DRUGS USED IN CARDIOVASCULAR

DISEASE AND RELATED

COMPLICATIONS
HYPERTENSION
ANGINA
ARRHYTHMIA
CARDIAC FAILURE
ANTILIPID TREATMENT
ANTITHROMBOTIC DRUGS
ANTIFIBRINOLYTICS
 HYPERTENSION
Definition
diastolic arterial pressure > 90mmhg and/or
systolic arterial pressure of > 140mmhg

3 factors determine b/p

a. blood volume
b. cardiac output
c. peripheral vascular resistance
 Control of vascular tone
1. α1-adrenoceptors
activation causes contraction of vascular smooth muscle

2. β2 -adrenoceptor
activation causes relaxation of vascular smooth muscle

3. M3 receptor
activation cause relaxation of vascular smooth muscle
 Control of vascular tone ct’d
4. renin-angiotensin system
a decrease in plasma volume results in activation of the
RAS.
ACE catalyses production of angiotensin II.
effects are:
a. Potent vasoconstrictor ( 40 x > NA)
b. release of NA
c. stimulates secretion of aldosterone
Drugs used to treat
hypertension
Diuretics
Vasodilators
 Diuretics
• thiazides
• loop diuretics
• potassium sparing drugs
 Diuretics
• Thiazide diuretics preferred
• Egs hydrochlorothiazide, bendrofluazide, chlortalidone
• Mechanism of action:
– Inhibit Na+/Cl- co-transporter in luminal membrane
causing increased sodium excretion.
• Clinical pharmacology
– Well absorbed orally
– Effects on kidney depend on renal excretion of drug into
renal tubule therefore become less effective with
increasing renal impairment
– Quick onset of action, lasts for about 12hrs
• Adverse effects
– Hypokalaemia
– Hyperuricemia
– Hyperglycemia
– Hypercalcemia
– Hyperlipidemia
– Impotence
– Thrombocytopenia
– Skin rashes
 Vasodilators
• Calcium channel blockers
• ACE inhibitors
• ARBs
• Beta-blockers
• Alpha-1 antagonists
• Centrally acting agents
 Calcium antagonists
• MOA
– Block calcium channels – negative ionotropic and chronotropic effects,
and vasodilatation.
• Subtypes:
– Dihydropiridines- nifedipine,amlodipine
– Phenyalkalamines-verapamil
– Benzothiazipines-diltiazem
• Clinical pharmacology
– Undergo first pass metabolism.
– Hepatic enzyme inhibitors
• Adverse effects
– Dihydropiridines-headache, facial flushing, ankle swelling on long term
use
– Verapamil-bradycardia, AV conduction delay, constipation
– Diltiazem- bradycardia, AV conduction effects.
– occassional rash
 ACE inhibitors
MOA
Inhibit ACE with consequent reduced angiotensin II and
aldosterone levels and increased bradykinin.
Effects: vasodilation, reduction in peripheral vascular resistance,
reduced sodium retention.
Adverse effects
– First dose hypotension
– Impairment of renal function
– Cough 15%
– Angioneurotic oedema
– Hyperkalaemia
– Skin rash and taste disturbance (captopril)
Contraindications
– Pregnancy and breastfeeding
– Renal vascular disease
 ARBs
• MOA- block angiotensin II receptors-
vasodilation and reduced peripheral
resistance
• Contraindications- pregnancy, breastfeeding,
caution in renal artery stenosis and aortic
stenosis.
• adverse effects- cough, orthostatic
hypotension, dizziness, headache, fatigue,
hyperkalaemia and rash.
 Βeta adrenoceptor antagonists
MOA:- Antagonise effects of sympathetic nerve stimulation or circulating
catecholamines
Clinical pharmacology
– Propranolol-lipid soluble, hepatic metabolism, undergoes first pass
metabolism
– Atenolol-water soluble, excreted in kidneys
Adverse effects
– Bradycardia
– Peripheral vasoconstriction mediated by blockade of beta2 receptors
in skeletal muscle beds-cold extremities- raynaud’s phenomenon
– Hallucinations, vivid dreams, nightmares
– Bronchospasm
– Tiredness and fatigue
– Masking hypoglycemia
– Metabolic disturbance
 Alpha-1 antagonists
• Prazosin and doxazosin
• Selective blockade of peripheral alpha-1
receptors
• First dose hypotension-palpitations
 Centrally acting agents
• Clonidine alpha-2 receptor agonists
• Methyldopa- alpha- methylnoradrenaline-
alpha-2 agonist.
 Hydralazine
MOA- direct vasodilator
Indications - moderate to severe htn,
hypertensive emergencies, and htn in
pregnant women.
CI- idiopathic SLE, severe tachycardia
adverse effects-tachycardia, fluid retention,
N&V, headache.
Antiarrhythmic drugs
 CLASS I
• block voltage dependent sodium channels.
• effects:
– prolong effective refractory period(terminate reentry)
– convert unidirectional block to bidirectional block(prevent
reentry)
• class 1a
– eg- quinidine, procainamide and dysopyramide
• class 1b
– eg lidocaine and phenytoin
• class 1c
– egs-flecainide
 CLASS II
• beta-adrenoceptor blockers- propranolol,
pindolol and atenolol
 CLASS III
• egs bretylium, amiodarone, sotalol, and
ibutilide
• MOA- potassium channel blockers
• indications- ventricular and supraventricular
arrhythmias
 Amiodarone
MOA
• Potassium channel blocker
• Prolongs action potential duration and effective refractive period.
PK
• Extensively bound to tissues- therapeutic action may take several weeks to
develop
• Long elimination half life over 30 days.
• Loading dose 600-1200mg/day given for weeks then decreased to 100-400/day.
• In acute cases IV 300mg given over 60mins
Adverse effects
• Precipitate torsade's de pointes
• photosensitivity
• Pulmonary alveolitis
• Hepatitis
• Neurological (tremor, ataxia)
• Hyper- or hypothyroidism
• orchitis
 Dronedarone
• Non-iodinated class III agent
• Shorter elimination half life
• Dose 400mg bd
 CLASS IV
• egs verapamil and diltiazem
• MOA- calcium channel blockers

• others ; digoxin, adenosine, adrenaline

 Adenosine
MOA
• Acts via purinergic receptors situated on SA and AV nodes
• Stimulation causes hyperpolarisation resulting in suppression of
automaticity and conduction
• Results in transient sinus bradycardia and AV block.
PK
• Half life <10 sec
• Given as IV bolus in a central or a large vein followed by saline
• Initial dose 3mg, if no successful 6mg after an interval of 3 mins.
Adverse effects
• Chest pain and tightness
• Heart block
• Bronchospasms
Drug interactions
• methylxanthines
Anti-anginal drugs

Organic nitrates
ß-blockers
Calcium channel blockers
Potassium channel activators.
 The overall aim of symptom
management in angina is to:
• dilate coronary arteries to allow maximal
myocardial perfusion
• decrease heart rate to minimise oxygen
demands of the myocardium
• lengthen diastole when cardiac perfusion
occurs
• and prevent further platelet aggregation
 Organic nitrates
• egs GTN, isosorbide dinitrate, and isosorbide
mononitrate
• MOA- decrease preload by causing dilatation
of systemic veins- decrease in oxygen demand
of heart.
• dilatation of coronary arteries increase blood
flow and oxygen delivery to the myocardium.
 Nitrates c’d
PK
• GTN rapidly inactivated by hepatic metabolism-
not swallowed( first pass metabolism)
• Duration of action approx. 30 mins
Side effects
• Postural hypotension
• Headache
• Tolerance with long acting- occurs quickly but
wears off after a brief nitrate free period.
 Isosorbide mononitrate
• Swallowed- metabolized slowly by the liver.
• Longer half life 40 mins
• 20-120mg/day
• Given twice daily usually morning and lunch
time.
 Beta adrenoceptor antagonists
• egs propranolol, atenolol, bisoprolol,
metoprolol.
• MOA- inhibit β-adrenoceptor effects in heart
leading to fall in heart rate, systolic b/p,
cardiac contractility and myocardial oxygen
demand.
 Calcium channel blockers
rate limiting- verapamil, diltiazem

MOA- block calcium channels in heart and vascular smooth muscle

effects- decreased cardiac contractility, vasodilation

• reduced preload
• reduced venous pressure,
• reduced afterload (reduced arteriolar pressure), increased
coronary blood flow,
• reduced myocardial oxygen demand.

Potassium channel activators

• egs- nicorandil
Drugs used in treatment of
heart failure
 Definition
• An inability of the heart to maintain a cardiac
output sufficient to meet the requirements of
the metabolizing tissues despite a normal
filling pressure.
 Neuroendocrine activation in heart
failure
• Cardiac dysfunction effects a reduction in
stroke volume and consequent reduction in
cardiac output.
• Triggers numerous neuroendocrine responses.
• Initially effective but later on contribute to
ventricular remodelling by inducing myocyte
hypertrophy, fibrosis and apoptosis.
 Increased sympathetic flow
• Activated by arterial baroreceptors
• Increases force of myocardial contraction and
heart rate.
• Peripheral vasoconstriction increases preload
and augment cardiac contractility
• However it also increases afterload which
increases myocardial work and oxygen
demand.
 Activation of renin-angiotensin
aldosterone system.
• Diminished renal perfusion
 Management of heart failure
• Diuretics
• Neuroendocrine antagonists
• Drugs with a positive ionotropic effect
• Vasodilator agents.
 Diuretics -loop diuretics
• Eg furosemide, bumetanide
MOA
Inhibit active chloride reabsorption and also Na+/K+/2CL-
ATPase in the thick ascending loop of Henle- increased
salt and water loss.
Pharmacokinetics
• can be given orally or intravenously.
• Well absorbed after oral administration
• Eliminated largely by renal
• Have rapid onset of action and short duration
• Adverse effects
– Water and salt depletion may occur
– Hypokalaemia
– Hyperuricemia
• Drug interactions
– Potentiate nephrotoxicity and ototoxicity of aminoglycosides
– Hypokalaemia increases risk of digoxin and lithium toxicity
• Contraindicated in severe renal impairment
• Dose
– Furosemide oral 20-240mg/day, I.V 20-80mg slowly
– Bumetanide- oral 0.-6mg/day in one or two divided doses, I.V 0.-
2mg
 ß-adrenoceptor antagonists
• Used to prevent ventricular remodelling due
to excessive sympathetic activity
• Drugs that have shown promising results are:
– Bisoprolol-1.2mg/day, target dose 10mg/day
– Carvedilol-3.12mg bd, target dose 2m bd (0mg bd
>8kg body weight)
– Metoprolol 12.mg/day, arge dose 200mg/day
 ACE Inhibitors
• MOA
– Block ACE with resultant decrease of RAAS
– Vasodilatation
• Dose
– Enalapril- 2.-20mg/day bd
– Lisinopril 2.-40mg/day
– Perindopril 2-8mg/day
– Ramipril- 1.2-0mg/day
 ARBs
• Have comparable hemodynamic and
neurohumeral effects as those of ACEI in CCF
• Egs
– Losartan 25mg/day, target dose 100mg/day
– Candesartan 4mg/day, target dose 32mg/day
– Valsartan 40mg/day, target 160mg/day
 Aldosterone antagonists
• Aldosterone escape occurs in 40% of patients
• Require aldosterone antagonists
Adverse effects:
• Hyperkalaemia
• Gynaecomastia in men
• May decrease renal excretion of digoxin
Hydrallazine and isosorbide dinitrate
• Direct vasodilators
• Affects afterload
• Alternatives to patients who cant take ACEI or
ARBs
 DIGOXIN
• Indications
– Patients refractory to first line treatment
– Heart failure and AF where β-blocker insufficient
or inappropriate
• Mechanism of action
– Inhibits Na+/K+ ATPase with resultant increase in
intracellular sodium→increased intracellular Ca2+
by Na+/Ca2+ exchange-myocardial contraction.
• Effects:
– Positive inotropy
– decreased ventricular rate in AF or flutter by
decreasing AV conduction
– Increased myocardial automaticity in toxic doses
• Pharmacokinetics
– Given orally
– High Vd- 7.3L/kg
– Clearance equivalent to creatinine clearance
– Half life 2 days with normal renal function
• Adverse effects
– Determined by plasma concentration of > 2.5ug/l and
electrolyte imbalance
– Digoxin and potassium compete for cardiac receptor
binding sites- hypokalaemia potentiates toxicity
• Extracardiac adverse effects
– Anorexia
– Nausea
common
– Diarrhoea
– Vomiting
– Fatigue
– weakness
• Neurological-difficulty in reading, confusion
and psychosis
• Abdominal pain
• Cardiac
• Bradycardia
• Sinus arrest
• Junctional rhythm
• Various degrees of heart block
• Drug interactions
– Potential for toxicity increased in presence of diuretics
• Treatment of digoxin induced toxicity
– Withdraw digoxin
– Correct hypokalaemia
– Severe intoxication treated by specific Fab antidigoxin-
which bind and inactivate digoxins
– Ventricular arrhthmias- IV amiodarone
– Ventricular arrhythmias- beta blocker
– Temporary pacing
ANTILIPID TREATMENT
Statins
Fibrates
Ezetimibe
Niacin
Cholestyramine
 Background information
• Atheromatous disease is a common cause of cardiovascular
disease.
• Dyslipidemia is one of the modifiable risk factors for
atheromatous disease.
• May be primary or secondary
• Primary results from a combination of diet and genetics.
• Familial hypercholesterolemia is due to a single gene defect
affecting LDL receptors.
• Secondary dyslipidemia are consequences of other
conditions.
• Reducing LDL is effective in preventing atheromatous
formation.
 Statins
• Mainstay of lipid therapy
• Average reduction in total cholesterol with a
statin is 1mmol/l
• 1mmol/l reduction = 30% CHD reduction, 15% for
stroke
• HDL increases by -15%

Who to treat:
• primary 10yr risk of event > 20%/DM/>40yrs
• Secondary- established IHD, CVD
• Intervention level TC > 5mmol/l, LDL >3mmol/l
MOA-
• competitive inhibition of HMG-CoA enzyme which is a rate limiting step in
synthesis of cholesterol.
• Decreased hepatic cholesterol up regulates LDL receptors synthesis
increasing clearing of LDL from plasma into liver cells.
PK/PD
• Well absorbed orally
• Subject to presystemic metabolism by the liver
• Given at night because cholesterol is synthesized during sleep
Adverse effects
• Muscle pain
• GI disturbance
• Elevated liver enzymes
• Myositis, serious form rhabdomyositis
 FIBRATES
• Markedly reduce VLDL and hence triglyceride
• Modest 10% reduction in LDL and increase in HDL
MOA- agonist at PPARα nuclear receptors
– increase transcription of genes for lipoprotein lipase
– increase hepatic LDL uptake.
Adverse effects
• Myositis
• Renal failure
• GI symptoms
• Pruritus and rash
 EZETIMIBE
• Blocks transport protein NPC1L1 in the brush border of
enterocytes
PK
• Given orally
• Absorbed into intestinal epithelial cells where it localises
• Extensively metabolised to an active metabolite, and
enterohepatic circulation results in slow elimination.
• Enters milk and therefore contraindicated in breastfeeding
Side effects
• Diarrhoea, abdominal pain,
• headache,
• rash,
• angioedema
 NICOTINIC ACID
• Converted to nicotinamide which inhibits
hepatic VLDL secretion leading to reduction of
triglyceride and LDL, increases HDL
Adverse effects
• Flushing
• Palpitations
• GI disturbance.
 DRUGS THAT INHIBIT CHOLESTEROL
ABSORPTION
• Cholestyramine and colestipol
• Bind bile acids in the intestine and prevent
absorption.
• HDL unchanged.
• Cause unwanted increased in triglyceride
 FISH OIL DERIVATIVES
• Omega-3 reduce plasma TGL but increases
cholesterol
 SUMMARY
• Statins are first line treatment and are hugely
effective
• Average dose gives 30% RRR CHD/15% RRR stroke
• The lower the cholesterol the better
• 4 and 2 mmol/l seem appropriate targets
• Standard dose enough in 2/3 patients, others will
need combination therapy
• Doubling statin dose gives 6% further LDL
reduction
ANTITHROMBOTIC DRUGS

THROMBOLYTICS
ANTICOAGULANTS
ANTIPLATELET DRUGS
ANTIFIBRINOLYTIC
 REVISE!!!!
• COAGULATION CASCADE
• FIBRINOLYTIC SYSTEM
 ANTICOAGULANTS
Heparins Vitamin K antagonists Direct thrombin inhibitors Factor Xa inhibitors

UFH warfarin Hirudin Apixaban

LMWH coumarin Dabigatran Rivoxabarin

Synthetic pentasaccharides
eg fondaparinux
 UNFRACTIONATED HEPARIN

• Mucopolysaccharide
• molecular weight 4000-30000

MOA
• Enhances activity of anti-thrombin

Indications
• Treatment of thromboembolic diseases (induction of vit. K
antagonists)
• VTE prophylaxis
• Renal dialysis
• ACS
Side effects
• Risk of bleeding
• HIT -occurs in about 3% of individuals. 4-14 day should
be treated seriously
• Osteoporosis following long term use > 20weeks,
especially in pregnancy
• Hypersensitivity

PK/PD
• Administered by continuous infusion or S.C
• Complex kinetics
• Effects monitored by aPTT
• Reversal with protamine
LOW MOLECULAR WEIGHT HEPARINS
MOA
• Enhances activity to anti-thrombin
Indications
Adverse effects
• HIT- less than unfractionated
PK/PD
• S.C
• More predicable dose response relationship than UFH
• Can be given once or twice daily
• Regular coagulation monitoring no required
• Less readily reversed
 Fondaparinux
MOA
• Enhances activity of anti-thrombin
Indications
• VE prophylaxis after major surgery
• ACS
Side effects
• Risk of bleeding
PK/PD
• Injectable only
• Long plasma half-life which allows for once daily regimen
• Exclusively eliminated by the kidneys
• Regular monitoring not required
• Less readily reversed
 WARFARIN
MOA
• Inhibits vit. K epoxide reductase
• Prevents recycling of vit. K to reduced form
after carboxylation of coagulation factors II,
VII, IX, and X
• Leads to deficiency of procoagulant forms
Decarboxyprothrombin Prothrombin

Vitamin KH2 Vitamin K epoxide

Warfarin

NAD+ NADH
Indications
• VTE
• thromboprophylaxis AF/valvular heart diseases/metallic
valves/cardiomyopathy
Side effects
• Bleeding-spontaneous or after minor trauma
• Necrosis
• Osteoporosis
• terotogenic –no given in first trimester.
PK/PD
• Given orally
• Onset of action determined by time required to clear hose factors which
are already formed usually 48-72 hrs, to achieve full effect
• Half-life VII-6hrs, IX-24hrs, X-40hrs, II-60hrs
• Highly protein bound-99%
• Numerous drug/food interactions
• Reversal by giving vit. k
• Polymorphisms in key metabolising enzymes VKORC1 and CYP2C9
• Needs DM
• Monitored with INR
 Factors that potentiate warfarin
Disease
• Liver disease interferes with synthesis of clotting
factors
• Hyperthyroidism and fever increase degradation of
clotting factors
Drugs
• Inhibit drug metabolism
• Inhibit platelet function
• Displace Warfarin from binding sites on albumin
• Inhibit reduction of vit. K- cephalosporins
• Decrease availability of vit. K- broad spectrum abx.
Factors that lessen effects of Warfarin
• Physiologic state eg pregnancy,
hypothyroidism
• Drugs
– Vitamin K
– Induce hepatic P450
– Reduce absorption -Cholestyramine
 DABIGATRAN
MOA
• Direct thrombin inhibitor
Indications
• VTE
• Thromboprophylaxis in AF/metallic
valves/cardiomyopathy
PK/PD
• No food /drug interactions- not metabolized by CYP
450 enzymes.
• No need for monitoring
• Less rapidly reversed.
 ASPIRIN
MOA
• Irreversible activation of cyclo-oxygenase and thus platelet thromboxane
production.
Indications
• Prevention of stroke/MI
• Pain relief
Side effects
• Bleeding
• Peptic ulceration
• Reyes syndrome
• Angioedema
• Hypersensitivity reactions
• bronchospasm
PK/PD
• Half life becomes longer with very large doses.
 ARACHDONIC ACID

ASPIRIN -
Cyclo-oxygenase enzyme

PGG2
PGH2

THROMBOXANES e.g TXA2 PROSTAGLANDINS e.g PGI2

( PLATELET) (ENDOTHELIAL CELL)
 CLOPIDOGREL
MOA
• Inhibits P2Y12 receptors
Indications
• MI,
• ischaemic stroke,
• AF where warfarin not suitable
Side effects
• Bleeding
• peptic ulcers
PK/PD
• Given orally.
Notes:
Used in combination with aspirin and more effective than aspirin alone in
prevention following coronary angioplasty with stenting.
 DIPYRIDAMOLE
MOA
• Inhibits phosphodiesterase enzyme that hydrolyse cAMP. increased cAMP
result in decreased calcium levels and inhibition of platelet aggregation.
Indications
• Used in combination with warfarin in Thromboprophylaxis in stroke
Side effects
• Hypotension
• Nausea
• Headache
• Diarrhea
• Bleeding
PK/PD
• Given orally
• Contraindicated in angina.
 FIBRINOLYTICS
Streptokinase
• Activates plasminogen
Alteplase
• More active on fibrin bound plasminogen
• Given by IV infusion coz of short half life
Reteplase longer half life allowing for bolus
administration.
ANTIFIBRINOLYTICS

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