PK and PD of commonly used cardiac drugs Flashcards
Describe digoxin
Digoxin is a cardiac glycoside, derived from foxgloves and related plants.
Action: slowing down of atrioventricular node due to increased vagal activity, increased force of cardiac contraction by inhibition of the Na+/K+ pump in the cardiac myocytes (not shown to be beneficial in long term heart failure treatment) ^[previously used for heart failure but not anymore- why?].
Indication: to reduce heart rate in atrial fibrillation
Pharmacokinetics: well absorbed orally (75%), elimination half life 36 hours, 90% renally cleared ^[important if comorbidity of renal disease or low GFR, lowers with age].
Adverse effects:
- narrow therapeutic window
- heart block
- ectopic beats
- nausea
- vomiting
- diarrhoea
- confusion
Reduce dose in elderly and renal impairment
Describe sotalol
Sotalol is a non-selective beta adrenoceptor antagonist.
Action: prolongs the cardiac action potential and the QT interval by delaying the slow, outward K+ current.
Pharmacokinetics:
- renally cleared
Avoid in patients with renal impairment or renal failure (aka a contraindication)
Indication:
- atrial fibrillation/flutter
- ventricular tachycardia (VT)
Adverse effects:
- fatigue
- tiredness
- bronchospasm
- bradycardia
- torsades de pointes (a type of VT caused by QT interval lengthening drugs)
Describe amiodarone
Amiodarone is a class III arrhythmic (potassium blocker). It is the most effective drug to revert heart in AF back to sinus rhythm.
Action: prolongs action potential, blocks potassium channels
Indication:
- atrial and ventricular arrhythmia
- atrial fibrillation
- ventricular tachycardia
Pharmacokinetics:
- extensively bound in tissues
- (very) long elimination half-life (10-100 days) and accumulates in the body
- loading dose is used ^[n.b. can take a month for patient to reach steady state], and for life-threatening dysrhythmias this is given intravenously via a central vein (causes phlebitis (necrosis) if given into a peripheral vein)
Adverse effects:
- photosensitive skin rashes and a slate-grey discoloration of the skin
- hyper- and hypo-thyroidism (contains iodine) ^[need 3 monthly blood tests for monitoring]
- hepatitis, raised liver enzymes
- neurological problems: tremor, ataxia
- pulmonary fibrosis, rare, late in onset but may be irreversible
- corneal deposits (generally asymptomatic, does not affect vision and is reversible)
- Proarrhythmic effects (Torsades de pointes VT) prolonged QT interval on the ECG
NB - in general most antiarrhythmics can also cause arrhythmias
NB - in general most antiarrhythmics can also cause arrhythmias – see also kuracloud 3 cardiac drugs
Describe ACE inhibitors
Action:
Inhibit conversion of Angiotensin I to Angiotensin II
Indications:
- hypertension
- LV dysfunction and systolic heart failure (evidence of mortality benefit)
Pharmacokinetics:
- orally absorbed
- halflife ~10 hours, mainly renally cleared
Adverse effects:
- cough
- hypotension
- renal impairment (in patients with renal artery stenosis)
- allergy
- hyperkalaemia
Examples of angiotensin converting enzyme inhibitors:
- Ramipril
- Perindopril
- Lisinopril
- Enalapril
Describe angiotension receptor blockers
Action:
Blocks Angiotensin II receptor (AT-1 subtype), similar to ACE inhibitors
Indication:
- hypertension (most prescribed)
- LV dysfunction
- systolic heart failure
Pharmacokinetics:
- good oral absorption
- half life ~ 8-10 hours
- cleared by hepatic metabolism
Adverse effects:
- rare cough
- hypotension
- allergy
- hyperkalaemia
- renal impairment
Examples of angiotensin receptor blockers include:
- valsartan
- telmisartan
- losartan
- irbesartan
Describe examples of combination therapy: valsartan and sacubitril
This is a fixed dose combination, indicated for heart failure with reduced ejection fraction as a replacement for ACEI or ARB.
Action:
- natriuretic peptides are naturally occurring
- promote sodium excretion and diuresis
- sacubitril inhibits the enzyme neprilysin that degrades natriuretic peptides resulting in an increase in the level of these peptides
- valsartan is an ATII receptor blocker (inhibits vasoconstriction, sodium retention)
~ Paradigm-HF trial showed a reduction in CV death and heart failure with Entresto compared with Enalapril ~
Adverse effects:
- angioedema
- hypotension
- renal impairment
- hyperkalaemia
Describe catecholamines
Catecholamines are alpha and/or beta agonists.
- Alpha receptors are located on the arteries (and cause vasoconstriction)
- Beta-1 receptors mainly found in the heart, cause increased HR and force of contraction
- Beta-2 receptors in lungs, gut, vessels, cause smooth muscle relaxation
Pharmacokinetics:
- intravenous use
- half-life 2 minutes
- metabolised
Indication:
- hypotension
- septic shock
- cardiogenic shock
- bradycardia (isoprenaline)
- anaphylactic shock (adrenaline)
Side effects:
- tachycardia
- VT
- vasoconstriction
- myocardial ischaemia
Examples: noradrenaline, adrenaline, isoprenaline, dopamine, dobutamine
Describe beta adrenoceptor blockers
Indications:
- Angina
- MI (reduce HR, reduce contractility)
- hypertension (reduce contractility, reduce renin production, reduce central sympathetic activity)
- prevention of arrhythmia caused by sympathetic activation
- HR control in atrial fibrillation (reduce AV node conduction)
- Systolic heart failure (block harmful effects of excess catecholamines on myocardium)
Side effects:
- Fatigue
- tiredness
- bronchospasm
- bradycardia
- cold extremities due to loss of beta receptor mediated vasodilation, bad dreams
Examples: metoprolol (beta-1), carvedilol (alpha and beta)
Describe statins
HMG CoA reductase inhibitors inhibit conversion of HMG CoA to mevalonic acid ^[ [[Biochemistry Lecture 6]] ].
Indication:
- clinical atherosclerotic disease
- prevention of atherosclerotic disease in high risk individuals
- use should be additional to diet, exercise and weight loss
Side effects:
- myalgia
- myositis
- diarrhoea
- abnormal LFT
- diabetes (rare)
- potentially cognitive impairment
Describe ezetemibe
Action:
- inhibits absorption of cholesterol from the duodenum by blocking a transport protein in the brush border of enterocytes
- without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids
Indication:
- an adjunct to diet and statins in hypercholesterolaemia
- weak outcome evidence
Pharmacokinetics:
- administered by mouth, absorbed into intestinal epithelial cells, localises to the brush border
- extensively (>80%) metabolised to an active metabolite. The terminal half-life is approximately 22 hours
Side effects:
- generally well tolerated but can cause diarrhoea, abdominal pain or headache
- rash and angio-oedema have been reported
Describe heparins
Commercial preparations of heparins are extracted from beef lung or hog intestine and differ in potency, assayed biologically against an agreed international standard: doses are specified in units of activity rather than of mass.
Low-molecular-weight heparins (LMWHs) are heparin fragments (enoxaparin, dalteparin) or a synthetic pentasaccharide (fondaparinux), are longer acting than unfractionated heparin.
Heparin and LMWH
Action:
- Heparin inhibits coagulation by activating antithrombin III
- LMWH inhibits thrombin and other serine proteases by binding active site
Pharmacokinetics:
- heparin is not orally absorbed, so it is administered as an intravenous bolus and infusion, t1/2 = 60m, metabolised
- LMWH is administered subcutaneously, t1/2 = 8 hours, and mainly undergoes renal clearance –therefore reduce dose OR avoid altogether in renal impairment
Indications:
- acute coronary syndromes ^[a combination of angina (unstable or stable), non-S–T elevation myocardial infarction(NSTEMI), and S–T elevation myocardial infarction (STEMI). It implies the presence of coronary artery disease]
- coronary angiogram
- pulmonary embolus
- venous thrombosis
- DVT prophylaxis
Side effect:
- Bleeding
For revision of platelet activation and aggregation see [[Pathology Lecture 4]]
Describe aspirin
Action:
- inhibits platelet thromboxane A2 synthesis by irreversible acetylation of COX-I
Indication:
- acute MI
- unstable angina
- coronary angioplasty and stent
- acute stroke
- secondary prevention of MI/stroke ^[note” benefit in patients without previous cardiovascular disease is NOT proven]
Side effects:
- peptic ulcer with or without haemorrhage
- abdominal pain
- bleeding
- allergy
Describe P2Y12 receptor antagonists
Adenosine P2Y12 receptor antagonists
Action:
- inhibit ADP-induced platelet aggregation by inhibiting receptor–often in combination with aspirin
Indication:
- acute coronary syndromes
- post PCI/stent for 1 year
- atherosclerotic CV disease
Pharmacokinetics:
- usually given as a loading dose to achieve to rapid platelet inhibition, followed by daily dose (ticagrelor, bidaily)
Side effects:
- haemorrhage
- allergy
- dyspnoea (Ticagrelor)
Describe calcium channel blockers
Calcium channel blockers
Action:
- inhibits calcium channels to induce vascular smooth muscle relaxation
- DHPs act on vascular smooth muscle (e.g. amlodipine)
- verapamil and diltiazem act on the heart directly - has negative ionotropic and chronotropic effects, causes vasodilatation
Indication:
- hypertension
- controlling HR in AF
Side effects:
- headache
- peripheral oedema
- reflux
- bradycardia (non-DHPs) ^[why? both CCB subtypes target L-type Ca2+ channels–what grants spec?]
- verapamil:
- increases blood digoxin ^[how?]
- Wolff-Parkinson-White: increases conduction, resulting in severe tachycardia (via accessory atrioventricular pathway)
