Pharmacology of the Heart
• Heart failures:
- Symptoms: SOB (PND), fatigue, decrease exercise capacity and oedema due to fluid overload from vasoconstriction.
- Causes: hypertension, volume overload, increase pressure load, septal defect, valve disease, contractile unit failure and toxin alcohol abuse etc.
• Acute heart failure: severe cases of pulmonary and peripheral oedema
- Treatment: sit up (stimulate frank-starling), O2 therapy (hypoxic patients), diuretic and frusemide to dilate venules and increase preload while reducing blood volume and pressure.
• Loop diuretics: diuretic drugs that act on the ascending loop of henle. These are used to as anti-hypertensive drugs usually in conjunction with ACE inhibitors to treat oedema, CCF and severe hypertension.
• Frusemide: loop diuretics that inhibit the Na+/K+/Cl- co-transporter.
- Must be first filtered by the renal corpuscles in order for action hence patient with renal failure requires more dose of frusemide
- Luminal side of the ascending loop stop reabsoprtion of K+ causes hypokaelemia
• Adverse effect of loop diuretics: e.g. over dose of frusemide can cause over toxicity and act on the symporters channels in other parts of the body
- in the ear causing numbness and deaf
- dehydration (monitor JVP and weight)
- inadequate body ion content
• Chronic heart failure: switches between chronic and acute. Patients suffer from chronic morbidity and mortality with symptoms of SOB, oedema and loss of energy
- Treatment: ACE inhibitor, and possible also AII blockers as heart failure result in hypotension (insufficient CO) and so increased angiotensin II. Aldosterone antagonists such as spironolactone and beta blockers.
• Treatment of acute congestive cardiac failure: diuretics and nitrates
- Milrinone: decrease the inhibition of cAMP and enhance contractility
- Dobutamine: beta 1 agonist
- Nesiritide: promote vasodilation and counter rennin system
- Levosimendan: calcium sensitiser which binds to troponin C and increase contractility
• Action of ACE inhibitors: examples include enalapril
- Blocks ACE to prevent Angiotensin II synthesis
- Block ACE to prevent breakdown of bradykinin which is a vasodilator
- Side effects: cough due to increase bradykinin; its renally excreted so can build up in renal failure; block K+ excretion and cause hyperkalemia, hypotension
• Action of AII antagonist: prevent binding of angiotensin II to receptors to prevent its effect. It is excreted by a variety of methods but renal impairment is still a problem. Examples are losartan.
- Side effects: hyperkaelemia
• Aldosterone antagonists: spironolcatone can help treat the following problems caused by aldosterone
- Cardiac myocyte hypertrophy
- Fibroblast hyperplasia and collagen synthesis leading to fibrosis
- Vasoconstriction and hypertrophy of periphery artery
- Potassium loss and sodium retention
- Side effects: hyperkaelemia and gynaecomastia
• Action of beta-blockers: examples are metoprolol, bisoprolol and carvedilol. For chronic heart failure, a balance of diuretics and beta blockers over time can improve conditions
- Used in acute heart failure, beta blockers will do harm as it reduce sympathetic response to improve cardiac output
- inhibits sympathetic response and reduce pressure/volume load on heart, i.e. decrease HR, and Q
- Decrease contraction and perfusion
- Increase diastolic filling
- Improve baroreceptor function and LV remodelling
- Side effect:
• Arrhythmia: irregular beating of the heart. Tachycardia is fast (>100) and bradycardia is slow (<60)
- Falls in elderly
- Co-morbidity (comes with heart failure)
- Sighs of breathlessness
- Supraventricular: atrial fibrillation and flutters with tachycardia
- Ventricle: unusual conduction starting from the ventricle and pass upwards (electrical aversion), fibrillations
• Causes of arrhythmia: abnormal pacemaker activity, impulse conduction and predisposed by conditions such as hypoxia, cardiac ischemia and electrolyte disturbances
• Anti-Arrhythmia drugs: modifies the ion channels of the heart to regulate the heart beat, Na+, K+ and Ca2+
- Class I: membrane-stabilizing agents that blocks fast Na+ channels and decrease rate of propagation. Further divide into 1a, 1b and 1c depending on their effect of either opening or closing the channel.
- Class II: beta blockers e.g. atenolol. Blocks sympathetic stimulation and decrease transmission of impulses by depressing phase 4 of AP. Used in atrial and ventricular dysrhythmia
- Class III: blocks K+ channels e.g. amiodarone and increase AP duration by prolonging phase 3 repolarization. Used in dysrhythmias that are hard to treat
- Class IV: block VO Ca2+ channels and depress phase 4 depolarization. Used for atrial tachycardia, fibrillation and flutter and not ventricular arrhythmias.
• Features of anti-arrhythmia drugs:
- Can cause arrhythmia as it tampers with the heart’s activity
- Negatively inotropic
• Class I drugs: slows conduction
- Class Ia: increase AP duration by blocking Na+ channel and slowing depolarization, e.g. quidinidine, procainamide. Used for atrial fibrillation, WPW syndrome.
- Class Ib: decrease AP duration by blocking Na+ channels and accelerate repolarization, e.g. mexiletine, lidocaine. Used for ventricular dysrhythmias only.
- Class Ic: block sodium channel with no effect on AP duration and repolarization. Used in severe dysrhythmias.
• Amidarone: class III drugs that treat atrial and ventricular arrhythmia. Can be taken orally or intravenous to treat acute and chronic heart disease.
- Adverse effect: affect other organs such as lung, eye, skin discolouration, interact with P450 etc
• Non-classified drugs:
- Digoxin: Na+/K+ ATPase inhibitor that increase vagal tone and slow fibrillation (block AV node)
- Adenosine: purine analogue
Pharmacology of Blood Vessels
• Cardiovascular disease prevent:
- Primary: long term/life-long management of people at increased risk of CVD
- Secondary: risk management for patient with evidence of end organ damage
• Types of CVS drugs:
- BP lowering and HF treatment
- Lipid lowering
- Antiplatelet/anticoagulant
- Thrombolytics
- Diabetics treatment
- Anti-arrhythmia
• Cardiovascular risk: the primary target for treatment. CHD, CVA and PVD risk all adds up to contribute to CVS risk.
• Hypertension: CVS risk doubles for each 20/10 mmHg rise in blood pressure.
- Risk of stroke increases greatly with increase in DBP
- Those with BP above >160/100 are treated.
- Comorbidities increases CVS risk despite lower BP, e.g. 130/80 diabetics and 125/75 proteinuria all should be treated.
- Treatment: diuretics, ACEi and vasodilator (combination therapy, e.g. bendrofluazide, cilazapril, felodipine
• Antihypertensives: all except calcium channel blocker are used to treat CCF
- ACE inhibitors
- Beta blockers
- Calcium channel blockers
- Diuretics
• Lipid lower therapy:
- Statin: simvastin and atorvastatin
- Fibrate: bezafibrate
- Cholesterol absorption inhibitor: ezetimibe
- Nicotinic acid
• Statin: HMG CoA reductase inhibitor.
- Primarily block the metabolic pathway for cholesterol
- Secondarily decrease the synthesis of isoprenoid which prenylate proteins (adding hydrophobic prenyl group) responsible for inflammation, cell differentiation/proliferation/apoptosis
- Inhibition of intrinsic cholesterol synthesis would stimulate uptake of peripheral cholesterol molecules (LDL) hence decrease blood cholesterol content.
- Treatment benefits: decreased in MI and CVA by 25% and mortality by 13% in secondary prevention. Minimal effect in primary prevention.
- Adverse effects: myalgias (muscle pain), myositis (inflammation of muscle), rhabdomyolysis (breakdown of skeletal muscle from injury), deranged LFT, teratogenic
• Fibrates: PPAR-alpha (peroxisome proliferator-activated receptor) agonist which decrease hepatic VLDL production and increase its clearance, and increase muscle FA storage. Fibrate also activate lipoprotein lipase
- Capable of decreasing triglyceride by 30 to 50%
- Used for hypertriglyceridaemia and in combination with statin for resistant hypercholesterolaemia
- Adverse effect: GI upset, deranged LFT, myositis
• Ezetimibe: low efficacy as a monotherapy so used with statin. It reduced cholesterol absorption (block uptake protein) and decrease delivery of cholesterol to liver. Ezetimibe also increase LDL receptor expression
• Aspirin: focused secondary prevention with minimal primary prevention effect
- Decrease vascular event by 25% and mortality by 16%
- Criteria: use if age >50 and BP is controlled below 150/90 and patient has diabetes with organ damage
• Antiplatelet/anticoagulant:
- Clopidogrel: inhibits platelet ADP receptor
- 2b/3a antagonist
- Warfarin: used in prosthetic valves patients and atrial fibrillation
• Adherence problem: only 50% adherence after 1 year. Due to:
- Long duration of treatment
- Asymptomatic condition
- Lack of immediate perceived effect
• Benefits of drugs:
- Improved life expectancy: aspirin, beta blocker, statins, and ACEi
- Improved morbidity: diuretics, beta blockers
• Summary:
- Acute use: STEMI
- Chronic use: primary prevention against hypertension and lipideamia while secondary prevention is rigorous control of risk factors with end organ damage