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