1. Pharmacology of the CVS

2. Pharmacology of the CVS
- Heart failure
- Cardiac arrhythmias
- Ischemic heart disease (IHD)
- Hypertension
- Hyperlipidemias
- Atherosclerosis & thrombosis
- Anemias

3. Drugs used in heart failure
Introduction:
CO: The amount of blood ejected from the heart/min. This depends on:
1. Pressure in venous system (preload)
2. Arterial blood, that is the resistance against which the heart pumps (afterload)
3. Heart rate

4. In normal individuals: ↑ HR → ↑ CO
In Ht. failure: ↑ HR → ↓ CO
4. Contractile efficiency of Ht. muscle
In Ht. failure ↓ contractility → ↓ CO → ↓ O2 to tissues → fatigue
Also ↓ CO → ↑ renin-angiotensin-aldosterone system → salt & water retention → edema in legs & lungs → dyspnea

5. Causes of heart failure:
- Hypertension
- Cardiac myopathies
- Coronary artery thrombosis
Drugs in heart failure:
- Drugs ↑ contractility of the heart (+ve inotropic effect)… Digitalis
- Drugs ↑ salt & water excretion… (diuretics)
- Drugs ↓ renin-Angio.-ald. system {ACE inhibitors; Ald. antagonists; Angio. receptor blockers (ARB’s)}

6. Angiotensinogen Angiotensin I Angiotensin II Aldosterone
Renin
Angiotensin I
Converting
Enzyme (CE)
Angiotensin II
Aldosterone

7. Cardiac glycosides
Digitalis: 2 in common use;
Digoxin & digitoxin; both are effective orally & I.V
Digoxin: - Short acting(2 days)
- Excreted by the kidneys
Digitoxin: - Long acting (7 days)
- Excreted by the liver

8. Digitalis effects:
More on failing heart
- ↑ Ht. contractility (+ve inotropic effect)
- ↓ Ht. rate (-ve chronotropic effect)
- ↓ conduction in A-V node & bundle of His
Digitalis clinical uses:
1. Heart failure…digitalization

9. Digitalization could be achieved orally or I.V
Oral dose: 0.5 mg stat, then 0.25 mg x 3 till control of disease (2-3 days), then mg maintenance dose
Less doses are required in old patients or patients with renal disease (digoxin)
2. Cardiac arrhythmias
Supraventricular tachycardia; atrial flutter; atrial fibrillation

10. Digitalis side effects:
Cardiac glycosides have narrow therapeutic window (low TI), drug monitoring is important
- Nausea & vomiting, blurred vision
- Confusion, bradycardia (if pulse rate < 60 stop drug)
- Heart block
** Important interaction: ↓ K+ ( hypokalemia) → ↑ digitalis toxicity
Diuretics → ↓ K+ blood level → ↑ toxicity of digitalis

11. Cardiac arrhythmias
** Bradyarrhythmias
Pacemaker; atropine I.V
** Tachyarrhythmias
- Extrasystoles
Common in normal healthy individuals
Mainly due to excessive smoking, tea or coffee drinking. Rarely require treatment

12. - Supraventricular tachycardia
Rapid Ht. rate ≈ beats/min
- Atrial flutter
Ht. rate > 300 beats/min but regular
- Atrial fibrillation
Ht. rate > 300 beats/min but irregular
- Ventricular fibrillation & tachycardia
- Digitalis-induced arrhythmias

13. Drugs in supraventricular tachycardia (SVT):
- Verapamil (drug of choice)
Ca++ channel blocker, inhibits flow of Ca++ into cells → ↓ contractility of myocardium & ↓ Ht. rate
It dilates coronary & peripheral B.V’s
Given orally & I.V
Don’t combine with β-blockers → severe drop in B.P & cardiac arrest

14. Other drugs effective in (SVT):
- β- blockers
- Digitalis
- Adenosine, given I.V
Drugs in atrial flutter & fibrillation
Digitalis (drug of choice)

15. Drugs in ventricular tachycardia & fibrillation:
- Lidocaine (lignocaine; xylocaine) (drug of choice); given I.V
- Mexiletine, effective orally & I.V
Drugs effective in both atrial & ventricular tachyarrhythmias:
- Disopyramide, given orally & I.V
- Amiodarone, given orally & I.V

16. - Flecainamide, given orally & I.V
Drugs in digitalis-induced cardiac arrhythmias:
- Lidocaine (drug of choice)
- Phenytoin
An anticonvulsant
Also effective in digitalis-induced arrhythmias

17. Drugs in angina pectoris
Atherosclerosis → narrowing of coronary arteries →↓ O2 to myocardium → ischemia; necrosis → chest pain
Objectives of Rx:
- ↑ O2 supply or
- ↓ O2 demand by myocardium or both

18. 1. Nitrates:
Dilate all smooth muscles of vessels especially coronary arteries
- Nitroglycerin (Glyceryl trinitrate)
Causes generalized vasodilatation & ↓ B.P
Highly lipid soluble drug
Nitroglycerin clinical uses:
Rx & prophylaxis of angina & M.I

19. Nitroglycerin dosage forms:
- Oral tab. & caps
- Buccal or transmucosal tab.; sublingual tab.
- Spray (metered aerosol) sprayed under tongue
- I.V preparation
- Transdermal skin patches & discs
Nitroglycerin disadvantage: development of rapid tolerance especially with the skin patches

20. - Isosorbide dinitrate
Similar to nitroglycerin
Available in immediate and sustained oral tab. and in chewable oral tab. Dosage forms
- Isosorbide mononitrate
Similar in its pharmacological properties to the dinitrate but has more prolonged action

21. 2. β-blockers:
↓ O2 demand, when given regularly they prevent pain rather than treating an attack
They block overactivity of sympathetic system (↑ Ht. rate & contractility) due to exercise
3. Calcium channel blockers (CCB’s):
Verapamil; nifedipine; diltiazem
Given orally

22. CCB’s pharmacological effects:
- Dilate coronaries → ↑ O2 supply
- ↓ Ht. contractility →↓ O2 demand
- Dilate peripheral B.V’s →↓ B.P → ↓ resistance to blood flow
4. Antiplatelet drugs:
Aspirin
Clopedogril
Dipyridamole

23. Antihypertensive drugs
Remember:
1. The equation of B.P
B.P = CO x Peripheral resistance
( diameter of B.V)
Ht. rate Blood volume
& contractility

24. 2. NA (NE) synthetic pathway

25. Angiotensinogen Angiotensin I Angiotensin II Aldosterone
3. Renin-angiotensin-aldosterone system
Angiotensinogen
Renin
Angiotensin I
Converting
Enzyme (CE)
Angiotensin II
Aldosterone

26. 1. Drugs ↓ blood volume
Diuretics
2. Drugs ↓ CO
β-blockers; CCB’s
3. Dugs ↓ peripheral resistance
a. Prazocin
α1-rceptor blocker → dilates arteries & veins,
Given orally
major side effect: Dizziness

27. b. Ca++ channel blockers (CCB’s)
Verapamil, nifedipine, diltiazem, amlodepine..
Lead to peripheral vasodilatation → ↓ in peripheral resistance → ↓ B.P
Side effect: Constipation
c. Directly acting vasodilators
- Hydralazine
Given orally & I.M
Side effect: Systemic lupus-like syndrome

28. - Minoxidil
Given orally
Side effect: Hirsutism
- Diazoxide
Given I.V & used in hypertensive emergency
- Sodium nitroprusside
Given I.V & used in hypertensive emergency (drug of choice)

29. 4. Centrally acting sympatholytics
- Clonidine
α2-agonist
Given orally
- α-methyl dopa
↓ NA release centrally

30. 5. Drugs blocking postsynaptic adrenergic neurons
- Reserpine
Depletes NA (NE) stores in CNS & periphery
Given orally
Side effect: Depression
- Guanethidine
↓ NA release in CNS & given orally

31. 6. Drugs interfering with renin-angiotensin-aldosterone system
a. ACE inhibitors
Angiotensin converting enzyme inhibitors
Captopril, enalapril, quinapril, lisinopril…
↓ angiotensin II synthesis & hence aldosterone
Effective orally

32. ACE inhibitors differ in potency, onset of action and duration of action
ACE inhibitors clinical uses:
- Hypertension
- Heart failure
- Hyperaldosteronism
ACE inhibitors side effects:
Dry cough (also considered major & absolute contraindication), allergy, and hyperkalemia

33. b. Angiotensin II receptor blockers (ARB’s)
Losartan; valsartan; candesartan…
Effective orally inhibiting angiotensin II- induced vasoconstriction
Actions and uses are similar to ACE inhibitors
Have similar side effects to ACE inhibitors but they don’t produce cough (known as non cough ACE inhibitors)

34. c. Aldosterone antagonists
Spironolactone
Known as K+-sparing diuretics
Compete with aldosterone receptor
Given orally
Side effects:
Hyperkalemia

35. Drugs in hyperlipidemias
High cholesterol → atherosclerosis → coronary artery disease → MI
Lipids are carried in blood by specific lipoproteins:
- Chylomicrones & VLDL… carry triglycerides
- LDL carries dangerous cholesterol
- HDL removes cholesterol from blood

36. High LDL & low HDL → bad
Normal or low LDL & high HDL → good
Management of hyperlipidemias:
a. Eliminate risk factors
High B.P; D.M; smoking; high cholesterol…
b. Diet, exercise, weight reduction
Avoid saturated fat (animal fat)

37. c. ↑ excretion of cholesterol
Cholestyramine; colestipol
Known as bile acid sequestering agents or resins
Bind bile acids which contain cholesterol & ↑ their excretion → ↓ cholesterol blood level
Given orally

38. d. ↓ absorption of cholesterol
Ezetimibe ± statins; neomycin; d-thyroxine
e. Interfere with metabolism of cholesterol
Clofibrate, bezafibrate, gemfibrozil
f. Inhibition of de novo synthesis of cholesterol
Statins (lovastatin; simvastatin; pravastatin)
All antihyperlipidemic drugs are given orally
Major side effect
Rhabdomyolysis

40. g. Nicotinic acid ( Niacin )
↓ TG’s ↑ HDL ↓ LDL in large doses
MOA
- Inhibition of the release of VLDL from the liver → ↓ IDL → ↓ LDL
- Also reduces release of free fatty acids from adipose
tissue into the general circulation → ↓ substrate for
TG synthesis → ↓ TG’s
- It increases HDL levels possibly by inhibiting its
Catabolism
Major side effect
Skin flushing