1. ANTI - HYPERTENSIVE

2. Anatomy of Heart

3. Circulation of Heart

6. Electrial Conduction System Of Heart

7. HYPERTENSION
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated.
Normal blood pressure is 120/80 mm of Hg.
High blood pressure is anything above 140/90 mm of Hg.
Hypertension is classified into :
Primary hypertension (Essential hypertension)
-90-95% cases –high blood pressure
with no medical cause.
Secondary hypertension -5%cases –caused by
conditions that affect kidneys,arteries,heart or endocrine systems.

9. Antihypertensive Drugs
All antihypertensive drugs act on the familiar formula…
BP = SVR x CO (HR v SV)
They act by
Reducing SVR .. or by...
Reducing cardiac output …by…
Reducing heart rate …or by…
Reducing stroke volume

10. Classes of Antihypertensive Agents
Diuretics
ACE Inhibitors
Angiotensin-II Receptor Blockers
Renin Inhibitors
Calcium Channel Blockers
Beta Adrenergic Blockers
Alpha Adrenergic Blockers
Centrally acting Sympatholytics
Vasodialators
Potassium Channel Openers
Endothelin Antagonist

11. Diuretics
A reduction in blood volume reduces blood returning to the heart and so preload is reduced
A reduction in preload reduces stroke volume
CO = HR x SV
Stroke volume and cardiac output decrease
BP = CO x SVR
Blood pressure decreases

12. 1. Diuretics Chlorthalidone (Hygroton) Ethacrynic acid (Edecrin)
1. Thiazides
Hydrochlorothiazide (HydroDIURIL, Esidrix);
Chlorthalidone (Hygroton)
2. Loop diuretics
Furosemide (Lasix); Bumetadine (Burmex);
Ethacrynic acid (Edecrin)
3. K+ Sparing
Amiloride (Midamor); Spironolactone (Aldactone);
Triamterene (Dyrenium)
4. Osmotic
Mannitol (Osmitrol); Urea (Ureaphil)
DIURETIC AGENTS
1. Diuretics commonly used for hypertension
a. vary in natriuretic efficacy, renal site of action, hypotensive efficacy
2. Generally 1st pharmacological therapy
a. unless contraindicated
b. Diuretic as or more effective than
1. Ca++ channel blockers or ACE inhibitors (Dec., 2002, JAMA)
2. Alpha-adrenergic antagonists (Sept, 2003, Hypertension)
1st line treatment for hypertension
5. Other
Combination - HCTH + Triamterene (Dyazide)
Acetazolamide (Diamox)

13. Potassium sparing diuretics
Loop diuretics
Thiazide diuretics
Potassium sparing diuretics
Diuretics reduce the rate at which water is reabsorbed. This results in more water being lost from the body and ultimately a fall in blood volume

14. Site of Action Renal Nephron Urinary Na+ excretion
2. Mechanism of Action
Urinary Na+ excretion
Urinary water excretion
Extracellular Fluid
and/or Plasma Volume
3. Effect on Cardiovascular System
1. Site of Action
a. renal nephron
b. diuretic agents work at different segments of nephron
2. Mechanism of Action
a. all diuretics decrease sodium reabsorption
b. act on renal systems, transporters, hormones, ion channels
c. Where Na+ goes, Water will surely follow
3. Effect on cardiovascular system
a. acute decrease in plasma volume
b. chronically, decrease in TPR, CO returns to normal
mechanism unknown
c. often used to compensate for Na+ retaining reflex induced by other
antihypertensive agents.
Acute decrease in CO
Chronic decrease in TPR, normal CO
Mechanism(s) unknown

15. Electrolyte imbalance/Depletion, Hypokalemia, Hyperlipidemia,
4. Adverse Reactions
Dizziness,
Electrolyte imbalance/Depletion,
Hypokalemia,
Hyperlipidemia,
Hyperglycemia (Thiazides)
Gout ( Hyperuricaemia)
5. Contraindications
Hypersensitivity,
Compromised kidney function
Cardiac glycosides (K+ effects)
Hypovolemia,
Hyponatremia
4. Adverse Reactions
a. most secondary to decreased volume or altered electrolyte status
1. many renal mechanisms of Na+ reabsorption tied to transport of other
electrolytes i.e. K+ Ca++, Mg++.
b. hyperlipidemia and increased low density lipoprotein- unknown mechanism
c. hyperglycemia, K+ depletion inhibits insulin secretion
5. Contraindications
a. exaggerated response leading to adverse reactions- hypersensitivity
b. compromised kidney function- insufficient delivery to site of action
1. agents act on lumen, decreased kidney function decreases access of
agent to renal tubule, due to decreased GFR and/or renal blood flow
c. cardiac glycoside sensitivity changes with K+
1. Decreased Plasma K+ increases sensitivity to cardiac glycosides
(Digitalis)
d. exacerbates existing low volume or salt conditions

16. Angiotensin Converting Enzyme (ACE) inhibitors
Examples – captopril, ramipril, perindopril etc.
Used to treat hypertension and also heart failure
ACE inhibitors interfere with the renin, angiotensin, aldosterone system that regulates long term BP. This system responds to a drop in blood pressure and works in conjunction with the baroreceptor reflex.

17. Renin, angiotensin, aldosterone systemBP
Renin
Angiotensinogen
Angiotensin I
Angiotensin Converting Enzyme
Angiotensin II

18. Renin, angiotensin, aldosterone system
Angiotensin II
ADH- vasopressin
Aldosterone
Vasoconstriction
Thirst
Blood Pressure
Sodium retention

19. 2. ACE Inhibitors & Angiotensin-II Receptor Blockers

20.   Angiotensin Converting Enzyme Inhibitors
2. Ang II Receptor Antagonists
Losartan (Cozaar);
Candesartan (Atacand);
Valsartan (Diovan)
Angiotensin Converting Enzyme Inhibitors
Enalapril (Vasotec);
Quinapril (Accupril);
Fosinopril (Monopril);
Moexipril (Univasc);
Lisinopril (Zestril)
Benazepril (Lotensin);
Captopril (Capoten)
Angiotensin II formation
A. Renin cleaves Ang I from angiotensinogen
B. Angiotenin I is inactive decapeptide
C. Angiotensin Converting Enzyme cleaves 2 amino acids-
resulting in the biologically active Angiotensin II
D. Cardiovascular/fluid volume effects mediated by AT1 receptor stimulation
2. Anti-angiotensin II Drugs/ Classes and Mechanism of Action
A. ACE inhibitors- mechanism of action
1. Reduce or eliminate activity of angiotensin II converting enzyme
2. Decrease formation of ang II
B. Angiotensin II AT1 receptor blockers- mechanism of action
1. Competitive antagonist at AT1 receptor
2. Prevents binding of angiotensin II
Angiotensinogen
Ang I
ACE
Lung
VSM
Brain
Kidney
Adr Gland
Ang I 
AT1
Ang II
ACE
AT2 
Ang II
Renin

21.         Volume Aldosterone Vasopressin HR/SV Angiotensin II
3. Effect on Cardiovascular System
Volume
Aldosterone
Vasopressin  
HR/SV
Angiotensin II
Norepinephrine 
Angiotensin II
3. Effects on Cardiovascular System
a. Renal
1. Maintenance of normal GFR
2. Reduces plasma vasopressin and aldosterone
Decreased CO
b. Cardiac
1. Decreased Ang II and Norepinephrine effects
Decreased SymNS influence; Decreased CO
c. Vascular
1. Decreased Ang II
Decreased TPR- due to Ang II
Decreased TPR- due to SymNS activation from CNS
Decreased TPR- due to Ang II/ NE terminal interaction
Vasoconstriction 
SymNS  
SymNS CO 
TPR  CO

22. 5. Contraindications 4. Adverse Effects Angiogenic edema (ACE inhib);
Hyperkalemia
Angiogenic edema (ACE inhib);
Cough (ACE inhib);
Rash;
Itching;
5. Contraindications
Pregnancy;
Hypersensitivity;
Bilateral renal stenosis

23. 3. Calcium Channel Blocker

24. Effect on Cardiovascular system
Vascular relaxation
Decreased TPR
Adverse Effects
Nifedipine –
Increase SymNS activity;
Headache;
Dizziness;
Ankle edema(joint btn leeg &feet

25. Drugs: Mechanism of Action 4. β Adrenergic Blocker
Propranolol (Inderal);
Metoprolol (Lopressor)
Atenolol (Tenormin);
Nadolol (Corgard);
Pindolol (Visken)
Mechanism of Action
Competitive antagonist at β- adrenergic receptors

26. 3. Effects on Cardiovascular System
a. Cardiac--  HR,  SV  CO
b. Renal--  Renin   Angiotensin II   TPR
4. Adverse Effects
Impotence;
Bradycardia;
Fatigue;
Exercise intolerance;
5. Contraindications
Asthma;
Diabetes;
Bradycardia;
Hypersensitivity

27. 5. A) Peripheral α-1 Adrenergic Blocker
Drugs:
Prazosin(Minipres);
Terazosin (Hytrin)
Site of Action-
Peripheral arterioles, smooth muscle
2. Mechanism of Action
Competitive antagonist at
α-1 receptors on vascular smooth muscle.

28. 3. Effects on Cardiovascular System
Vasodilation,
Reduces peripheral resistance
4. Adverse effects
Nausea;
Drowsiness;
Postural hypotenstion;(first dose phenmenone)

29. B) Central Sympatholytics (α-2 Agonists)
Drugs:
Clonidine ( Direct α-2 Agonist )
Methyldopa ( False Neurotransmitter )
Site of Action
CNS medullary
Cardiovascular centers
Mechanism of Action
CNS α-2 Adrenergic Stimulation
Peripheral Sympatho inhibition
Decreased norepinephrine release

30. Effects on Cardiovascular System
Decreased NE Vasodilation Decreased TPR
Adverse Effects
Dry mouth;
Sedation;
Impotence;

31. 6 ) Vasodialators Drugs: Hydralazine (Apresoline);
Minoxidil (Loniten);
Nitroprusside (Nipride);
Diazoxide (Hyperstat I.V.);
Fenoldopam (Corlopam)
Site of Action-
Vascular smooth muscle

32.    NO DA Mechanism of action Nitroprusside Fenoldopam (Dopamine D1
Agonist) DA    K+
Minoxidil
Diazoxide
Na+
Ca++
Ca++
Hydralazine
(directly acting arteriolar vasodilator)

33. Effect on cardiovascular system Decrease TPR
Vasodilation,
Decrease TPR
Adverse Effects
Reflex tachycardia
Increase SymNS activity (hydralazine, minoxidil,diazoxide)
Lupus (hydralazine)
Cyanide toxicity (nitroprusside)
Hypertrichosis (minoxidil)

34. 7) Endothelin Antagonist
Bosentan, a non-selective ET-1 receptor antagonist (blocks for ETA and ETB receptors) is currently used in the treatment of pulmonary hypertension

35. Sites and Mechanisms of Action
Summary
Sites and Mechanisms of Action
3. -2 agonists
Receptor antag.
2. α-antag.
5. A-II Antag.
7. Vasodilators
6. Ca2+ Antag.
4. β-blockers
1. Diuretics
4. b-blockers
Other- 5. ACE inhibitors
Lung, VSM, Kidney, CNS
1. Sites of action
a. each class acts by specific mechanism, some at multiple sites
2. Antihypertensives work on all systems and all levels of regulation
a. Neural (SymNS)
1. Brain
2. Vascular Smooth Muscle
3. Kidney
b. Hormonal
1. Blocks circulating catecholamines
2. Blocks Ang II system
c. Local
1. Alters mechanism of smooth muscle contraction
2. releases vasodilatory factors
3. All alter CO and/or TPR
CRITICAL POINTS!
1. Can alter CO/TPR at number of sites and/or mechanisms.
2. Antihypertensives mechanistically specific, and alter blood
pressure through physiologically diverse effects on CO/TPR.
3. All organ systems and/or effector mechanisms are p’col targets.

36. Antiarrhythmic Drugs

37. Normal heartbeat and atrial arrhythmia
Normal rhythm
Atrial arrhythmia
AV septum

38. ECG (EKG) showing wave segments
Contraction of ventricles
ECG (EKG) showing wave segments
Repolarization of ventricles
Contraction of atria

39. PHASES OF ACTION POTENTIAL
>Plateau Stage
>Cell less permeable to Na+
>Ca++ influx through slow Ca++ channels
>K+ begins to leave cell
Phase 1
>Limited depolarization
>Inactivation of fast
Na+ channels→ Na+
ion conc equalizes
>↑ K+ efflux & Cl- influx
Phase 3
>Rapid repolarization
>Na+ gates closed
>K+ efflux
>Inactivation of slow Ca++ channels
Phase 0
>Rapid depolarization
>Opening fast Na+
channels→ Na+ rushes in →depolarization
Phase 4
>Resting Membrane Potential
>High K+ efflux
>Ca++ influx

40. ARRHYTHMIAS result from:
ARRHYTHMIA Absence of rhythm
DYSRRHYTHMIA Abnormal rhythm
ARRHYTHMIAS result from:
Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction
Block results from severely depressed conduction
Re-entry or circus movement / daughter impulse

42. ARRHYTHMIAS: Supraventricular: Ventricular: - Atrial Tachycardia
- Paroxysmal Tachycardia
Multifocal Atrial Tachycardia
- Atrial Fibrillation
- Atrial Flutter
Ventricular:
Wolff-Parkinson-White (preexcitation syndrome)
Ventricular Tachycardia
Ventricular Fibrillation
Premature Ventricular Contraction

43. CLASS I: Sodium Channel Blocking Drugs
IA - lengthen AP duration
- Intermediate interaction with Na+ channels
- Quinidine, Procainamide, Disopyramide
IB - shorten AP duration
- rapid interaction with Na+ channels
- Lidocaine, Mexiletene, Tocainide, Phenytoin
IC - no effect or minimal  AP duration
- slow interaction with Na+ channels
- Flecainide, Propafenone, Moricizine

47. CLASS II: BETA-BLOCKING AGENTS
Increase AV nodal conduction
Increase PR interval
Prolong AV refractoriness
Reduce adrenergic activity
Propranolol, Esmolol, Metoprolol, Sotalol

48. CLASS III: POTASSIUM CHANNEL BLOCKERS
Prolong effective refractory period by prolonging Action Potential
Drugs :
Amiodarone
Ibutilide
Bretylium
Dofetilide
Sotalol BIDAS

50. CLASS IV: CALCIUM CHANNEL BLOCKERS
Blocks cardiac calcium currents
→ slow conduction
→ increase refractory period
*esp. in Ca++ dependent tissues (i.e. AV node)
Verapamil, Diltiazem, Bepridil

52. Miscellaneous:
ADENOSINE → Inhibits AV conduction & Increases AV refractory period
MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels
POTASSIUM → Normalize K+ gradients

53. Implantation of Pacemaker