1. Drugs acting on the Cardiovascular
Pharmacology–I PHL-313
Drugs acting on the Cardiovascular
System
Dr. Hassan Madkhali Assistant Professor Department of Pharmacology E mail: 1

2. Drugs acting on the CVS
The drugs having their primary action on heart or blood vessels, or those used primarily for treatment of cardiovascular disorder.
These drugs include:
Cardiotonic Drugs
Antihypertensive Drugs
Diuretics Drugs
Antiarrhythmic Drugs

3. CVS overview

4. What is the Cardiovascular System (CVS)?
The CVS (known also as the circulatory system or the vascular system) is is an organ system that is consist of three parts the heart, vessels , and the blood (~5 L/min).
The heart works as a pump that pushes blood through the vessels to the body’s organs, tissues, and cells.
The blood delivers nutrients (including amino acids and electrolytes), oxygen, carbon dioxide, hormones, and blood cells to and from the cells in the body.

5. What are the functions of the CVS?
CVS functions
Pump blood
Transportation
Regulation
Protection & Hemostasis
The heart is pump the blood throughout the circulatory system..
Transport of substances including
Respiratory (RBC, O2 and CO2), Nutritive (absorbed products of digestion), and Excretory (Metabolic wastes such as urea, excess water and ions, and others)
Regulation include
Hormonal (blood carries hormones to target tissues), and Temperature (by diversion of blood from deeper to more superficial
cutaneous vessels or vice versa).
Clotting (protects against
blood loss) and
Immune (white blood cells protect against
many pathogens that cause several disease.

6. Anatomy of the Heart

7. Blood circulation: HeartArteries Arterioles  
 
VeinsVenules Capillaries

8. What are cardiovascular diseases?
Cardiovascular diseases (CVDs) are a group of diseases of the heart and blood vessels including coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease and deep vein thrombosis and pulmonary embolism.
Statistically, CVDs considered as number 1 cause of death globally (about 17.5 million people died from CVDs in 2012, representing 31% of all global deaths).
Early detection and management of CVDs are needed for individuals having these diseases or at high cardiovascular risk (due to the presence of one or more risk factors such as coronary artery disease, hypertension, obesity and diabetes).

9. Prevalence of CVD in Saudi Arabia
Proportional mortality (% of total deaths,
all ages, both sexes)
Age-standardized death rates
Source: World Health Organization - Noncommunicable Diseases (NCD) Country Profiles, 2014.

10. Cardiotonic Drugs

11. Heart Failure (HF)
Heart failure: it is the inability of the heart to meet the metabolic requirements of the peripheral system due to an inadequate contractility.
Results in rise in venous blood pressures which then lead to impair fluid drainage from the tissues and produce a variety of serious clinical effects:
Right side HF: causes lower limb edema. Blood pooling in the lower extremities
Left side HF: produces pulmonary edema and respiratory distress
-There are two types of left-side heart failure:
Systolic failure: The left ventricle loses its ability to contract normally.
The heart can't pump with enough force
Diastolic failure: The left ventricle loses its ability to relax normally.
The heart can't properly fill with blood

12. Heart Failure Pathophysiology Comparison

13. Heart Failure Manifestations Comparison
Manifestation of Left side HF
Manifestation of right side HF
External & nocturnal dyspnea
Blood-tinged sputum
Orthopnea
Cough
Cyanosis
Decrease urinary output
Rale (abnormal lung sound)
Fatigue
Ascites
Gastrointestinal disorders
Liver & spleen enlargement
Distended jugular veins
Elevated venous pressure
Dependent edema (?)
Fatigue

14. Chronic vs. Acute Heart Failure
Chronic heart failure: symptoms appear slowly over time and worsen gradually.
Acute heart failure: develops suddenly and symptoms are initially severe. It either follows a heart attack that has caused damage to an area of your heart or caused by a sudden lack of ability by the body to compensate for chronic heart failure.
Compensation: adjust to the effects of heart failure in the short term followed by enlargement of the heart and reducing its pumping ability.
Compensation by nervous system (increase sympathetic activity)
Compensation by hormones release (increase release of renin, angiotensin and aldosterone).

15. Common HF Risk Factors
Coronary Artery Disease (CAD): narrowed arteries may limit the heart supply of oxygen-rich blood, resulting in weakened heart muscle.
Cardiomyopathy: heart muscle diseases.
Myocardial Infarction: irreversible death (necrosis) of heart muscle secondary to prolonged lack of oxygen supply (ischemia)
Hypertension: the heart works harder than it has to.
Diabetes: high blood glucose can damage parts of the body such as the heart and blood vessels. This damage weakens the heart, often leading to heart failure).
Obesity: people who are obese have a higher risk of developing heart failure (heart can't pump enough blood to meet your body's needs).

16. Cardiotonic Drugs Drugs that increase force of contraction of heart
The cardiotonics are drugs used to increase the efficiency & improve the contraction of the heart muscle, which leads to improved blood flow to all tissues of the body

17. Drug groups commonly used in management of Heart Failure
Cardiac Glycosides
Digitoxin, Gitoxin, Digoxin
Phosphodiesterase 3–Inhibitors
Milrinone (Primacor), Amrinone (Inocor)
β1-adrenoceptors agonists
Dobutamine, dopamine, Epinephrine
Diuretics
Carbonic anhydrase inhibitors: Acetazolamide
Loop diuretics: Furosemide
Thiazides: Hydrochlorothiazide
Potassium Sparing Diuretics: Amiloride, Spironolactone

18. Drug groups commonly used in management of Heart Failure
• ACE inhibitors:
Captopril (Capoten), Enalapril (Vasotec),
Enalaprilat (Vasotec IV)
Fosinopril, Monopril, Ramipiril (Altace)
AT-II antagonists [Angiotensin II receptor blockers (ARBs) ]
Losartan (Cozaar), Valsartan (Diovan)
β-adrenergic receptor antagonists
Propranolol, carvedilol
Aldosterone antagonists
Spironolactone, Eplerenone
• Vasodilators
Nitrates/Nitrites: Nitroglycerin, Hydralazine (Apresoline),
Sodium Nitroprusside (Nipride) ?

19. HF Treatment A) Drug B) Lifestyle modifications Chronic heart failure
Digoxin
Beta-agonists
Diuretics
ACE inhibitors
AT-II antagonists
Aldosterone antagonists
Acute heart failure
Diuretics
PDE3 inhibitors
vasodilators
B) Lifestyle modifications
Reduce cardiac work (Generally)
Exercise-based program of cardiac rehabilitation
Smoking cessation
Rest
Weight loss
low Na+ diet

20. Cardiac Glycosides
• Cardiac glycosides slow the heart rate and increase the force of contraction (=positive inotrope)
• Digitalis is the drug of choice for heart failure associated with atrial fibrillation
Increases cardiac output, Increase urine output, Decreased renin release
Sources: Glycosides:
1. D. purpurea - Digitoxin, Gitoxin, Gitalin
2. D. lanata - Digitoxin, Gitoxin, Digoxin

21. Cardiac glycosides
The cardiac glycosides inhibit the Na+/K+-ATPase pump, which causes an increase in intracellular Na+ leading to slowing of
the Na+/Ca++-exchanger and ultimately increase in intracellular Ca++.

22. Pharmacological Action
Cardiac Effects: Digitalis direct affects on myocardial contractility & electrophysiological properties.
Positive inotropic effect: increase the force of contraction of the normal and failing myocardium.
Negative chronotropic effect: cardiac glycosides slow down the heart rhythm.
Positive tonotropic effect: reduce the size of the heart.
Positive bathmotropic effect: increase the excitability of the myocardium, which can cause arrhythmias (extrasystole, ventricular fibrillation).
Other Effects:
Indirect vasodilation (little effect on the BP)
Increase diuresis, secondary to improved circulation.
Induce contractions of intestinal muscles

23. Pharmacokinetic of Digoxin
Amongst various cardiac glycosides used, digoxin & digitoxin are very common.
Available IV & Orally
Oral ABS: Depend on formulation (Soft Gelatin Caps > Elixir > Tablets )
Absorption is confined to small intestine.
Digoxin absorption is variable (60-80%), digitoxin is absorbed almost (100%).
Digitoxin is the most lipid soluble, digoxin is relatively polar.
Digitoxin metabolized in liver, partly to digoxin & undergoes some enterohepatic circulation.
Digoxin excreted by kidney

24. ADRs of Digoxin Central nervous system reaction:
Headache; weakness; drowsiness; visual disturbance,
Cardiovascular and gastrointestinal reactions:
Arrhythmias; gastrointestinal upset; anorexia, Nausea, Vomiting,
Rare ADR
Eosinofilia, skin rashes, gynecomastia

25. Preparation Uses Digoxin 0.25 mg tab, 0.05 mg/ml pediatric elixir,
0.5 mg/2ml inj.
Digitoxin
0.1 mg tab
Uses
Chronic heart failure
Atrial fibrillation (will discussed in antiarrhythmic drugs lecture)

26. ↓ peripheral vascular resistance
PDE3 Inhibitor: MOA
Inhibition of type III phosphodiesterase
↑ intracellular cAMP
activation of protein kinase A
Ca2+ entry through L type Ca channels
Inhibition of Ca2+ sequestration by SR
↑ contractility
↑ cardiac output and
↓ peripheral vascular resistance ×
PDE3 Inhibitor
SR: sarcoplasmic reticulum

27. PDE III Inhibitor Drug – Amrinone (Inocor) , Milrinone (Primacor)
Have a positive inotropic effect.
Cause vasodilatation, decrease BP & decrease preload & afterload
ROA: IV
Effective in patients taking Beta-blockers
Indications: Used only for short term in acute heart failure and Unresponsive CHF to other treatment
ADRs: Arrhythmia, hypotension, thrombocytopenia, GI Complaint (pain, nausea, vomiting), Liver dysfunction, allergy.
Long-term use increases the risk of mortality.
Sudden death secondary to ventricular arrhythmia

28. β1 – Agonist
MOA: Adrenergic stimulation of β1-adrenergic receptors produces positive inotropic effect.
Drugs: Dobutamine, Dopamine, Epinephrine
ROA: IV
Most widely used, but limited to emergency case due to cardiogenic, traumatic & hypovolemic shock.
SE: Restlessness, tremor, headache, cerebral hemorrhage, cardiac arrhythmias,
used with caution in patients taking β-blockers, can develop dobutamine tolerance
Long-term use increases risk of cardiac arrhythmias, hypertension and the risk of mortality

29. Diuretics: MOA & ADRs
Failing heart pumping function
Diuretics decreases preload through several mechanisms:
diuresis (excretion of water and electrolytes)
vasodilation (loop diuretic: furosemide)
ADRs :
Skin rashes
Hepatic dysfunction
Sodium and water retention
Increased intravascular volume
Increased preload

30. Renin-Angiotensin-Aldosterone system antagonists

31. Angiotensin Converting Enzyme Inhibitors
Examples: Quinipril, captopril, enalapril, benaepril
MOA: Block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. There will be reduction in blood pressure by vasodilation. This results in decreased PVR.
Decreased preload & decreased afterload
Adverse Effects: Dry cough, hyperkalemia, Angioedema, Hypotension, Renal insuffiency, Rashes
Contraindications: Pregnancy – renal failure in infants, renal impairment.

32. Angiotensin II receptor blockers
They block angiotensin II effect at the angiotensin type 1 receptors. Thus, there is vasodilatation and blood pressure lowering.
Has comparable effect to ACE I
Can be used in certain conditions when ACE I are contraindicated (angioneurotic edema, cough)
Therapeutic uses:
Hypertension, Heart failure,
Diabetic nephropathy, Myocardial infarction,
Stroke prevention, Migraine headache
Adverse effects: Angioedema, Fetal harm, Renal failure
Examples: Losartan (Cozaar), Valsartan (Diovan), Irbesartan, Candesartan, Telmisartan, Olmesartan

33. Aldosterone Antagonists
Elevated Angiotensin II levels increase production of aldosterone in the adrenal cortex (~20X increase)
Aldosterone activates mineralocorticoid receptors in epithelial cells in kidney
aldosterone promotes
Na+ retention, water retention, Mg2+ and K+ loss
increased SNS activity
decreased PSNS activity
myocardial/vascular fibrosis

34. Therapeutic Use Goal: inhibit aldosterone negative effects in CHF
Aldosterone receptor antagonists
spironolactone
eplerenone
Reduce mortality in patients with moderate to severe CHF
Only use in patients with normal renal function and K+ levels
Use with K+ sparing diuretic

35. Side Effects hyperkalemia agranulocytosis anaphylaxis hepatotoxicity
renal failure
Spironolactone: gynecomastia, sexual dysfunction
Eplerenone: arrhythmia, myocardial infarct/ischemia

36. Vasodilators
Examples: Hydralazine (Apresoline), Nitroprusside (Nipride), Nitroglycerine.
MOA: Vasodilators cause a direct relaxation of vascular smooth muscle to decrease PVR and lower BP. There are two types: atreriolar dilators and venous dilators.
They are usually given with a beta blocker.
Reduction of afterload by arteriolar vasodilatation (hydralazine)  reduce LVEDP, O2 consumption, improve myocardial perfusion,  stroke volume and CO
Reduction of preload By venous dilation (Nitrate)  ↓ the venous return ↓ the load on both ventricles.
Usually the maximum benefit is achieved by using agents with both action.

37. Vasodilators Nitrovasodilators NO release
Activate guanylyl cyclase and ↑cGMP
↓Intracellular calcium
Smooth muscle relaxation
Vasodilation
Preload and afterload reduction
Improved cardiac function -5

38. β-adrenergic receptor antagonists
β- blockers were once contraindicated in CHF, as they have the potential to worsen the condition, studies in the late 1990s showed their efficacy at reducing morbidity and mortality in CHF.
Carvedilol and sustained-release metaprolol are specifically indicated as adjuncts to standard ACEIs and diuretic therapy in CHF.
reduce sudden death caused by other drugs
Propranolol: prototype
Carvedilol: combination effects
Carvedilol has both α- and β-blocking pharmacologic activities

39. Mechanism of Action
β-blockers, in addition to their sympatholytic β1 activity in the heart, influence the renin/angiotensin system at the kidneys. β blockers cause a decrease in renin secretion, which in turn reduce the heart oxygen demand by lowering extracellular volume and increasing the oxygen carrying capacity of blood.
Prevents development of arrhythmias

40. Therapeutic Use Side Effects
Administered orally
Effective in patients with chronic systolic heart failure
Prevents remodeling and cardiac damage
Side Effects
Cardiac decompensation
Bradycardia
Hypoglycemia
Cold extremities
Fluid retention
Fatigue

41. Thank you ?