CARDIOVASCULAR DISEASES

DISEASE DRUGS/TREATMENT MECHANISM OF ACTION NOTE

Lipoprotein disorders and 1. The cholesteryl 1. people w high CETP in Japan has high HDL SIDE EFFECTS:
atherosclerosis (CVR 20, ester transfer protein Are compound specific,
26,27) (CETP) inhibitor e.g. high b.p
torcetrapib
PRIMARY cause (familial)
*Hyperlipidemia (LPL HMG-CoA Reductase *Competitive inhibitors of HMG-CoA reductase, Best at ↓ LDL
deficiency) Inhibitors which catalyzes an early& rate-limiting step in Most effective n tolerated
*Hypertriglyceridemia (hi (statins) cholesterol biosynthesis. Other effects of Statins
VLDL n LDL) -atorvastatin (which results in increased expression of the • Endothelial function
*Hypercholesteremia (hi -iovastatin LDL receptor). • Plaque stability
LDL, lo LDL R) -fluvastatin • Inflammation
• Lipoprotein oxidation
SECONDARY cause • Platelet aggregation
*Diabetis melitus SIDE EFFECTS:
*Hypothyroidism • Generally well tolerated
*Obesity • Hepatotoxicity and Myopathy
*Drugs (Thiazide, OCP, - Hepatitis
steroids) - Muscle aches
*Liver n renal dz - Myositis
- Angio-oedema
- Sleep disturbance

Bile Acid Bind bile acids, since 95% of bile acids are -oldest hypolipidemic drugs
Sequestrants reabsorbed, deplete pool of bile acids and -Safest as not absorbed from the gut.
• Cholestyramine thus hepatic cholesterol declines, stimulating SIDE EFFECTS:
• Colestipol Increase in LDL • Not absorbed. Bloating and
Dyspepsia

• Interfere with absorption of

• Occasionally used as an addition to a drugs, thus administer all drugs 1
 statin if patient fails to respond to statin hour before or 3-4 hours after
alone administration of cholestyramine.
• Combination therapy can reduce the risk
Bile Acid Binding Resins of events related to heart disease by more
than 50%

Fibrates • Mechanism of action unclear, involves Best at ↓ TG

- Clofibrate, interaction with the nuclear transcription Side effects:
Fenofibrate, factor PPAR that regulates several genes • Combination of Gemfibrozil and
Bezafibrate, involved in lipid metabolism Statin can increase the risk of
Gemfibrozil • Increase activity of peripheral lipoprotein myotoxicity.
lipase
• Reduce VLDL production, increase • Most common side effects GI
hepatic LDL uptake disturbance,
• Decrease TG by 50% and mild increase in • Elevated liver enzymes
HDL
Nicotinic Acid  Inhibits mobilization of free fatty acids Best at ↑ HDL
from peripheral tissues SIDE EFFECTS:
 reduces hepatic triglyceride synthesis, • Flushing and dyspepsia limit
secretion of VLDL and thus indirectly ¯ patient compliance.
LDL (10-25%) • Cutaneous flushing and itch,
 Increases HDL (15-35%) worse at start, prostaglandin
mediated, aspirin may help.
• Hepatotoxicity
• Hyperuricemia, gout is a
contraindication

Stanols / Sterols  Cholesterol like plant extracts

 inhibit cholesterol absorption in intestine
 as ester (sterol ester) can be mixed in
margarine spread
  2-3 g / day reduces total cholesterol by
10%, LDL cholesterol by 15%
Fish Oils  w-3 fatty acids containing eicosapentaenoic No proven benefit, not used
acid cause reduced VLDL synthesis routinely
Þ ¯ triglycerides but “LDL”
Angina: (CVR 21) Modify Risk factors: Diet, DRUGS. 1.Nitrates:
 chest pain from Exercise, Weight loss Too high/much exposure
myocardial ischaemia Reduce cholesterol,Control 1.Nitrates: attenuation in magnitude of pharm
 Retrosternal blood pressure, Control increase in guanylyl cyclase increases effect (intolerance)
discomfort, pressure diabetes, Stop smoking cyclic guanosine monophosphate (cGMP) Due to Decrease in free –SH groups
like, occurs with activates endogenous protein kinases So require a nitrate free period in
exertion, relieved by Anti-platelets: Aspirin etc decrease in intracellular calcium each 24 hours.
rest, may radiate down In smooth muscle, the net result is reduced
arm or into neck. Anti-anginal phosphorylation of myosin light chain, reduced SE: headache, hypotension
 Usually associated therapy:improve the calcium and relaxation
with the presence of balance of myocardial *at low concentrations nitratesdecrease Other uses:
significant obstructive oxygen supply and demand the preloadreduce heart work Un/stable angina
coronary disease * higher concentrations vasodilation Myocardial infarction
DRUGS of large and medium-sized coronary arteries and Heart failure
Angina Pectoris : Mismatch Increase the blood supply to the myocardium Hypertensive crises
between myocardial oxygen 1.Nitrates(Nitroglycerin-
supply and demand sublingual, 2. Beta adrenergic antagonists: Nitrates + Phosphodiesterase 5
Isosorbide Dinitrate- cornerstone of therapy in chronic stable angina. Inhibitors = erectile dysfunction
Categories: oral,Isosorbide-5- -Block action of adren/nor-adren on the beta
• Stable: no change in mononitrate) adrenergic receptors sildenafil +other phosphodiesterase 5
symptoms over - reduce mortality and reinfarction in post- inhibitors+organic nitrate
previous weeks myocardial infarction patients vasodilators=extreme
• Unstable: abrupt 2.Beta adrenergic - They reduce the myocardial oxygen demand by: hypotension
pattern change antagonists 1) Reducing the HR. cannot be given with
• Variant: usually stress Types: 2) Decrease the blood pressure (afterload). -Sildenafil (Viagra)
related, patients Non selective: 3) Decrease contractility. -Tadalafil (Cialis)
develop coronary *Propranolol – thyroid -Vardenafil (Levitra
spasm Crises, tremor, 3.Calcium channel blockers
*Timolol- glaucoma -treatment of chronic stable angina 2.Beta blockers
 -block L-type calcium channels.This decreases Side effects:
Cardioselective: calcium entry and consequently reduces  Bronchoconstriction: block beta-
*Metoprolol intracellular calcium. 2 mediated smooth muscle
* Atenolol -causes vascular smooth muscle relaxation relaxation in the bronchi. Thus
-decrease in contractility relatively contra-indicated in
Alpha 1 antagonist activity: -alter the ratio of supply and demand in chronic reversible airways disease eg
Carvedilol- heart failure stable angina by reducing; asthma
**arteriolar pressure (afterload)  Mask symptoms of
**myocardial contractility hypogylcaemia
3.Calcium channel **HR  May precipitate heart failure
blockers  Bradycardia
Dihyropyridines predominately affect the  Exacerbate peripheral vascular
vasculature ie decrease blood pressure. disease
A) Dihydropyridines eg  Somnolence, Depression
nifedipine, amlodipine Non Dihyropyridines predominately affect the
 Impotence
heart ie decrease heart rate.
 Adversely alter lipid profile
B) non-dihydropyridines
eg verapramil, diltiazem Blockade of voltage-operated L-type calcium
Clinical use:
channels in vascular smooth
muscle, by dihydropyridines and diltiazem, causes  Angina- stable and unstable
a reduction in calcium  Myocardial infarction
influx and vasodilatation, useful in  Heart Failure, arrythmias
– Hypertension,
– Angina 3.Calcium channel blockers
– Raynauds phenomena Side effects:
• Arterial dilatation (more marked
Blockade of voltage-operated L-type calcium with dihydropyridines)
channels in pacemaker cells of – Headache, Flushing,Ankle oedema,
the SA and AV nodes, by verapamil and diltiazem, Reflex tachycardia
stabilizes phase 4 of the • Reduced cardiac contractility
action potential (pacemaker depolarization) and – Cardiac failure may be precipitated
reduces calcium entry during in susceptible patients by verapamil.
phase 0 (rapid depolarization). Hence both • Bradycardia and heart block
pacemaker activity and AV – Verapamil and diltiazem may cause
 conduction are inhibited. These features are useful heart block , particularly if
in used in combination with digoxin or
– Supraventricular arrhythmias B-blockers
• Altered gut motility
– Constipation
– Nausea and heartburn
Clinical uses:
Arrythmias
Hypertension
Angina
Hypertension (CVR28): lifestyle measures (Lower Anti-hypertensive 1.ACE inhibitors
“that blood pressure level BP n CVR dz) 1.ACE inhibitors S.E.s :Dry cough, Renal failure in
above which – smoking cessation Ex. Captopril, Lisinopril bilateral renal artery stenosis,
investigation and treatment do – weight reduction M.A. Reduction in formation of angiotensin II Hyperkalaemia,Angioedema
more good - reduce alcohol
than harm” – physical exercise 2.Beta blockers 2. Beta blockers
– reduction of salt n sat fat *Non-selective; Propranolol, Clinical use:
Target bp: intake *β1 selective; Atenolol Hypertension
** < 140/90 mmHg = in al *With vasodilatation; Angina
hypertensive patients Drug Therapy Pindolol (β1 selective antagonist and partial Post-Myocardial Infarct
**<130/80 mmHg in -Anti-hypertensive drugs agonist at B2 adrenoceptors) cardiovascular protection
diabetics and high risk •ACE-Inhibitors Carvidalol (non-selective β-blocker but also α1 Supra-ventricular tachycardias
patients (stroke, myocardial •Beta-blockers blocker) Heart failure
infarction, re •Calcium-channel blockers Nebivolol (releases NO) Hyperthyroidism / Thyrotoxicosis
dysfunction, proteinuria) (refer angina) Symptom relief in Anxiety
•Diuretics MA: Lower HR, and CO Prophylaxis of Migraine
•Angiotensin II antagonists inhibition of renin secretion Glaucoma
 Alpha-blockers
 Vasodilators SE: Bronchospasm (non-selective)
 Central Worsening of peripheral vascular
sympathophlegics disease (non-selective)
Glucose intolerance
Dyslipidaemia
 – Other vascular protective 4.Thiazide diuretics 4.Thiazide diuretics
agents Ex. Hydrochlorthiazide SE: Fatigue, Hypokalaemia,
• Lipid lowering agents - M.A. Inhibition of NaCl reabsorption in early Impotance
Statins distal tubule of renal nephron Glucose intolerance,Dyslipidaemia
• Hypoglycaemics Hyperuricaemia
• Anti-thrombotics 5. Angiotensin II antagonists
• Anti-obesity agents • Ex. Losartan, Candesartan
• M.A. Blockade of actions of AII

 Alpha-blockers (e.g. Doxazosin)

M.A. Blockade of α1 adrenoceptors resulting
in vasodilation
 Vasodilators
 Central sympathophlegics
Heart Failure (CVR 32) Natural: Diuretics SE(loss of electrolytes Na, Mg, K)
is the pathological state in Increased Cardiac HF congestion, i.e. oedema and breathlessness • Overuse depletion of total body
which the heart is unable to Compensation (dyspnoea). Na+
pump enough blood for the ƒ Decreased renal blood :-Diuretics enhance Na+ excretion in the • Hypokalemia, Hyperglycemia
needs of metabolising tissues flow causes renal kidneyreduce vascular volume n preload. •Increased Mg++ and Ca++
vasoconstriction. excretionhypomagnesemia and
primary cause is an ƒ This activates the renin- **Thiazide Diuretics: hypocalcemia
impairment of the angiotensin axis. Act on distal tubule. • Ototoxicity, deafness, tinnitus,
heart’s ability to fill or empty ƒ Aldosterone is released Bind to Na/Cl co-transport, vertigo
the left ventricle properly and results in Na+ and Orally and IV, • Can cause hyperuricemia leading to
water retention **Spironolactone: gout
is a complex of symptoms: ƒ Low blood pressure can Limited diuretic action, • Loop diuretics may increase LDL
Fatigue, Shortness of breath, increase sympathetic tone Antagonist of aldosterone receptor. *impotence,pancreatitis (thiazide)
and congestion- which can increase , *gynaecomastia(spirolactone)
related to the inadequate afterload. ACE inhibitiors SE:
perfusion of tissue during These adaptive e.g. Captopril, Enalopril, Lisonopril. *Hypotension
exertion and often to the mechanisms work in the MA: predicted from understanding the R-A system *Renal dysfunction and
retention of fluid. short term. Long term in Heart failure. Hyperkalemia (ACE inhibitors limit
leads to heart failure as •Reduce circulating AII levelsdecrease in the Kidneys ability to autoregulate
eventually the heart fails peripheralvascular resistance. (decreased glomerular perfusion pressure due to
afterload). their selective effect on efferent
Drug treatment relief of •Prevent release of aldosterone and hence Na+ and arteriolar tone).
symptoms and reduce water retention(decreased preload) *10% of patients develop a cough
mortality. •Decrease sympathetic nervous system activity. (this can be severe enough
•Potentiate the effects of diuretics in heart failure to prevent them taking the drug)
Main aim of therapy is:
*reduce congestion ACE INHIBITORS PROLONG LIFE
*improve the “ work” of IN HEART FAILURE
the heart, Angiotensin II receptor blockers
i.e. contraction and Nitrates Nitrate Side effects.Headache and
relaxation. *vasodilate both arterial and venous Hypotension
smoothmuscle.
Diuretics *produce vascular relaxation by enhancement of combination of Hydralazine together
ACE inhibitiors cGMP activity. with nitrates has been shown to
Angiotensin II receptor  decreasing cardiac preload but reduce mortality in heart failure
blockers at higher doses also have an affect on afterload
Hydralazine/Nitrates reflex increase in heart rate
B-Blockers Organic nitrates: glyceryl trinitrate (myocardial oxygen consumption)
Inotropes (nitroglycerin),Isosorbide dinitrate and a drug-induced lupus like
Heart failure is both an Isosorbide mononitrate., syndrome.
acute and chronic disease
and treatment of the acute Hydralazine
and chronic state differs.. relax the smooth muscle in precapillary
resistance vessels.
ACC/AHA guidelines for B-Blockers: Start low dose and titrate upwards
treatment of symptomatic MA:block actions at…..
left ventricular Beta1 receptor in the heart. Increased force and *antagonise the effect of a chronic
systolic dysfuntion rate of increase in sympathetic tone and may
• Diuretics in all patients contraction. Increase conduction velocity. reduce the the down regulation of
who have evidence Beta2 receptor in smooth muscle mediates beta receptor expression in response
of fluid retention relaxation. to the chronically elevated
• ACE inhibitors in all e.g. Metoprolol, bisoprolol and carveldilol sympathetic tone that occurs in heart
patients, unless, failure.
contraindicated Inotropes MA inotrope:
• Beta-adrenergic blockade short term treatment Cardiac glycosides inhibit membrane
in all stable patients, unless e.g. digoxin bound Na+/K+ ATPase. increase in
contraindicated 1. acts as a positive ionotrope. intracellular Na+,a marked increase
• Digoxin for symptomatic ( in the failing heart the Frank-Starling in intracytoplasmic calcium.-
rx, unless ci ventricular function curve is shifted down and to increase in contractility i.e. positive
the right. Digoxin shifts this inotropic effect.
Withdrawal of drugs know curve up and to the left)
to adversely affect the 2. It has an effect on the electrical activity of Cardiac glycosides affect the
clinical status of the the heart. (slows SA node firing rate, and slows electrical activity of the heart.
patient, e.g. NSAID, most conductionthrough the AV node) *Increase the activity of the vagal
antiarrhythmic drugs and nerveslows the firing of the SA
most calcium channel Beta1 adrenoceptor agonists node (pacemaker)Slows
blockers Dobutamine and dopamine :short term conduction through the AV node.

• Spironolactone in patients Phophodiesterase inhibitors:short term increase Adverse:

with recent of current cardiac ouput, e.g. Milrinone. *a low therapeutic ratio.
Class IV symptoms *electrical activity can cause
• Exercise training NEW!!:Recombinant Human Brain disordered electrical activity, i.e.
• AII blockade in patients Naturetic Peptide arrythmias..
on digoxin, diuretic and • Approved for treatment of dyspnea due to *GITdisturbance, nausea, vomiting,
beta blocker who cannot CHF diarrhoea
tolerate ACE inhibitor • Naturetic peptides, family of endogenous *CNS effects;visual hallucinations
• Combination of neurohormones that possess potent *Narrow pharmacotherapeutic
hydralazine and nitrate in naturetic, diuretic and vasodilator properties window, therefore measure plasma
those on • Secreted by ventricular cardiac myocytes in levels.
dig, diuretic and beta response to stretch *Toxicity exacerbated by
blocker who cannot • Produce vasodilation, naturesis, and diuresis hypokalemiatreated in life-
tolerate threatening situations with
an ACE inhibitor a specific antibody to digoxin