Patients on ACEIs are at an increased risk of anaphylactoid reaction when streptokinase is administered

IMPORTANT POINTS

• Fibrinolytics are licensed for ST-elevation MI within 12h of the onset of chest pain (administered ideally within one hour). 
• Streptokinase is derived from b-haemolytic Streptococci of Lancefield group C; persistence of antibodies to streptokinase may reduce the effect of subsequent doses. It has effectively been superseded by the newer fibrinolytics(e.g.reteplase)in acute mi(where primary percutaneous coronary intervention is not available). 
• Alteplase is a recombinant tissue-type plasminogen activator. 
• Does not cause allergic reactions and can be used in patients with recent streptococcal infections or recent use of streptokinase

Flecainide 
MECHANISM OF ACTION 

• Blocks Naþ dependent channels hence depressing phase 0 of the cardiac action potential.
• Increased PR and QRS intervals and lengthened ventricular refractory period lead to slower conduction of electrical impulses, with the greatest effect noted on the bundle of His and Purkinje system. 
• In addition to the negative chronotropic effect, flecainide also reduces contractility.

INDICATIONS

• Wolff–Parkinson–White syndrome. 
• AV nodal reciprocating tachycardia (AVNRT).
• Ventricular tachyarrhythmias

CAUTIONS AND CONTRA-INDICATIONS

• Second and third-degree AV block. SA node dysfunction. Impaired LV function. 
• Long-standing AF. History of structural heart disease e.g. previous MI

SIDE-EFFECTS 

• Arrhythmia.
• Dyspnoea. 
• Dizziness. 
• Hypersensitivity. 
• Oedema. 
• Fatigue. 
• Fever. 
• Visual disturbances

METABOLISM AND HALF-LIFE 

• t½ is 12–27h. 
• Predominantly metabolised in the liver to an active metabolite.

MONITORING 

• Cardiac monitoring is required during intravenous administration.

DRUG INTERACTIONS

• Increased concentrations of flecainide when given with amiodarone. 
• Risk of myocardial depression and bradycardia with b blockers. 
• Increased risk of cardiac toxicity when given with diuretics (secondary to hypokalaemia).
• Risk of ventricular arrhythmias when given with tricyclic antidepressants

IMPORTANT POINTS.

• Flecainide should be initiated by a specialist. 
• Bolus dose should only be given in an emergency situation with cardiac monitoring and resuscitation facilities available. 
• Flecainide demonstrates use-dependence i.e. its effect on Naþ channels increases with increasing heart rate. 
• Can be used as a ‘pill-in-the-pocket’ for self-administration in paroxysmal SVT

Glycoprotein IIb/IIIa inhibitors 
EXAMPLES 
Tirofiban, eptifibatide

MECHANISM OF ACTION 
a non-peptide antagonist that prevents fibrinogen from binding to the glycoprotein IIb/IIIa receptor, thus blocking platelet aggregation.

INDICATIONS

• Unstable angina/non-ST elevation MI (given with aspirin and heparin). 
• Reduce the immediate risk of vascular occlusion in patients undergoing percutaneous coronary intervention

CAUTIONS AND CONTRA-INDICATIONS

• Active bleeding. 
• Major surgery or trauma in the past 6 weeks.
• Ischaemic stroke within 30 days or any history of haemorrhagic stroke.
• Intracranial pathology (e.g. aneurysm, neoplasm or AV malformation).
• Severe hypertension.
• Deranged clotting or thrombocytopenia

SIDE-EFFECTS 

• Bleeding. 
• Nausea. 
• Headaches. 
• Fever. 
• Reversible thrombocytopenia 

METABOLISM AND HALF-LIFE 

• t½ of tirofiban is 90min. 
• Excreted largely unchanged in the urine.

MONITORING 

• Continuous cardiac monitoring. 
• Monitor clinically for signs of bleeding.

DRUG INTERACTIONS

• Risk of haemorrhage is increased with heparin and antiplatelet drugs

IMPORTANT POINTS

• Treatment should be for a minimum of 48 h a maximum of 108h if the patient remains unstable with a view to in-patient angiography and potential revascularisation as soon as possible

Inotropic sympathomimetics 

EXAMPLES 
Adrenaline, dopamine, dobutamine, isoprenaline

MECHANISM OF ACTION 

• Actions vary depending on which receptors are stimulated. 
• Adrenalineactsona-(peripheral vasculature)and-adrenoceptors(myocardium), producing positive inotropic and chronotropic effects. 
• Low-dose dopamine and dobutamine stimulate b1-adrenoceptors in the myocardium, predominantly increasing contractility.

INDICATIONS 

• Cardiogenic shock. 
• Septic shock. 
• Acute hypotension. 
• Cardiac arrest (adrenaline)

CAUTIONS AND CONTRA-INDICATIONS

• Phaeochromocytoma (dopamine). 
• Atrial and ventricular tachyarrhythmias (dobutamine)

SIDE-EFFECTS

• Nausea and vomiting.
• Hypotension/hypertension .
• Peripheral vasoconstriction. 
• Tachycardia

METABOLISM AND HALF-LIFE 

• Metabolised by the liver, kidney or plasma MAO and COMT; t½ 2min. 

MONITORING 

• Continuous cardiac monitoring in a high-dependency area is required. 
• Monitoring of oxygen saturation, urine output and renal function is also necessary.

DRUG INTERACTIONS. 

• Adrenaline should not be used with other sympathomimetic agents due to the additive effect. 
• Hypertensive crisis when given in combination with MAOIs. 
• Hypertension and reflex bradycardia when given in combination with b blockers

IMPORTANT POINTS. 

• In patients with septic or haemorrhagic shock, the volume must be replaced (though this may worsen cardiogenic shock), after which sympathomimetics may be required to improve cardiac output. 
• Often used in the intensive care setting to maintain perfusion to vital organs. Adrenaline is used as part of the Resuscitation Council UK guidelines

Loop diuretics 
EXAMPLES 
Furosemide, bumetanide 

MECHANISM OF ACTION 

• Inhibits the reabsorption of Na+ and Cl in the ascending limb of the Loop of Henle by inhibiting the Na+/K+/2Cl co-transporter. 
• This results in increased Naþ excretion and free water clearance, thereby reducing preload.

INDICATIONS 

• Pulmonary oedema is secondary to LVF. 
• Chronic heart failure

CAUTIONS AND CONTRA-INDICATIONS

• Severe hypokalaemia/hyponatraemia. 
• Hypovolaemia. 
• Renal failure due to nephrotoxic drugs. 
• Comatose patients with liver cirrhosis. 
• Anuria.

SIDE-EFFECTS 

• Electrolyte disturbances (hypokalaemia, hyponatraemia, hypocalcaemia). Hypotension. 
• Tinnitus and deafness (associated with large IV boluses). 
• GI disturbance. 
• Dyslipidaemia 

METABOLISM AND HALF-LIFE 

• t½ is variable (furosemide 90 min). 
• The onset of action occurs within 1h and diuresis is complete within 6 h. 
• Excreted largely unchanged in the urine.

MONITORING 

• Check U&Es prior to initiating and during treatment.

DRUG INTERACTIONS

• Risk of cardiotoxicity when given with digoxin (secondary to hypokalaemia). 
• Risk of ototoxicity when given with aminoglycosides or vancomycin. 
• Enhanced hypotensive effect with other antihypertensives. 
• Can reduce lithium excretion. 
• NSAIDs can reduce the effectiveness of loop diuretics (due to reduced GFR)

IMPORTANT POINTS

• Patients with low GFR may require higher doses(diuretic resistance due to poor perfusion to target tissues). 
• IV furosemide has a very early vasodilatory effect

Low molecular weight heparins (LMWH) 
EXAMPLES 
Dalteparin, enoxaparin, tinzaparin

MECHANISM OF ACTION 

• Activate antithrombinIII(serine protease inhibitor)thus inhibiting factors IIa (thrombin) and Xa in the common pathway of the clotting cascade. 
• Secondary effects mediated by impairing adhesion and aggregation of platelets.

INDICATIONS

• Prevention of VTE. 
• Treatment of VTE and acute coronary syndrome/MI. 
• Prevention of clotting in extracorporeal circuits

CAUTIONS AND CONTRA-INDICATIONS

• Heparin sensitivity.
• Haemophilia and other bleeding disorders.
• Severe hypertension.
• Severe hepatic or renal disease.
• In patients undergoing surgery on brain, eye or spinal cord

SIDE-EFFECTS

• Bleeding.
• Heparin-induced thrombocytopenia.
• Hypersensitivity reaction.
• Osteoporosis (long-term use)

METABOLISM AND HALF-LIFE

• Metabolised by heparinase in the liver and reticuloendothelial cells. 
• Metabolites are excreted in the urine. t½ is 2–4h (prolonged in renal or hepatic failure).

MONITORING 

• Monitoring is not routinely required.
• In LMWH toxicity there is no effective antidote.

DRUG INTERACTIONS

• Increased risk of bleeding with NSAIDs (including aspirin), warfarin, clopidogrel and dipyridamole.
• Nitrate infusion reduces efficacy of LMWH

IMPORTANT POINTS

• Maximum plasma levels after subcutaneous injection are achieved more rapidly and bioavailability is improved. 
• Shorter half-life (approximately half that of unfractionated heparin).
• Predictable response reduces the need for monitoring (monitored by measurement of anti-factor Xa activity instead of APTT in patients at increased risk of bleeding). As effective as unfractionated heparin in the prevention and treatment of venous thromboembolism and associated with fewer bleeding complications.
• Osteoporosis may occur in long-term use (usually >6 months)

Nitrates 
EXAMPLES 
Glyceryl trinitrate (GTN), isosorbide mononitrate (ISMN)

MECHANISM OF ACTION 

• Metabolised to nitric oxide that activates guanylyl cyclase, increasing production of cGMP in vascular tissues. 
• This secondary messenger causes smooth muscle relaxation resulting in coronary artery dilatation (increasing oxygen supply to myocardium) and systemic vasodilatation (reducing preload and thereby reducing oxygen demand).

INDICATIONS

• Prophylaxis and treatment of angina
• LVF

CAUTIONS AND CONTRA-INDICATIONS

• Hypersensitivity to nitrates.
• Hypotension/hypovolaemia . 
• Cardiac outflow obstruction (aortic stenosis, cardiac tamponade, hypertrophic obstructive cardiomyopathy, constrictive pericarditis). 
• Closed-angle glaucoma

SIDE-EFFECTS

• Postural hypotension. 
• Headache. 
• Tachycardia. 
• Dizziness
• METABOLISM AND HALF-LIFE 
• Metabolised by the liver and other cells including red blood cells. 
• t½ is variable – for intravenous GTN t½ is 4–6min and for oral ISMN t½ is 6h. 

MONITORING 

• BP monitoring is required for intravenous infusion.

DRUG INTERACTIONS

• Reduce the anticoagulant effect of low molecular weight heparin.
• Risk of severe hypotension with phosphodiesterase type 5 inhibitors (e.g. sildenafil) 

IMPORTANT POINTS

• Tolerance to nitrates may develop hence patients should have at least 8h nitrate-free every 24h (except when administered intravenously in the acute setting)

Potassium channel activators 
EXAMPLES 
Nicorandil 
MECHANISM OF ACTION 

• Dual mechanism of action. 
• Opens ATP-sensitive Kþ channels resulting in smooth muscle relaxation, thereby promoting arterial vasodilatation and reducing afterload. 
• Nitric oxide moiety activates guanylyl cyclase to achieve venous relaxation and a reduction in preload. 
• Direct effects on coronary arteries are also seen.

INDICATIONS

• Prophylaxis and treatment of angina

CAUTIONS AND CONTRA-INDICATIONS

• Cardiogenic shock.
• Hypotension.
• LVF with poor filling pressures

SIDE-EFFECTS

• Headaches on initiation.
• Nausea and vomiting.
• Dizziness.
• Flushing.
• Weakness.
• Oral ulceration.
• Angioedema.

METABOLISM AND HALF-LIFE

•  t½ is 40–80min. Metabolised by the liver via nicotinamide pathway; <20% excreted in the urine.

MONITORING 

• Monitor clinically for adverse effects.

DRUG INTERACTIONS

• Hypotensive effects significantly enhanced when taken with phosphodiesterase type 5 inhibitors (e.g. sildenafil). 
• Hypotensive effects possibly enhanced with tricyclic antidepressants and alcohol.

IMPORTANT POINTS

• Start at a lower dose in patients susceptible to headaches. 
• Patients are advised not to drive or operate machinery until it is established that their performance is unaffected.
• Titrate dose to symptomatic relief. 
• Used as an add-on therapy

Statins 
EXAMPLES 
Simvastatin, atorvastatin, pravastatin, rosuvastatin

MECHANISM OF ACTION 

• Inhibition of HMG CoA reductase, preventing the hepatic conversion of mevalonic acid to cholesterol.
• Reduced cholesterol synthesis in the liver results in decreased plasma LDL.

INDICATIONS

• Prevention of cardiovascular events in patients with atherosclerotic disease or diabetes mellitus. 
• Primary hyperlipidaemia

CAUTIONS AND CONTRA-INDICATIONS

• Active liver disease (caution needed in patients with alcohol dependence). Pregnancy and breastfeeding.

SIDE-EFFECTS

• Rhabdomyolysis (rare but may manifest as myalgia, myositis or myopathy).
• Altered liver function tests.
• GI disturbance.

METABOLISM AND HALF-LIFE 

• Metabolised by Cytochrome P450 (except pravastatin and rosuvastatin); clinical effects largely due to active metabolites. 
• t½ is variable – 2h for simvastatin; 14h for atorvastatin.

MONITORING 

• Patients should be warned about possible rhabdomyolysis; if suspected check creatine kinase level. 
• LFTs should be checked 3 months following initiation.

DRUG INTERACTIONS

• Increased risk of myopathy with fibrates, amiodarone and calcium channel blockers. Plasma concentration increased by grapefruit juice and macrolides.
• Plasma concentration reduced by rifampicin.

IMPORTANT POINTS

• Statins are more effective than any other lipid-lowering agents. 
• The greatest reduction of LDL is achieved with atorvastatin and rosuvastatin (60–65% reduction at maximum dose)

Thiazide diuretics 

EXAMPLES 
Bendroflumethiazide 

MECHANISM OF ACTION

• InhibitNa+/Cl symporter in the distal convoluted tubules thereby reducing Na+ reabsorption and reducing water reabsorption.

INDICATIONS

• Hypertension. 
• Oedema in heart failure.

CAUTIONS AND CONTRA-INDICATIONS

• Electrolyte disturbances (including refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia). 
• Addison’s disease. 
• Avoid in breastfeeding mothers due to suppression of lactation.

SIDE-EFFECTS

• Postural hypotension. 
• Hyponatraemia. 
• Hypokalaemia. 
• Hyperuricaemia (e.g. gout). 
• Hypercalcaemia. 
• Hyperglycaemia. 
• Male sexual dysfunction. 
• Suppression of lactation. 
• Raised LDL cholesterol

METABOLISM AND HALF-LIFE 

• Metabolised in the liver. 
• t½ is 3–4h.

MONITORING 

• Monitor plasma electrolytes for adverse effects as above.

DRUG INTERACTIONS

• Enhanced hypotensive effect with other antihypertensives. 
• Increased risk of nephrotoxicity with NSAIDs.
• Reduced hypoglycaemic effect of oral antidiabetic agents.

IMPORTANT POINTS 

• Thiazides are less effective than loop diuretics because 90% of Na+ has been reabsorbed by the time the filtrate reaches the distal convoluted tubule. 
• Hypokalaemia results from increased activity of Naþ/Kþ ATPase in collecting ducts.
• This is caused by increased Naþ in filtrate and an aldosterone-mediated effect (diuretic-induced hypovolaemia causes activation of the renin-angiotensin-aldosterone system)

Tranexamic acid 

MECHANISM OF ACTION 

• Competitively inhibits the activation of plasminogen to plasmin, thereby reducing fibrin clot degradation. 
• At high doses can directly inhibit plasmin activity.

INDICATIONS 

• Menorrhagia. 
• Epistaxis. 
• Thrombolytic overdose. 
• Prevent excessive bleeding (dental extraction in haemophilia)

CAUTIONS AND CONTRA-INDICATIONS

• Thromboembolic disease
• SIDE-EFFECTS
• GI disturbance. 
• Disturbance in colour vision.

METABOLISM AND HALF-LIFE 

• Plasma t½ is between 2–3h.

MONITORING 

• No specific drug monitoring required. 
• Eye tests for long-term treatment.

DRUG INTERACTIONS

• Counters the effects of fibrinolytic agents (e.g. streptokinase, alteplase)

IMPORTANT POINTS

• Treatment should be initiated during menstruation when managing menorrhagia

Vasoconstrictor sympathomimetics 
EXAMPLES 
Noradrenaline, ephedrine, phenylephrine

MECHANISM OF ACTION 

• Stimulation of peripheral a-adrenoceptors within the vasculature, leading to vasoconstriction and increased systolic and diastolic blood pressure.

INDICATIONS

• Acute hypotension. 
• Cardiac arrest.

CAUTIONS AND CONTRA-INDICATIONS

• Hypertension

SIDE-EFFECTS

• Hypertension. 
• Headache. 
• Arrhythmias. 
• Bradycardia/tachycardia.

METABOLISM AND HALF-LIFE 

• Metabolised in the liver and other tissues by MAO and COMT.

MONITORING 

• Continuous cardiac monitoring in a high-dependency area is required. 
• Monitoring of oxygen saturation, urine output and renal function is also necessary.

DRUG INTERACTIONS

• Severe, prolonged hypertension when given in combination with MAOIs.

IMPORTANT POINTS

• Ephedrine can be used to treat hypotension resulting from spinal/epidural anaesthesia.

Warfarin 

MECHANISM OF ACTION 

• Coumarin anticoagulant; inhibits hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) and co-factors (proteins C and S). 
• Thus the predominant action of warfarin is on the extrinsic pathway of the clotting cascade.

INDICATIONS 

• DVT. 
• PE. 
• Prophylaxis of VTE in AF, rheumatic heart disease and in patients with prosthetic heart valves.

CAUTIONS AND CONTRA-INDICATIONS

• Peptic ulceration. 
• Severe hypertension. 
• Pregnancy (due to teratogenicity). 
• Caution if recent surgery.

SIDE-EFFECTS 

• Haemorrhage.
• Hypersensitivity/rash.
• Hepatic dysfunction.
• Skin necrosis (due to thrombosis in the microvasculature of subcutaneous fat) 

METABOLISM AND HALF-LIFE

•  t½ is 37h; metabolised by the liver. 

MONITORING 

• Monitor INR (initially daily and then at progressively lengthening intervals when steady INR is achieved).

DRUG INTERACTIONS 
The anticoagulant effect of warfarin is increased by:-

• Antibiotics (due to reduced vitamin K synthesis by gut flora) 
• Amiodarone and diuretics (displace warfarin from plasma proteins)
• Cimetidine, fluconazole, alcohol (reduce the metabolism of warfarin)
• Aspirin, clopidogrel, NSAIDs (due to impaired platelet function)
• Also by advanced age, biliary disease, CCF, hyperthyroidism, cranberry juice and intermittent alcohol binges. 

The anticoagulant effect of warfarin is reduced by

• Antiepileptic agents, rifampicin, alcoholism (due to induction of hepatic enzymes) Oestrogens and OCP (increase the concentration of vitamin K-dependent clotting factors)
• Also by hypothyroidism and nephrotic syndrome.

IMPORTANT POINTS

• Effects proteins C and S precede anticoagulant effect thereby transiently increasing the risk of thrombosis; anticoagulation with heparin should, therefore, be used concomitantly for at least 5 days and until INR is within the target range for treatment of a thrombotic event. 
• Target INR depends on indication(e.g.2.0–3.0forVTEandAF;3.0–4.5 for prostheti cheart valves; 4.0–5.0 for high-risk heart valves). 
• Vitamin K may be used to reverse anticoagulation with warfarin; use should be limited to major bleeding or high INR in a patient with other risk factors for bleeding. 
• Prothrombin complex concentrate may so be used to reverse effects of warfarin in severe bleeding