The Cardiovascular System

• Heart
• Blood
Cardiovascular Drugs • Blood Vessels
– Arteries
– Veins
– Capillaries

The Heart Blood

Blood Vessels Circulation

 In simple terms…

• The heart is a pump.

• It pumps blood through a system of
blood vessels that has a limited
volume capacity.
• An electric conduction system
maintains regular rate and rhythm.
• Myocardial cells require oxygen.

Malfunctions Malfunctions
when the heart
can no longer
when the electrical
pump enough
conduction
blood to meet the HEART FAILURE ARRHYTHMIA
pathways
metabolic
malfunction
demands of the
body

when blood the heart’s way of

volume is great signaling that
compared to the HYPERTENSION some of the cells ANGINA
space available are not getting
inside blood enough oxygen
vessels

Malfunctions

when oxygen-
starved areas of MYOCARDIAL
the heart begin INFARCTION Cardiovascular Drugs
dying

when you broke

with someone…
Cardiovascular Drugs
• Anti-hypertensives
• Drugs for Heart Failure
Anti-Hypertensive Drugs
• Anti-anginal and Drugs for MI
• Anti-arrhythmic Agents

Factors that alter the Blood Pressure Equation

Physiology of BP Regulation Sympathetic Adrenergic
System

Blood Cardiac Total Peripheral

= Output
x Arterial Resistance
Pressure
Aldosterone

vasoconstriction
• Hydraulic Equation: Na+& H2O
Reabsorption

Heart Stroke Blood

Venous
Volume
Rate x Volume Return
Rises
BP = CO x TPR Pituitary
Angiotensin II
Gland
Renin –
Angiotensin ACE
System Angiotensin I
Low Blood Pressure
Low Blood Volume Kidney
Na+ depletion
Renin

Determinants of Blood Determinants of Blood

Pressure Pressure
• Cardiac Output (CO) • Stroke Volume (SV)
– volume of blood pumped out by the – volume of blood pumped out by the
heart in 1 minute heart in every contraction
– approximately 2.2 – 3.5 L / min / m2 BSA – determined by:
– determined by Stroke Volume (SV) and • Inotropic activity –strength of cardiac
Heart Rate (HR) contraction
• Venous return – cardiac preload; amount of
blood delivered to the heart from the veins;
affected by the tone of the veins
Determinants of Blood Mechanisms of BP
Pressure Regulation
• Heart Rate (HR) • Baroreceptor Reflex Arch Mechanism
– speed of heart contraction – aka: Postural Reflex Mechanism
– chronotropism – moment-to-moment BP regulation
• Fluid Content of the Blood • Baroreceptor – a type of sensory nerve
• Total Peripheral Resistance (TPR) ending found in the walls of the atria of the
heart, the vena cava, the aortic arch, and
– resistance or pressure encountered by the carotid sinus that is stimulated by
the heart as it pumps out blood into the changes in pressure
peripheral circulation (cardiac afterload)
– determined by the arterioles
• Renin Angiotensin Aldosterone

Renin Angiotensin Aldosterone

System (RAAS)
Angiotensinogen (from the liver)
Renin

Angiotensin I (inactive)
Hypertension
Angiotensin Converting Enzyme (ACE)
or
Peptidyl dipeptidase
(majority found in the lungs)

Angiotensin II (active)

-direct vasoconstriction
-stimulates synthesis & release of Epi & NE
-stimulates the synthesis & release of
aldosterone

Hypertension Hypertension
• persistent or recurrent elevation of BP • Systole
defined as having a: – the period during which the ventricles
– Systolic reading > 140 mmHg are contracting
– Diastolic reading > 90 mmHg • Diastole
– BP > 140/90 – the period during which the ventricles
• most common cardiovascular are relaxed and filling with blood
disorder
 Classification of BP based on the 7th Report of the
Hypertension Joint National Committee on Detection, Evaluation
and Treatment of High Blood Pressure (JNC VII)
• Essential (Primary, Idiopathic)
– hypertension with no identifiable cause
– accounts for > 90% of HTNsive cases Classification of Blood Pressure (JNC VII)
Systolic BP, mm Hg Diastolic BP, mm
• Secondary Hg
– resulting from identifiable causes Normal <120 and <80
• kidney diseases
• adrenal cortical disorders Prehypertension 120-139 or 80-89
• pheochromocytoma (adrenal medulla tumor) 140-159 or 90-99
Stage 1 hypertension
• coarctation of the aorta
• drugs such as steroids, sympathomimetics, contraceptives Stage 2 hypertension >160 or >100
– treat the underlying cause Adapted from JNC VII
– accounts for ~ 10% of HTNsive cases

Hypertensive Emergency Risk Factors

• Family history • Sedentary lifestyle
• aka: Hypertensive Crisis • Patient history • DM
• Racial predisposition • Hyperlipidemia
– More common in blacks • Gender – males
• rare, but life-threatening situation
• Obesity • Age > 60
• Smoking • Postmenopausal
• systolic pressure > 210 mm Hg • Stress women

• diastolic pressure > 150 mm Hg • High dietary intake

– Saturated fats and
sodium

Treatment Goals Complications

• Cardiac effects
• Rule out uncommon secondary causes of – Increased oxygen requirements  angina pectoris;
hypertension because of atherosclerosis  angina, MI, sudden death
• Determine the presence and extent of • Renal effects
target organ damage – Increased blood volume; renal parenchymal damage due
to atherosclerosis
• Determine the presence of other CV risk
factors • Cerebral effects
– Transient ischemic attacks, cerebral thromboses,
• To lower BP with minimal side effects aneurysms with hemorrhage
• Retinal effects
– Visual defects (blurred vision, spots, blindness)
Treatment Anti-hypertensives
• First line: diuretics (thiazides) and beta blockers
• Diuretics
• Alternatives: ACE inhibitors, ARBs, alpha blockers, calcium-
channel blockers  for px who cannot tolerate first line • Sympathoplegics
agents
• Vasodilators
• Monitor: • Calcium Channel Blockers (CCBs)
– blood pressure routinely
– observe adverse effects • ACE Inhibitors
• Angiotensin II Receptor Blockers
• Patient Counseling:
– Importance of compliance  make px realize seriousness (ARBs)
of noncompliance

Diuretics
• agents that cause urinary loss of Na+
and H2O

• Gen MOA: act on their specific sites

in the renal tubule

Five major classes Renal Tubule

1. Thiazides and thiazide-like
2. Loop diuretics
3. Potassium-sparing
4. Carbonic anhydrase inhibitors
5. Osmotic diuretics
Carbonic Anhydrase Carbonic Anhydrase
Inhibitors Inhibitors
• MOA: inhibit carbonic anhydrase (the • Acetazolamide
enzyme that catalyzes the reaction of • Brinzolamide
CO2 and H2O leading to H+ and • Dorzolamide
HCO3-) that can lead to the spillage of
Na+ causing diuresis.

• act on the proximal convoluted tubule

(PCT)

Carbonic Anhydrase
Loop Diuretics
Inhibitors
• limited diuretic effect (2 to 3 days) • aka: High Ceiling Diuretics

• SE: metabolic acidosis, bone marrow • high ceiling (most efficacious) as

depression (sulfonamide-like toxicity), compared with other diuretics
allergic reactions (Stevens-Johnson’s
Syndrome)
• act on the thick ascending Loop of
Henle

Loop Diuretics Loop Diuretics

• MOA: inhibit the Cl-Na-K- • for px who cannot tolerate thiazides,
cotransporter at the thick ascending have renal impairment, or
LOH ineffectiveness of thiazides

• SE: hypovolemia, ototoxicity, increase

• Furosemide serum creatinine
• Bumetanide
• Torsemide • DI: their efficacy can be reduced by
• Ethacrynic acid NSAIDs
Loop Diuretics Thiazide Diuretics
• Side-effects • MOA: inhibit Na-Cl-cotransporter at
–Hypokalemia the distal convoluted tubule
–Bicarbonate is lost in the urine
–INCREASED calcium excretion • Chlorothiazide
Hypocalcemia • Hydrochlorothiazide
–Ototoxicity • Chlorthalidone
• due to the electrolyte imbalances • Indapamide

Thiazide Diuretics Thiazide Diuretics

• first-line drug for uncomplicated
hypertension as recommended by • SE: hypokalemia, hyponatremia,
JNC 7 hyperuricemia, hyperglycemia,
hyperlipidemia
• effective initial therapy together with
beta-blockers • DI: their efficacy can be reduced by
NSAIDs

• also used for Nephrogenic Diabetes

Insipidus

Thiazide Potassium-Sparing Diuretics

• Side effects • MOA: act in the collecting tubule by
–Hypokalemia inhibiting Na+ reabsorption, K+
secretion and H+ secretion
–DECREASED calcium
excretion hypercalcemia
–DECREASED uric acid • Spironolactone
secretion hyperuricemia • Eprenolone
–Hyperglycemia • Amiloride
• Triamterene
Potassium-Sparing Diuretics Potassium Rich Foods
• for patients where potassium loss is TOPP PNBB’S
significant and supplementation is not
feasible
• often combined with thiazides 
potentiation
– Amiloride, Spirinolactone, Triamterene
• precautions
– Avoid in px with acute renal failure; use
with caution  px with impaired renal
function

Potassium-Sparing Diuretics
• T- Tomatoes
• O-Oranges • not associated with hypokalemia
• P- Peaches
• P-potatoes • can be given with other diuretics to
• P-Prunes lessen the risk of hypokalemia
• N-Nuts
• B-Banana
• SE: hyperkalemia, gynecomastia,
• B-Broccoli
impotence, sterility
• S-Spinach

Osmotic Diuretics Osmotic Diuretics

• MOA: increase the osmotic pressure • used to induce forced diuresis
at the proximal convoluted tubule and • mostly used to reduce intracranial
Loop of Henle preventing water pressure
reabsorption

• SE: hypernatremia, hypovolemia

• Mannitol
• Sorbitol
• Urea
Diuretic class Major site of action Special Side effect
Diuretic class Special Uses
Diuretics Compariso n (s) Diuretics Comparison
1. Carbonic Proximal tubule Acidosis 1. Carbonic Mountain sickness
anhydrase
anhydrase
inhibitor Meniere’s disease
inhibitor
2. Thiazide and Nephrolithiasis due to calcium
2. Thiazide and Distal tubule Hyperuricemia thiazide like stones
thiazide like Hypokalemia Hypocalcemia
3. Loop diuretics L p of Henle Hypokalemia 3. Loop diuretics Hypercalcemia
Ototoxicity
4. Potassium CHF taking digoxin
4. Potassium Distal tubule Hyperkalemia sparing
sparing 5. Osmotic Increased ICP
diuretic
5. Osmotic Glomerulus Hypovolemia & LITHIUM TOXICITY
diuretic hypotension

Sympathoplegics
• Centrally-acting
• Peripherally-acting
Sympathoplegics
• Alpha-1 blockers
• Beta blockers

Centrally-Acting
Sympathoplegics
• MOA: act primarily within the CNS on
Centrally-Acting alpha-2 receptors to decrease
sympathetic outflow to the CVS
Sympathoplegics
• Clonidine
• Methyldopa
• Guanfacine
• Guanabenz
Clonidine Methyldopa
• reduce TPR with little effect on CO
• MOA: agonist at alpha-2 receptors
and blood flow to vital organs (such
(leading to vasodilation)
as kidneys)

• effective in patients with renal

• effective for patients with renal
impairment
impairment
• used in the management of HTN in
• SE: transient increase in BP, pregnancy (pre-eclampsia,
sedation/depression, rebound eclampsia)
hypertension on abrupt withdrawal

Methyldopa Guanfacine, Guanabenz

• SE: sedation, depression, • adjunctive therapy to other anti-
hepatotoxicity (at doses >2g / day), HTNsive drugs
(+) Coomb's Test*
• avoided unless necessary to treat
* Coomb’s Test – indicator of a severe refractory HTN that is
possible immune-mediated hemolytic unresponsive to other meds
anemia

Peripherally-Acting
Sympathoplegics

Peripherally-Acting • Trimethaphan
Sympathoplegics • Reserpine
• Guanethidine
• Guanadrel
Trimethaphan Reserpine
• ganglionic receptor blocker • plant alkaloid

• given via IV infusion • inhibits catecholamine (NE, Epi,

Dopamine, Serotonin) storage
• used in hypertensive emergencies
caused by pulmonary edema or aortic • impairs sympathetic function because
aneurism when other agents cannot of decreased release of
be used Norepinephrine (NE)

Guanethidine, Guanadrel
• inhibit the response of the adrenergic
nerve to stimulation or to indirectly-
acting sympathetic amines Alpha-1 Blockers
• blocks the release of stored
Norepinephrine

• SE: orthostatic hypotension, impaired

male sexual function

Alpha-1 Blockers Alpha-1 Blockers

• MOA: inhibit the alpha-1 receptors, • alternative drugs for the management
resulting to vasodilation of arteries of HTN esp among patients with BPH
and veins
• First-Dose Phenomenon:
• Prazosin – orthostatic hypotension
• Doxazosin – syncope
• Alfazosin – remedy: take the drug at bedtime, slow
increase in dose
• Terazosin
 Beta Blockers
• used for the initial therapy of HTN;
effective for patients with rapid resting
Beta Blockers HR or concomitant IHD
• MOA
– Block stimulation of renin secretion
– Decrease contractility  decrease CO
– Decrease sympathetic output centrally
– Reduction in HR  reduced CO
– Combination of all

Beta Blockers Beta Blockers

• Selective • Membrane Stabilizing
• SE/Precautions/Contraindications: Activity
B– Betaxolol
– can mask hypoglycemia B– Bisoprolol
– Anesthetic-like effect
– Cannot be given as
– CI to patients with bronchospastic E– Esmolol ophthalmic drops
disease: COPD, Bronchial Asthma A– Acebutolol P– Propranolol
– rebound tachycardia and HTN A– Atenolol P– Pindolol
A–
– easy fatigability M– Metoprolol Acebutolol
L– Labetalol
– severe bradycardia and heartblock M– Metoprolol
(seen esp with concomitant use of
verapamil and diltiazem)

Beta Blockers
• Mixed alpha and • Intrinsic
beta blocking sympathomimetic
activity
effect
– partial agonist effect Vasodilators
– not usually associated
L – Labetalol with rebound
C – Carvedilol hypertension
A – Acebutolol
B – Bisoprolol
C – Carteolol
P – Pindolol
P - Penbutolol
Vasodilators Vasodilators
• second-line agents • common SE: reflex tachycardia,
peripheral edema
• directly relax the peripheral vascular
smooth muscles • common CI: as single agents, should
be avoided in patients with Ischemic
Heart Disease (IHD)
• not used alone  inc in plasma renin
activity, CO, HR

Vasodilators Hydralazine
• Hydralazine • used in the management of HTN in
• Diazoxide pregnancy
• Minoxidil
• Sodium Nitroprusside • SE: Lupus-like side effect (drug-
induced SLE or Systemic Lupus
Erythematosus)

Diazoxide Minoxidil
• used in the emergency treatment of • most effective arteriolar vasodilator
hypertensive crisis
• SE: hypertrichosis, hirsutism
Sodium Nitroprusside Sodium Nitroprusside
• metabolized in the body into nitric • Caution: use freshly prepared
oxide (NO) also called EDRF or solutions or admixtures
Endothelium-Derived Relaxing Factor
• protect from light
• 1st
line drug for almost all types of
HTNsive emergencies
• SE: thiocyanate or cyanide toxicity,
acute psychosis, severe hypotension,
coma, death

Calcium Channel Blockers

(CCBs)
• alternative for the mgt of HTN

Calcium Channel Blockers

• MOA
– Inhibit influx of Ca through the slow
channels in vascular smooth muscle
and cause relaxation

Calcium Channel Blockers

Classification (CCBs)
• Dihydropyridine (DHP) • SE:
– block Ca channels in the blood vessels – peripheral edema
– Nifedipine, Nicardipine, Felodipine,
Amlodipine
– reflex tachycardia (DHP)
– bradycardia (Non-DHP)
• Non-dihydropyridine (Non-DHP) – heart block (Non-DHP + Beta Blocker)
– block Ca channels both in the heart and blood
vessels
– Verapamil – heart > blood vessels
– Diltiazem – heart = blood vessels
 Angiotensin Converting Enzyme
Inhibitors
• MOA: inhibit ACE, thereby preventing the
conversion of angiotensin I into the active
form angiotensin II
ACE Inhibitors
• Short-acting
– Captopril
Generally, long acting ACE
• Long-acting Inhibitors are prodrugs:

– Enalapril Enalapril Enalaprilat

(prodrug) (active)
– Lisinopril
– Perindopril

Angiotensin Converting Enzyme

Inhibitors
• SE:
– idiosyncratic dry cough Angiotensin II Receptor
ACE Blockers
Bradykinin inactive
fragments
(causes cough)

– angioedema
– hyperkalemia

1. A friend has very severe hypertension and asks

Angiotensin II Receptor about a drug her doctor wishes to prescribe. Her
Blockers (ARBs) physician has explained that this drug is
associated with tachycardia and fluid retention (w/c
may be marked) and increased hair growth. Which
• direct inhibitors of angiotensin II receptors of the following is most likely to produce the effects
that your friend has described?
A. Captopril
• Losartan, Valdesartan, Candesartan
B. Guanethidine
C. Minoxidil
• clinical use: same as ACE Inhibitors
D. Prazosin
E. Propanolol
• Advantage over ACE inhibitors: less
associated with dry cough
2. A patient is admitted to the emergency 2. A patient is admitted to the emergency
department with severe bradycardia following a department with severe bradycardia following a
drug overdose. His family reports that he has been drug overdose. His family reports that he has been
depressed about his hypertension. Each of the depressed about his hypertension. Each of the
following can slow the heart rate EXCEPT following can slow the heart rate EXCEPT

A. Clonidine A. Clonidine
B. Guanethidine B. Guanethidine
C. Hydralazine C. Hydralazine
D. Propanolol D. Propanolol
E. Reserpine E. Reserpine

2. A patient is admitted to the emergency 3. Which one of the following is characteristic of

department with severe bradycardia following a enalapril treatment in patients with essential
drug overdose. His family reports that he has been hypertension?
depressed about his hypertension. Each of the
following can slow the heart rate EXCEPT
A. Competitively blocks angiotensin II at its
receptor
A. Clonidine
B. Decreases angiotensin II concentration in the
B. Guanethidine blood
C. Hydralazine C. Decreases renin concentration in the blood
D. Propanolol D. Increases sodium and decreases potassium in
E. Reserpine the blood
E. Decreases sodium and increases potassium in
the urine

4. A pregnant patient is admitted to the

hematology service with moderately severe 5. Postural hypotension is a common
hemolytic anemia. After a thorough workup, the adverse effect of which one of the
only positive finding is a history of treatment with following types of drugs?
an antihypertensive drug since 2 months after
beginning the pregnancy. The most likely cause of
the patient’s blood disorder is A. ACE inhibitors
A. Atenolol B. Alpha receptor blockers
B. Captopril C. Arteriolar dilators
C. Hydralazine D. Beta-selective receptor blockers
D. Methyldopa E. Nonselective B-blockers
E. Minoxidil
5. Postural hypotension is a common 5. Postural hypotension is a common
adverse effect of which one of the adverse effect of which one of the
following types of drugs? following types of drugs?

A. ACE inhibitors A. ACE inhibitors

B. Alpha receptor blockers B. Alpha receptor blockers
C. Arteriolar dilators C. Arteriolar dilators
D. Beta-selective receptor blockers D. Beta-selective receptor blockers
E. Nonselective B-blockers E. Nonselective B-blockers

Heart Failure
• is the failure of
the heart as a
Congestive Heart Failure pump
• inability of the
heart to pump
sufficient
amount of
blood to the
body

Congestive Heart Failure Forms of CHF

• High-output • Low-output
• pumping ability of the heart becomes – uncommon – caused by disorders
impaired – caused by excessive that impair the
• accompanied by congestion of body need for cardiac pumping ability of the
output heart (IHD)
tissues
– high metabolic – normal metabolic
• etiology demands demands, heart
unable to meet them
– acute MI, HPN, cardiomyopathies
– excessive work demands on the heart
 Forms of CHF Treatment Goals
• To remove or mitigate the underlying
cause
• Right sided • Left-sided
• To relieve the symptoms and improve
– fatigue – exertional dyspnea
pump
– jugular vein – paroxysmal nocturnal
function by:
distension dyspnea
– Reducing metabolic demands (rest,
– liver engorgement – cough relaxation, pharm’l controls)
– blood-tinged sputum – Reduce fluid volume excess (food intake,
– anorexia, GI distress
– cyanosis meds)
– cyanosis – Administer digitalis and other inotropic
– pulmonary edema
– elevation in agents
peripheral venous – Promote px compliance and self-regulation
pressure through education
– Select appropriate px for cardiac transplants
– peripheral edema

Compensatory Mechanism Compensatory Mechanism

• Frank-Starling Mechanism
• Myocardial Hypertrophy – is the intrinsic ability of the heart to
– long-term compensatory mechanism adapt to changing volumes of inflowing
blood
– increase in the number of contractile – the greater the heart muscle is stretched
elements in myocardial cells as a means during filling, the greater the force of
of increasing their myocardial contraction and the greater the quantity
performance of blood pumped into the aorta
– ventricular remodeling – within physiologic limits, the heart
pumps all the blood that comes to it
without allowing excessive damming of
blood in the veins

Drugs for CHF

• Inotropic Agents
– Cardiac glycosides
Drugs for CHF – Beta Agonists
– Phosphodiesterase Inhibitors
• Unloaders
– ACE Inhibitors & ARBs
– Beta Blockers
– Diuretics
– Vasodilators
Cardiac Glycosides Cardiac Glycosides
• from Digitalis species • Digoxin • Digitoxin
– ~75% Bioavailable – >90% Bioavailable
– half-life: 36-40 – half-life: 168 hours
• Digoxin, Digitoxin hours – >90% protein bound
– excreted in the bile
– 20-40% protein
bound
• MOA: inhibit the Na-K-ATPase pump – excreted in the
leading to an increase in intracellular urine
calcium

Cardiac Glycosides Toxicity

- have low therapeutic indices • Cardiac Manifestations
- toxicity can be enhanced by: – arrhythmias (ventricular tachycardia)
- hypokalemia – cardiac death
- hypomagnesemia
- hypercalcemia • Extra-cardiac Manifestations
– GI disturbances (nausea & vomiting)
– visual disturbances (blurred vision,
alteration of color perception, haloes on
dark objects)

Management of Toxicity Beta-1 Agonists

• give potassium supplement • Dopamine
• Dobutamine
• give digitalis antibodies (FAB
fragments) • MOA: increase intracellular cAMP,
which results in the activation of
• for arrhythmias, give lidocaine or protein kinase, that leads to an
amiodarone increase in intracellular calcium
Dobutamine Phosphodiesterase Inhibitors
• given as an IV infusion • MOA: inhibits the enzyme
phosphodiesterase which hydrolyses
cAMP , thereby prolonging the action
• primarily used in the management of
of protein kinase
acute heart failure in the hospital
setting
• Amrinone
• Milrinone

Unloaders 1. Drugs that have been found to be useful in one

• ACE Inhibitors & ARBs or more types of heart failure include all of the
– preload and afterload unloaders following EXCEPT
– vasodilating effect
A. Na+/K+ ATPase inhibitors
– Captopril, Enalapril
B. Alpha-adrenoceptor agonists
• Beta Blockers
C. Beta-adrenoceptor agonists
– vasodilating effect
– Carvedilol,labetalol D. ACE inhibitors
• Diuretics
– preload unloaders
– Spironolactone
• Vasodilators
– Hydralazine, Nitroprusside

4. A 65-year old woman has been admitted to the

2. The mechanism of action of digitalis is
coronary care unit with a left ventricular myocardial
associated with
infarction. If this patient develops acute severe
heart failure with mark pulmonary edema, which
A. A decrease in calcium uptake by the one of the following would be most useful?
sarcoplasmic reticulum
B. An increase in ATP synthesis A. Digoxin
C. A modification of the actin molecule B. Furosemide
D. An increase in systolic intracellular calcium C. Minoxidil
levels
D. Propanolol
E. A block of cardiac B adrenoceptors
E. Spironolactone
 7. Successful therapy of heart failure with digoxin
6. Drugs associated with clinically useful or
will result in which one of the following?
physiologically important positive inotropic effects
include all of the following EXCEPT

A. Decreased heart rate

A. Amrinone
B. Increased afterload
B. Captopril
C. Increased aldosterone
C. Digoxin
D. Increased renin secretion
D. Dobutamine
E. Increased sympathetic outflow to the heart
E. Norepinphrine

8. Which of the following has been shown to 10. Which of the following is the drug of choice in
prolong life in patients with chronic congestive treating suicidal overdose of digitoxin?
failure but has a negative inotropic effect on
cardiac contractility?

A. Digoxin antibodies
A. Carvedilol B. Lidocaine
B. Digoxin C. Magnesium
C. Dobutamine D. Phenytoin
D. Enalapril E. Potassium
E. Furosemide

Coronary Artery Diseases

Coronary Artery Diseases
(CAD)
or
Ischemic Heart Diseases
(IHD)
Coronary Artery Diseases Coronary Artery Diseases
• occur when the • Angina Pectoris
coronary arteries – episodic, reversible oxygen insufficiency
become so narrowed
– severe chest pains generally radiating to the left
by atherosclerosis shoulder and down the inner side of the arm
that they are unable – usually precipitated by physical exertion or emotional
to deliver sufficient stress
blood to the heart
muscle
• Myocardial Ischemia
– Localized areas of
– deprivation of oxygen to a portion of the myocardium
thickened tunica
(reversible)
intima associated with
accumulation of • Myocardial Infarction
smooth muscle cells – severe, prolonged deprivation of oxygen to a portion
and lipids, principally of the myocardium that leads to myocardial tissue
cholesterol necrosis (reversible)

Risks Factors Etiology

• Decreased blood flow
• Smoking – Atherosclerosis – most common cause
• Hypertension – Coronary artery spasm – sustained
contraction of 1 or more coronary arteries 
• Diabetes Mellitus Prinzmetal’s angina or MI
• Males >45 yo; Females >55 yo – Traumatic injury – that interferes with blood
flow in the heart
• Dyslipidemia – Embolic events – can abruptly restrict oxygen
• Obesity supply
• Family history of CAD • Increased oxygen demand
– Exertion and emotional stress  sympathetic
• Others: stimulation  increase HR
– sedentary lifestyle, hx of chronic inflammation • Reduced blood oxygenation
– Reduced O2-carrying capacity (anemia)

Angina Pectoris Angina Pectoris

• Types:
• chest pain – Stable Angina
• aka: Classical Angina
• develops on exertion and lasts for < 5 min
• a symptom of myocardial ischemia in • relieved with rest or drugs
the absence of an infaction • mechanism: imbalance oxygen supply

– Unstable Angina
• can be experienced at rest, or with increasing
severity for the last 1-2 months or a new chest pain
for < 1 month
• mechanism: thrombosis
Angina Pectoris
• Types:
– Angina Decubitus
• nocturnal angina
• occurs in recumbent position

– Prinzmetal Angina
• aka: Variant Angina
• precipitated by coronary artery spasm

Drugs for Angina Pectoris Nitrates

• MOA: metabolized into NO in the
• Nitrates body, leading to peripheral
• Beta Blockers vasodilation
• Calcium Channel Blockers • examples
– amyl nitrite
– nitroglycerin
– isosorbide dinitrate (ISDN)
– isosorbide mononitrate (ISMN)
• SE:
– throbbing headache, tolerance

Nitrates
• MOA
– Decrease oxygen demand and facilitate
coronary blood flow
– converted to nitric oxide intracellularly which
activates guanylate cyclase  increase
cGMP  dephosphorylation of myosin
light chain  relaxation of vascular smooth
muscle  vasodilation
• Important SE
– HEADACHE – most common side effect
– Tolerance (“Nitrate-free interval ”)
– Postural hypotension, facial flushing,
reflex tachycardia
Beta Blockers CCBs
• drug of choice for stable angina • MOA
– inhibits calcium influx into vascular smooth
muscle & heart muscles  increased blood
flow  enhance oxygen supply  prevent
• MOA: decreases HR & contractility  and reverse coronary spasm
reduce oxygen demand (rest and – dilates peripheral arterioles & reduce
contractility reduce total peripheral vascular
during exertion)  reduce arterial BP resistance  reduced oxygen demand
• Indications
– Stable angina not controlled by nitrates & beta
blockers; px who could not take beta blockers
– Prinzmetal’s angina (with or without nitrates)
– DOC of angina at rest

Other Agents
• Morphine
– Unstable angina with no CI; IV doses
given after 3 sublingual nitroglycerin Myocardial Infarction
tabs have failed to relieve pain
• Aspirin
– Indefinite in px with stable or unstable
angina
• Heparin, Enoxaparin, Dalteparin
– Together with aspirin  hospitalized px
with unstable angina until resolved

Myocardial Infarction (MI) Myocardial Infarction (MI)

– Results from prolonged myocardial
ischemia, precipitated in most cases by
an occlusive coronary thrombus at the
site of a pre-existing atherosclerotic
plaque
Note:
Damage on myocardial tissue
Cellular ischemiais not reversible 
myocardial tissue dies
Tissue injury
Tissue necrosis
Myocardial Infarction (MI) Signs and Symptoms of MI
• persistent, severe chest pain or • Compared to angina
pressure  “crushing”, “squeezing” or – Pain persists longer
– Not relieved by rest or nitroglycerin
heavy “an elephant sitting on the – Sense of impending doom, sweating, nausea,
chest” vomiting, difficulty in breathing; some px 
fainting and sudden death
– Extreme anxiety, restlessness, ashen pallor
• Some px:
– Mild or indigestion-like pain, manifest in
worsening CHF, loss of consciousness, acute
confusion, dyspnea, sudden drop in BP, lethal
arrhythmia

IMMEDIATE TREATMENT FOR

MYOCARDIAL INFARCTION

Drugs for MI
M MORPHINE

OXYGEN
O
NITROGLYCERINE
N ASA

Drugs for MI Oxygen

• Nitrates • for patients who have chest pain and
• Oxygen who may be ischemic
• Morphine • improve oxygenation of myocardium
• Thrombolytic Agents
Morphine Thrombolytic Agents
• MOA • MOA:
– causes venous pooling and reduces preload, – Lysis of thrombus clot
cardiac workload, and oxygen consumption • The following are given IV within 12 h to
– IV until pain is relieved restore normal blood flow in an acute MI:
• Indication – Recombinant t-PA (recombinant tissue-type
plasminogen activator
– DOC for MI pain and anxiety
– alteplase
• Precautions
– Streptokinase
– can produce orthostatic hypotension and
– Anisoylated plasminogen streptokinase
fainting
activator complex (APSAC)
– monitor for hypotension & signs of resp
– Reteplase
depression
– Tenecteplase
– GI SE: nausea and vomiting; constipation

Post thrombolysis adjunctive Post thrombolysis adjunctive

therapy therapy
• Aspirin • Beta Blockers
– prevents platelet aggregation; shown to – if administered early  reduce ischemia,
reduce post-infarct mortality reduce potential zone of infarction, decrease
oxygen demands, preserve left ventricular
– also: dipyridamole, ticlopidine, clopidogrel function, decrease cardiac workload
• Heparin • ACE Inhibitors
– prevent re-occlusion once a coronary artery – improve exercise capacity and reduce
has been opened mortality in px with CHF; aid in the prevention
– not used with streptokinase  increased risk of progressive ventricular remodelling
of hemorrhage • “Statins”
• Warfarin – reduced mortality due to MI when used by px
to aggressively lower cholesterol
– reduce mortality, prevent recurrent MI

Post thrombolysis adjunctive

therapy Items 1-3. Mr. Green, 60 years old, has
severe chest pain when he attempts to carry
• Lidocaine parcels upstairs to his apartment. The pain
– used for px who develop ventricular rapidly disappears when he rest. A decision
arrhythmia is made to treat him with nitroglycerin.
• Calcium Channel Blockers
– decrease incidence of reinfarction in px
with non-Q-wave infarcts; not for acute
mgt.
2. In advising Mr. Green about the adverse effects 3. 2 years later, Mr. Green returns complaining
he may notice, you point out that nitroglycerin in that his nitroglycerin works well when he takes it
moderate doses often produces certain symptoms. for an acute attack but that he is having frequent
These toxicities result from all of the following attacks now and would like something to prevent
EXCEPT them. Useful drugs for the prophylaxis of angina of
effort include which one of the following?
A. Meningeal vasodilation
B. Reflex tachycardia A. Amyl nitrite
C. Hypotension B. Diltiazem
D. Methemoglobinemia C. Sublingual isosorbide dinitrate
D. Sublingual nitroglycerin

4. The antianginal effect of propanolol may be 5. The major common determinant of myocardial
attributed to which one of the following? oxygen consumption is

A. Blood volume
A. Block of exercise-induced tachycardia
B. Cardiac output
B. Decreased end-diastolic ventricular volume
C. Diastolic blood pressure
C. Dilation of constricted coronary vessels
D. Heart rate
D. Increased cardiac force
E. Myocardial fiber tension
E. Decreases heart rate

6. You are considering therapeutic options for a 7. A patient is admitted to the emergency
new patient who presents with hypertension and department following a drug overdose. He is noted
angina. In considering adverse effects, you note to have severe tachycardia. He has been receiving
that an adverse effect which nitroglycerin, therapy for hypertension and angina. A drug that
prazosin, and ganglion blockers have in common often causes tachycardia is
is

A. Bradycardia A. Diltiazem
B. Impaired sexual function B. Guanethidine
C. Lupus erythematosus syndrome C. Isosorbide dinitrate
D. Orthostatic hypotension D. Propanolol
E. Throbbing headache E. Verapamil
 Arrhythmias

• deviations from normal heartbeat

Arrhythmias pattern
– abnormalities in impulse formation
– conduction disturbances

Arrhythmias Cardiac Conduction System

• The heart is endowed with a • Sinoatrial node
specialized electrogenic system for: – Pacemaker of the heart
– 60 – 100 beats/min
– Generating rhythmical impulses to
cause rhythmical contraction of the – Location: posterior wall of the right atrium
near the entrance of the superior vena cava
heart muscle
– Conducting these impulses rapidly • Atrioventricular node
– Location: posterior septal wall of the right
throughout the heart
atrium immediately behind the tricuspid valve
– Connects the atrial and ventricular conduction
systems

Cardiac Conduction System Cardiac Conduction System

• Bundle of His (AV bundle)
– Delayed transmission
• Delays in transmission provide mechanical
advantage  atria complete ejection of
blood before initiating ventricular contraction
• Pu r k I n j e f Ib e r s
– Supplies the ventricles
– Has large fibers that allow for rapid conduction and
almost simultaneous excitation of the entire left and
right ventricles
– Rapid rate of ejection is necessary for the swift and
efficient ejection of blood from the heart
 Myocardial Action Potential Myocardial Action Potential
• electric current generated by nerve
and muscle cells

• involve movement or flow of

electrically charged ions at the level
of the cell membrane

Resting Membrane Potential Depolarization

• membrane is • cell membrane
relatively permeable suddenly becomes
to K+ selectively
• charges of opposite permeable to
polarity become current-carrying ions
aligned along the such as Na+
membrane • Na+ enters cell 
(+)  outside sharp rise of
(-)  inside intracellular potential
to positivity while K+
migrate outside

Repolarization Myocardial Action Potential

• re-establishment of • Five Phases:
the resting potential
Phase 0: Rapid Depolarization
• slower process;
increased Phase 1: Early Rapid Repolarization
permeability to K+  Phase 2: Plateau Phase of
K+ ions move outward Repolarization
 removes (+)
charges inside the Phase 3: Final Rapid Repolarization
cell Phase 4: Slow Depolarization
– The Na-K pump
helps to preserve
the intracellular
Myocardial Action Potential Myocardial Action Potential

Electrocardiography (ECG) Electrocardiography (ECG)

• A recording of the electrical activity of – Isoelectric line between P wave & Q
the heart during depolarization- wave
repolarization • Depolarization of the AV node, bundle
branches, Purkinje system
– P wave
– ST segment
• SA node and atrial depolarization
• Absolute refractory period; part of
– QRS complex ventricular repolarization
• Ventricular depolarization – Atrial repolarization occurs during
– T wave ventricular depolarization and is hidden
• Ventricular repolarization in the QRS complex.

Cardiac arrhythmia may

CAUSES OF ARRHYTHMIA
cause the heart to
• To beat too slowly • Abnormal automaticity
• To beat too rapidly • Effect of drug
• To respond to impulses originating from • Abnormalities in impulse conduction
sites other than the SA node
• To respond to impulses travelling along
extra pathways
 Electrocardiography (ECG)

Action Potential & ECG Classification of Arrhythmias

• By origin
– Supraventricular arrhythmia
• Stem from enhanced automaticity of the SA
node or from re-entry conduction

– Ventricular arrhythmia
• Occur when an ectopic pacemaker triggers
a ventricular contraction before the SA
node fires

Normal ECG Pattern ECG Patterns of Arrhythmias

 •Quinidine
Antiarrhythmics Class IA •Procainamide
•Disopyramide

Sodium Channel Blockers •Lidocaine

•Tocainide
Class IB •Mexiletine
•Phenytoin

Anti-arrhythmic Agents Class IC

•Flecainide
•Propafenone
• Moricizine
• Propranolol
Beta Adrenergic Blockers Class II •Esmolol
•Acebutolol

•Amiodarone
Potassium Channel Blockers Class III •Sotalol
•Bretylium

• Verapamil
Calcium Channel Blockers Class IV •Diltiazem

CLASS 1A
• Slows phase 0 depolarization
• Prolong action potential
• Slow conduction

CLASS 1B CLASS 1C
• Shortens phase 3 repolarization • Markedly slow phase 0 depolarization
• Decrease duration of action potential
CLASS II CLASS III
• Suppresses phase 4 depolarization • Prolongs phase 3 repolarization

CLASS IV Miscellaneous Agents

• Slows phase 4 spontaneous • Adenosine
depolarization
• MgSO4
• Shorten action potential

TYPE OF ARRHYTHMIA
AND DRUGS
• Atrial flutter • Atrial fibrillation
• Class 1 – quinidine • 1- quinidine
• Class II - propranolol • 2- propranolol
• Class IV – verapamil • 3- amniodarone
• Others - digoxin • 4 – anticoagulant
• AV –NODAL REENTRY • ACUTE SUPRAVENTRICULAR
• PROPRANOLOL TACHYCARDIA
• VERAPAMIL • Verapamil
• DIGOXIN • adenosine

• ACUTE VENTRICULAR TACHYCARDIA • VENTRICULAR FIBBRILLATION

• Lidocaine • Lidocaine
• Sotalol • Bretylium
• Amniodarone • Amnidarone
• epinephrine

Procainamide Quinidine
• can cause SLE (Systemic Lupus • drug interaction with digoxin
Erythematosus) • can increase serum levels of digoxin
by at least 2x
Lidocaine Propafenone
• anesthetic • for acute atrial fibrillation
• DOC for digitalis-induced arrhythmias

Amiodarone Verapamil
• iodine-containing molecule • alternative for acute SVT
• first-line treatment for almost all types (Supraventricular Tachycardia)
of Ventricular Tachycardia and Atrial
Fibrillation

Adenosine
• first-line drug for acute SVT
Drugs for Coagulation
Disorders
Clotting Mechanism Clotting Mechanism
• inciting event: epithelial vascular injury • thrombus
• followed by:
– migration of platelets to the site of injury
– clot that adheres to a blood vessel wall
– platelet aggregation
• aka: primary hemostasis
• white thrombus • embolus
• platelet plug – detached thrombus
• unstable clot
– deposition of fibrin over the plug
– attachment of other blood cells
• aka: secondary hemostasis
• red thrombus
• stable clot

Coagulation Cascade
Clotting Mechanism
• the coagulation process that
generates thrombin that is essential in
the formation of fibrin used in clot
formation involves coagulation
cascade

Drugs for Coagulation

Disorders
Anticoagulants

Anti-Platelet Drugs Anticoagulants

Fibrinolytic Agents

Pro-coagulant Drugs
Anticoagulants
• Site of action
– synthesis of or directly against clotting factors
(II, IIa) Parenteral Anticoagulants
• Types:
– Parenteral
• Hirudin, Heparin
– Oral
• Dicumarol, Warfarin

Hirudin Heparin
• heterogeneous mixture of sulfated
• obtained from medicinal leeches mucopolysaccharides
(Hirudo medicinalis) – Regular or Unfractionated heparin
• activates antithrombin III which in turn
inactivates thrombin (IIa); Ixa, Xa, Xia
• used in the management of HIT • SQ/IV
(Heparin-Induced Thrombocytopenia)
– Low MW Heparin
• Inactivates IIa and Xa
• Lepirudin – produced by recombinant • Enoxaparin,fraxiparin,dalteparin
DNA technology • SQ

Heparin CONTRAINDICATIONS
• Clinical use
– initiation of anticoagulant therapy • Hypersensitivity
– mgt of MI or unstable angina • Active bleeding
– tx & prevention of pulmonary embolism • Thrombocytopenia
& DVT • Severe HPN
– anticoagulation in pregnancy (APAS) • Active TB
• SE:
– hemorrhage (monitor aPTT – activated
partial thromboplastin time) 2-2.5x or
delay of 50 – 80 secs except SQ
– Thrombocytopenia
 • DICUMAROL
• aka: bis-hydroxycoumarin
Oral Anticoagulants
• high incidence of GI side-effects
• PHENPROCOUMON
• INDANEDIONES ex:
anisindione,phenindione
• WARFARIN

• MOA: blocks carboxylation of X, IX,VII,II • delay in the anticoagulant effect

• ONSET: 8 – 12 hrs maximum after 1 to • Clinical use
3days – Chronic anticoagulation (DVT prophylaxis,
cardiac thrombus, prosthetic heart valves)
• SE:
– Hemorrhage
• Monitor PT (Prothrombin Time) and INR
(International Normalized Ratio)
• Goal for INR = 2-3
• <2  insufficient dose
• >3  x’sive dose
• With prosthetic heart valves INR goal = 3-4

SE:
• Hemorrhagic dse of the newborn
• Teratogenic: abnormal bone formation
• Cutaneous necrosis Anti-Platelet Drugs
• Purple toe syndrome
• Alopecia, urticaria,dermatitis
 Thromboxane Synthesis
Anti-Platelet Drugs Inhibitors
• Thromboxane Synthesis Inhibitors • Irreversibly acetylates COX- inhibition
• Phosphodiesterase Inhibitors of TXA2 synthesis, lasts for 8 – 10
• ADP Inhibitors
days
• Glycoprotein IIb/IIIa Inhibitors
• Aspirin
– primary prophylaxis for MI
– secondary prophylaxis for MI and stroke

ADP Inhibitors -
Phosphodiesterase Inhibitors
Thienopyridines
• Dypiridamole • Ticlopidine
– given together with antiplatelet; – SE: thrombocytopenia
ineffective when alone purpura,neutropenia,
– Inc CAMP – n/v,diarrhea
– SE: coronary steal phenomenon
• Clopidogrel
– safer than ticlopidine

Glycoprotein Inhibitors
• Abciximab
• Eptifibatide
Fibrinolytic Agents
• Tirofiban
Fibrinolytic Agents / Thrombolytics
• MOA
– catalyse activation of plasminogen to
plasmin(serine protease)
• Use
– mgt of severe pulmonary embolism Pro-coagulant Drugs
– heart attack, acute MI,DVT
• Ex
– Streptokinase – destroy fibrin that is either
bound to clots or is in the unbound form
– Tissue plasminogen activator – binds to fibrin
bound to a clot
– Anistreplase (APSAC)
– Urokinase – from the kidneys

Pro-coagulant Drugs
• Mgt of bleeding disorders
– Vitamin K
• K1 – phytonadione (in plants, useful Drugs for Dyslipidemia
clinically)
• K2 – menaquinone (intestinal bacteria)
• K3 – menadione (synthetic)
• used for Vit. K deficiency; hemorrhagic
disorders in newborns
– Aminocaproic Acid
• prevents activation of plasminogen
– Tranexamic Acid (analogue)

Dyslipidemia Cholesterol Synthesis

• Hypercholesterolemia (inc LDL, dec HMG-CoA
HDL) Reductase
HMG-CoA Mevalonate Cholesterol
• Hypertriglyceridemia (inc TG, ~ inc
VLDL, chylomicrons)
• Liver hydroxymethylglutaryl-
Cholesterol Source
–Diet (exogenous)
– Only organ in the body that efficiently Coenzyme A (HMG-CoA)
–Endogenous
uses cholesterol
• Converts it to bile salts
 Atherosclerosis
Condition
associated with
cholesterol
deposition in
vascular smooth
muscles (arthroma)
with consequent
narrowing of the
lumen of the
affected blood
vessels

Atherosclerosis Atherosclerosis
• Major Risk factors
• Could lead t o … – Age (males: > 45;
• Minor Risk Factors
– Chronic infection
– CAD females: > 55)
– Sedentary lifestyle
– Cerebrovascular disease – Smoking
– Aortic disease – DM • Modifiable Risk
– HPN Factors
– Renal artery disease
– Dyslipidemia – By therapy
– Obesity – By lifestyle change
– Family history of
premature heart
attack

HMG-CoA Reductase
Drugs for Dyslipidemia
Inhibitors
• HMG-CoA Reductase Inhibitors • “-statins”
• Nicotinic Acid
• Bile Acid Sequesterants • MOA: inhibit the enzyme HMG-CoA
• Fibric Acid Derivatives Reductase, thereby inhibiting the first
step (rate-limiting step) in cholesterol
• Probucol
synthesis

• first-line drugs for dyslipidemia

HMG-CoA Reductase HMG-CoA Reductase
Inhibitors Inhibitors
• Diurnal Pattern of Cholesterol • Short-acting
Synthesis – simvastatin
– lovastatin
– means that the biosynthesis of
cholesterol in the body occurs at night – fluvastatin

– thus most statins are given at bedtime • Long-acting

(esp the short-acting ones) – atorvastatin
– rosuvastatin Long-acting statins can
be given any time of
the day.

HMG-CoA Reductase
Nicotinic Acid
Inhibitors
• SE:
– hepatotoxicity • MOA: In adipose tissue, niacin inhibits the
– myositis lipolysis of triglycerides by hormone-
sensitive lipase, which reduces transport
– rhabdomyolysis (muscle wasting)
of free fatty acids to the liver and
decreases hepatic triglyceride synthesis

Nicotinic Acid Bile Acid Sequesterants

• aka: Bile Acid – Binding Resins
• used in the management of
hypertriglyceridemia • MOA: Inhibit reabsorption of bile acid

• SE: flushing (due to percutaneous • since liver must maintain a certain

vasodilation), myositis amount of bile, it will synthesize bile
from endogenous cholesterol when
bile levels go low
Bile Acid Sequesterants Fibric Acid Derivatives
• Cholestyramine • MOA: stimulate lipoprotein lipase
• Colestipol which decreases triglycerides

• first-line drug in hypertriglyceridemia

• SE:
– constipation
• Gemfibrozil
– impaired absorption of certain drugs
• Fenofibrate
– may increase incidence / risk of biliary
stone formation • Clofibrate (withdrawn)

Fibric Acid Derivatives Probucol

• SE: • MOA: anti-oxidant
– myositis
– rhabdomyolysis • SE:
– increase risk of bile stone formation – increase risk of arrhythmia
– hepatobiliary cancer (Clofibrate) – produces fetid odor

Question 1:
• Which enzyme is responsible for the
Ok, before we end our conversion of Angiotensin I into the
lecture, quiz muna tayo… active form Angiotensin II?
 A. Renin
B. ACE
C. HMG-CoA
D. Streptokinase
Question 2: Question 3:
• A 55 y/o male patient was • From the list of anti-hypertensive
diagnosed to have uncomplicated drugs below, select the one most
HTN. Which of the following drugs likely to lower blood sugar:
would most likely be given to him?
A. Prazosin
A. Thiazide diuretic + Beta Blocker
B. Nifedipine
B. ACE Inhibitor
C. Propranolol
C. CCB + ACE Inhibitor
D. Hydralazine
D. ACEi + ARB
E. Labetalol

Question 4: Question 5:
• All of the following mechanisms of
• Which of the following conditions
action correctly match a drug,
predisposes a patient taking digitalis
EXCEPT:
into arrhythmia?
A. Quinidine: blocks Na+ channels
A. hypocalcemia
B. Bretylium: blocks K+ channels
B. decreased heart rate
C. Propranolol: blocks β-receptors
C. hyponatremia
D. Procainamide: blocks K+ channels
D. hypokalemia

Question 6: Question 7:
• Which of the following adverse • A patient experienced orthostatic
effects is associated with nitrates? hypotension after taking the first
A. nausea dose of her drug. She most likely
B. throbbing headache took:
C. sexual dysfunction A. Labetalol
D. anemia B. Valdesartan
C. Prazosin
D. Digoxin
Question 8: Question 9:
• Mrs. G. R. is a hypertensive patient
under therapy. After some time, she • Which of the following antagonizes
developed Lupus-like symptoms. the co-factor functions of Vitamin K?
Which of the ff drugs may have A. Tranexamic acid
cause this? B. Heparin
A. Hydralazine C. Warfarin
B. Losartan D. Hirudin
C. Furosemide
D. Metoprolol

Question 10:
• The following drugs for dyslipidemia
can cause rhabdomyolysis,
EXCEPT:
A. simvastatin
B. atorvastatin
C. colestipol
D. fenofibrate