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Cardiovascular Cardiovascular DrugsDrugs

Dra. Hena W. Alcantara

The Cardiovascular SystemThe Cardiovascular System

• Heart

• Blood

• Blood Vessels– Arteries

– Veins

– Capillaries

The HeartThe Heart

BloodBlood

Blood VesselsBlood Vessels

CirculationCirculation

In simple terms…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.

MalfunctionsMalfunctionswhen the heart can no longer pump enough blood to meet the metabolic demands of the body

HEART FAILURE

when blood volume is great compared to the space available inside blood vessels

HYPERTENSION

MalfunctionsMalfunctions

when the electrical conduction pathways malfunction

ARRHYTHMIA

the heart’s way of signaling that some of the cells are not getting enough oxygen

ANGINA

MalfunctionsMalfunctions

when oxygen-starved areas of the heart begin dying

MYOCARDIAL INFARCTION

when you broke with someone…

Cardiovascular DrugsCardiovascular Drugs

• Anti-hypertensives

• Drugs for Heart Failure

• Anti-anginal and Drugs for MI

• Anti-arrhythmic Agents

Anti-Hypertensive DrugsAnti-Hypertensive Drugs

Physiology of BP RegulationPhysiology of BP Regulation

• Hydraulic Equation:

BP = CO x TPR

BloodPressure

HeartRate

Low Blood PressureLow Blood VolumeNa+ depletion

Angiotensin I

Sympathetic AdrenergicSympathetic AdrenergicSystemSystem

PituitaryGland

Na+& H2OReabsorption

Aldosterone

BloodVolume

VenousReturn

StrokeVolumex

Renin – Renin – AngiotensinAngiotensin

SystemSystem

Angiotensin II

vasoconstriction

Factors that alter the Blood Pressure EquationFactors that alter the Blood Pressure Equation

Kidney

CardiacOutput

Total PeripheralArterial Resistance

Determinants of Blood Determinants of Blood PressurePressure• Cardiac Output (CO)

– volume of blood pumped out by the heart in 1 minute

– approximately 2.2 – 3.5 L / min / m2 BSA

– determined by Stroke Volume (SV) and Heart Rate (HR)

• Stroke Volume (SV)– volume of blood pumped out by the

heart in every contraction

– determined by:• Inotropic activity –strength of cardiac

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 Determinants of Blood PressurePressure

• Heart Rate (HR)– speed of heart contraction– chronotropism

• Fluid Content of the Blood• Total Peripheral Resistance (TPR)

– resistance or pressure encountered by the heart as it pumps out blood into the peripheral circulation (cardiac afterload)

– determined by the arterioles

Determinants of Blood Determinants of Blood PressurePressure

Mechanisms of BP Mechanisms of BP RegulationRegulation• Baroreceptor Reflex Arch Mechanism

– aka: Postural Reflex Mechanism– moment-to-moment BP regulation

• Baroreceptor – a type of sensory nerve ending found in the walls of the atria of the heart, the vena cava, the aortic arch, and the carotid sinus that is stimulated by changes in pressure

• Renin Angiotensin Aldosterone System

Angiotensinogen (from the liver) Renin

Angiotensin I (inactive)

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

Renin Angiotensin Aldosterone Renin Angiotensin Aldosterone System (RAAS)System (RAAS)

HypertensionHypertension

• persistent or recurrent elevation of BP defined as having a:– Systolic reading > 140 mmHg

– Diastolic reading > 90 mmHg

– BP > 140/90

• most common cardiovascular disorder

HypertensionHypertension

• Systole– the period during which the ventricles

are contracting

• Diastole– the period during which the ventricles

are relaxed and filling with blood

HypertensionHypertension• Essential (Primary, Idiopathic)

– hypertension with no identifiable cause– accounts for > 90% of HTNsive cases

• Secondary – resulting from identifiable causes

• kidney diseases • adrenal cortical disorders• pheochromocytoma (adrenal medulla tumor)• coarctation of the aorta• drugs such as steroids, sympathomimetics, contraceptives

– treat the underlying cause– accounts for ~ 10% of HTNsive cases

Classification of BP based on the 7Classification of BP based on the 7 thth Report of the Report of the Joint National Committee on Detection, Evaluation Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)and Treatment of High Blood Pressure (JNC VII)

Classification of Blood Pressure (JNC VII)

Systolic BP, mm Hg Diastolic BP, mm

Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 hypertension 140-159 or 90-99

Stage 2 hypertension >160 or >100

Adapted from JNC VII

Hypertensive EmergencyHypertensive Emergency

• aka: Hypertensive Crisis

• rare, but life-threatening situation

• systolic pressure > 210 mm Hg

• diastolic pressure > 150 mm Hg

Risk FactorsRisk Factors• Family history • Patient history • Racial predisposition

– More common in blacks

• Obesity• Smoking• Stress• High dietary intake

– Saturated fats and sodium

• Sedentary lifestyle• DM• Hyperlipidemia• Gender – males• Age > 60• Postmenopausal

Treatment GoalsTreatment Goals

• Rule out uncommon secondary causes of hypertension• Determine the presence and extent of target organ damage• Determine the presence of other CV risk factors• To lower BP with minimal side effects

ComplicationsComplications

• Cardiac effects– Increased oxygen requirements angina pectoris;

because of atherosclerosis angina, MI, sudden death

• Renal effects– Increased blood volume; renal parenchymal damage due

to atherosclerosis

• Cerebral effects– Transient ischemic attacks, cerebral thromboses,

aneurysms with hemorrhage

• Retinal effects– Visual defects (blurred vision, spots, blindness)

TreatmentTreatment

• First line: diuretics (thiazides) and beta blockers

• Alternatives: ACE inhibitors, ARBs, alpha blockers, calcium-channel blockers for px who cannot tolerate first line agents

• Monitor: – blood pressure routinely– observe adverse effects

• Patient Counseling:– Importance of compliance make px realize seriousness

of noncompliance

Anti-hypertensivesAnti-hypertensives

• Diuretics

• Sympathoplegics

• Vasodilators

• Calcium Channel Blockers (CCBs)

• ACE Inhibitors

• Angiotensin II Receptor Blockers (ARBs)

DiureticsDiuretics

• agents that cause urinary loss of Na+ and H2O

• Gen MOA: act on their specific sites in the renal tubule

Five major classesFive major classes

1. Thiazides and thiazide-like

2. Loop diuretics

3. Potassium-sparing

4. Carbonic anhydrase inhibitors

5. Osmotic diuretics

Renal TubuleRenal Tubule

Carbonic Anhydrase Carbonic Anhydrase InhibitorsInhibitors• MOA: inhibit carbonic anhydrase (the

enzyme that catalyzes the reaction of CO2 and H2O leading to H+ and HCO3

-) that can lead to the spillage of Na+ causing diuresis.

• act on the proximal convoluted tubule (PCT)

Carbonic Anhydrase Carbonic Anhydrase InhibitorsInhibitors• Acetazolamide

• Brinzolamide

• Dorzolamide

Carbonic Anhydrase Carbonic Anhydrase InhibitorsInhibitors• limited diuretic effect (2 to 3 days)

• SE: metabolic acidosis, bone marrow depression (sulfonamide-like toxicity), allergic reactions (Stevens-Johnson’s Syndrome)

Loop DiureticsLoop Diuretics

• aka: High Ceiling Diuretics

• high ceiling (most efficacious) as compared with other diuretics

• act on the thick ascending Loop of Henle

• MOA: inhibit the Cl-Na-K-cotransporter at the thick ascending LOH

• Furosemide• Bumetanide• Torsemide• Ethacrynic acid

• for px who cannot tolerate thiazides, have renal impairment, or ineffectiveness of thiazides

• SE: hypovolemia, ototoxicity, increase serum creatinine

• DI: their efficacy can be reduced by NSAIDs

• Side-effects–Hypokalemia

–Bicarbonate is lost in the urine

–INCREASED calcium excretion Hypocalcemia

–Ototoxicity• due to the electrolyte imbalances

Thiazide DiureticsThiazide Diuretics

• MOA: inhibit Na-Cl-cotransporter at the distal convoluted tubule

• Chlorothiazide

• Hydrochlorothiazide

• Chlorthalidone

• Indapamide

• first-line drug for uncomplicated hypertension as recommended by JNC 7

• effective initial therapy together with beta-blockers

• also used for Nephrogenic Diabetes Insipidus

• SE: hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hyperlipidemia

• DI: their efficacy can be reduced by NSAIDs

ThiazideThiazide

• Side effects–Hypokalemia

–DECREASED calcium excretion hypercalcemia

–DECREASED uric acid secretion hyperuricemia

–Hyperglycemia

Potassium-Sparing DiureticsPotassium-Sparing Diuretics

• MOA: act in the collecting tubule by inhibiting Na+ reabsorption, K+ secretion and H+ secretion

• Spironolactone• Eprenolone• Amiloride• Triamterene

• for patients where potassium loss is 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 Rich Foods Potassium Rich Foods

TOPP PNBB’S

• T- Tomatoes• O-Oranges• P- Peaches• P-potatoes• P-Prunes• N-Nuts• B-Banana• B-Broccoli• S-Spinatch

• not associated with hypokalemia

• can be given with other diuretics to lessen the risk of hypokalemia

• SE: hyperkalemia, gynecomastia, impotence, sterility

Osmotic DiureticsOsmotic Diuretics

• MOA: increase the osmotic pressure at the proximal convoluted tubule and Loop of Henle preventing water reabsorption

• Mannitol• Sorbitol• Urea

Osmotic DiureticsOsmotic Diuretics

• used to induce forced diuresis

• mostly used to reduce intracranial pressure

• SE: hypernatremia, hypovolemia

Diuretics ComparisonDiuretics ComparisonDiuretic class Major site of action Special Side effect

1. Carbonic anhydrase inhibitor

Proximal tubule Acidosis

2. Thiazide and thiazide like

Distal tubule Hyperuricemia

Hypokalemia

3. Loop diuretics L p of Henle Hypokalemia

Ototoxicity

4. Potassium sparing

Distal tubule Hyperkalemia

5. Osmotic diuretic

Glomerulus Hypovolemia & hypotension

Diuretics ComparisonDiuretics ComparisonDiuretic class Special Uses

1. Carbonic anhydrase inhibitor

Mountain sickness

Meniere’s disease

2. Thiazide and thiazide like

Nephrolithiasis due to calcium stones

Hypocalcemia

3. Loop diuretics Hypercalcemia

4. Potassium sparing

CHF taking digoxin

5. Osmotic diuretic

Increased ICP

LITHIUM TOXICITY

SympathoplegicsSympathoplegics

• Centrally-acting

• Peripherally-acting

• Alpha-1 blockers

• Beta blockers

Centrally-Acting Centrally-Acting SympathoplegicsSympathoplegics

Centrally-Acting Centrally-Acting SympathoplegicsSympathoplegics• MOA: act primarily within the CNS on

alpha-2 receptors to decrease sympathetic outflow to the CVS

• Clonidine• Methyldopa• Guanfacine• Guanabenz

ClonidineClonidine

• MOA: agonist at alpha-2 receptors (leading to vasodilation)

• effective in patients with renal impairment

• SE: transient increase in BP, sedation/depression, rebound hypertension on abrupt withdrawal

MethyldopaMethyldopa

• reduce TPR with little effect on CO and blood flow to vital organs (such as kidneys)

• effective for patients with renal impairment

• used in the management of HTN in pregnancy (pre-eclampsia, eclampsia)

MethyldopaMethyldopa

• SE: sedation, depression, hepatotoxicity (at doses >2g / day), (+) Coomb,s Test*

* Coomb’s Test – indicator of a possible immune-mediated hemolytic anemia

Guanfacine, GuanabenzGuanfacine, Guanabenz

• adjunctive therapy to other anti-HTNsive drugs

• avoided unless necessary to treat severe refractory HTN that is unresponsive to other meds

Peripherally-Acting Peripherally-Acting SympathoplegicsSympathoplegics

• Trimethaphan

• Reserpine

• Guanethidine

• Guanadrel

TrimethaphanTrimethaphan

• ganglionic receptor blocker

• given via IV infusion

• used in hypertensive emergencies caused by pulmonary edema or aortic aneurism when other agents cannot be used

ReserpineReserpine

• plant alkaloid

• inhibits catecholamine (NE, Epi, Dopamine, Serotonin) storage

• impairs sympathetic function because of decreased release of Norepinephrine (NE)

Guanethidine, GuanadrelGuanethidine, Guanadrel

• inhibit the response of the adrenergic nerve to stimulation or to indirectly-acting sympathetic amines

• blocks the release of stored Norepinephrine

• SE: orthostatic hypotension, impaired male sexual function

Alpha-1 BlockersAlpha-1 Blockers

• MOA: inhibit the alpha-1 receptors, resulting to vasodilation of arteries and veins

• Prazosin• Doxazosin• Alfazosin• Terazosin

Alpha-1 BlockersAlpha-1 Blockers

• alternative drugs for the management of HTN esp among patients with BPH

• First-Dose Phenomenon:– orthostatic hypotension– syncope– remedy: take the drug at bedtime, slow

increase in dose

Beta BlockersBeta Blockers

• used for the initial therapy of HTN; effective for patients with rapid resting 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

• SE/Precautions/Contraindications:– can mask hypoglycemia– CI to patients with bronchospastic disease:

COPD, Bronchial Asthma– rebound tachycardia and HTN– easy fatigability– severe bradycardia and heartblock (seen

esp with concomitant use of verapamil and diltiazem)

Beta BlockersBeta Blockers• Selective

B – Betaxolol

B – Bisoprolol

E – Esmolol

A – Acebutolol

A – Atenolol

M – Metoprolol

• Membrane Stabilizing Activity – Anesthetic-like effect– Cannot be given as

ophthalmic drops

P – Propranolol

P – Pindolol

A – Acebutolol

L – Labetalol

M – Metoprolol

Beta BlockersBeta Blockers• Mixed alpha and

beta blocking effect

L – Labetalol

C – Carvedilol

• Intrinsic sympathomimetic activity– partial agonist effect– not usually associated

with rebound hypertension

A – Acebutolol

B – Bisoprolol

C – Carteolol

P – Pindolol

P - Penbutolol

Nematodes (Roundworms)Nematodes (Roundworms)

VasodilatorsVasodilators

• second-line agents

• directly relax the peripheral vascular smooth muscles

• not used alone inc in plasma renin activity, CO, HR

• common SE: reflex tachycardia, peripheral edema

• common CI: as single agents, should be avoided in patients with Ischemic Heart Disease (IHD)

• Hydralazine

• Diazoxide

• Minoxidil

• Sodium Nitroprusside

HydralazineHydralazine

• used in the management of HTN in pregnancy

• SE: Lupus-like side effect (drug-induced SLE or Systemic Lupus Erythematosus)

DiazoxideDiazoxide

• used in the emergency treatment of hypertensive crisis

MinoxidilMinoxidil

• most effective arteriolar vasodilator

• SE: hypertrichosis, hirsutism

Sodium NitroprussideSodium Nitroprusside

• metabolized in the body into nitric oxide (NO) also called EDRF or Endothelium-Derived Relaxing Factor

• 1st line drug for almost all types of HTNsive emergencies

Sodium NitroprussideSodium Nitroprusside

• Caution: use freshly prepared solutions or admixtures

• protect from light

• SE: thiocyanate or cyanide toxicity, acute psychosis, severe hypotension, coma, death

Calcium Channel BlockersCalcium Channel Blockers

Calcium Channel Blockers Calcium Channel Blockers (CCBs)(CCBs)• alternative for the mgt of HTN

• MOA– Inhibit influx of Ca through the slow

channels in vascular smooth muscle and cause relaxation

• Dihydropyridine (DHP)– block Ca channels in the blood vessels– Nifedipine, Nicardipine, Felodipine, Amlodipine

• Non-dihydropyridine (Non-DHP)– block Ca channels both in the heart and blood

vessels– Verapamil – heart > blood vessels– Diltiazem – heart = blood vessels

ClassificationClassification

Calcium Channel Blockers Calcium Channel Blockers (CCBs)(CCBs)• SE:

– peripheral edema

– reflex tachycardia (DHP)

– bradycardia (Non-DHP)

– heart block (Non-DHP + Beta Blocker)

ACE InhibitorsACE Inhibitors

Angiotensin Converting Enzyme Angiotensin Converting Enzyme InhibitorsInhibitors• MOA: inhibit ACE, thereby preventing the

conversion of angiotensin I into the active form angiotensin II

• Short-acting– Captopril

• Long-acting– Enalapril– Lisinopril– Perindopril

Generally, long acting ACE Inhibitors are prodrugs:

Enalapril Enalaprilat

(prodrug) (active)

• SE:– idiosyncratic dry cough

Bradykinin inactive fragments

(causes cough)

– angioedema– hyperkalemia

Angiotensin Converting Enzyme Angiotensin Converting Enzyme InhibitorsInhibitors

Angiotensin II Receptor Angiotensin II Receptor Blockers Blockers

Angiotensin II Receptor Angiotensin II Receptor Blockers (ARBs)Blockers (ARBs)

• direct inhibitors of angiotensin II receptors

• Losartan, Valdesartan, Candesartan

• clinical use: same as ACE Inhibitors

• Advantage over ACE inhibitors: less associated with dry cough

1. A friend has very severe hypertension and asks 1. A friend has very severe hypertension and asks about a drugabout a drug her doctor wishes to prescribe. Her her doctor wishes to prescribe. Her physician has explained that this drug is physician has explained that this drug is associated with tachycardia and fluid retention (w/c associated with tachycardia and fluid retention (w/c may be marked) and increased hair growth. Which may be marked) and increased hair growth. Which of the following is most likely to produce the effects of the following is most likely to produce the effects that your friend has described?that your friend has described?

A. Captopril

B. Guanethidine

C. Minoxidil

D. Prazosin

E. Propanolol

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 EXCEPTfollowing can slow the heart rate EXCEPT

A. Clonidine

B. Guanethidine

C. Hydralazine

D. Propanolol

E. Reserpine

A. Clonidine

B. Guanethidine

C. Hydralazine

D. Propanolol

E. Reserpine

A. Clonidine

B. Guanethidine

C. Hydralazine

D. Propanolol

E. Reserpine

3. Which one of the following is characteristic of 3. Which one of the following is characteristic of enalapril treatment in patients with essential enalapril treatment in patients with essential hypertension?hypertension?

A. Competitively blocks angiotensin II at its receptor

B. Decreases angiotensin II concentration in the blood

C. Decreases renin concentration in the blood

D. Increases sodium and decreases potassium in the blood

E. Decreases sodium and increases potassium in the urine

4. A pregnant patient is admitted to the 4. A pregnant patient is admitted to the hematology service with moderately severe hematology service with moderately severe hemolytic anemia. After a thorough workup, the hemolytic anemia. After a thorough workup, the only positive finding is a history of treatment with only positive finding is a history of treatment with an antihypertensive drug since 2 months after an antihypertensive drug since 2 months after beginning the pregnancy. The most likely cause of beginning the pregnancy. The most likely cause of the patient’s blood disorder isthe patient’s blood disorder is

A. Atenolol

B. Captopril

C. Hydralazine

D. Methyldopa

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

B. Alpha receptor blockers

C. Arteriolar dilators

D. Beta-selective receptor blockers

E. Nonselective B-blockers

A. ACE inhibitors

Congestive Heart FailureCongestive Heart Failure

Heart FailureHeart Failure

• is the failure of the heart as a pump

• inability of the heart to pump sufficient amount of blood to the body

Congestive Heart FailureCongestive Heart Failure

• pumping ability of the heart becomes impaired

• accompanied by congestion of body tissues

• etiology– acute MI, HPN, cardiomyopathies

– excessive work demands on the heart

Forms of CHFForms of CHF• High-output

– uncommon– caused by excessive

need for cardiac output

– high metabolic demands

• Low-output– caused by disorders

that impair the pumping ability of the heart (IHD)

– normal metabolic demands, heart unable to meet them

Forms of CHFForms of CHF• Right sided

– fatigue– jugular vein distension– liver engorgement– anorexia, GI distress– cyanosis– elevation in peripheral

venous pressure– peripheral edema

• Left-sided– exertional dyspnea– paroxysmal nocturnal

dyspnea– cough– blood-tinged sputum– cyanosis– pulmonary edema

Treatment GoalsTreatment Goals• To remove or mitigate the underlying cause • To relieve the symptoms and improve pump

function by:– Reducing metabolic demands (rest, relaxation,

pharm’l controls)– Reduce fluid volume excess (food intake, meds)– Administer digitalis and other inotropic agents– Promote px compliance and self-regulation

through education– Select appropriate px for cardiac transplants

Compensatory MechanismCompensatory Mechanism

• Myocardial Hypertrophy– long-term compensatory mechanism

– increase in the number of contractile elements in myocardial cells as a means of increasing their myocardial performance

– ventricular remodeling

Compensatory MechanismCompensatory Mechanism

• Frank-Starling Mechanism– is the intrinsic ability of the heart to adapt to

changing volumes of inflowing blood– the greater the heart muscle is stretched

during filling, the greater the force of contraction and the greater the quantity of blood pumped into the aorta

– within physiologic limits, the heart pumps all the blood that comes to it without allowing excessive damming of blood in the veins

Drugs for CHFDrugs for CHF

• Inotropic Agents– Cardiac glycosides– Beta Agonists– Phosphodiesterase Inhibitors

• Unloaders– ACE Inhibitors & ARBs– Beta Blockers– Diuretics– Vasodilators

TREATING CONGESTIVE HEART FAILURE

UPRIGHT POSITION

NITRATES (LOW DOSE)

OXYGEN

AMINOPHYLLINE

DIGOXIN

FLUIDS (DECREASE)

AFTERLOAD (DECREASE)

SODIUM RESTRICTION

TEST (Dig Level, ABGs, Potassium Level)

Cardiac GlycosidesCardiac Glycosides

• from Digitalis species

• Digoxin, Digitoxin

• MOA: inhibit the Na-K-ATPase pump leading to an increase in intracellular calcium

• Digoxin – ~75% Bioavailable– half-life: 36-40

hours– 20-40% protein

bound– excreted in the

• Digitoxin– >90% Bioavailable– half-life: 168 hours– >90% protein bound– excreted in the bile

- have low therapeutic indices

- toxicity can be enhanced by:- hypokalemia

- hypomagnesemia

- hypercalcemia

ToxicityToxicity

• Cardiac Manifestations– arrhythmias (ventricular tachycardia)– cardiac death

• Extra-cardiac Manifestations– GI disturbances (nausea & vomiting)– visual disturbances (blurred vision, alteration

of color perception, haloes on dark objects)

Management of ToxicityManagement of Toxicity

• give potassium supplement

• give digitalis antibodies (FAB fragments)

• for arrhythmias, give lidocaine or amiodarone

Nematodes (Roundworms)Nematodes (Roundworms)

Beta-1 AgonistsBeta-1 Agonists

• Dopamine

• Dobutamine

• MOA: increase intracellular cAMP, which results in the activation of protein kinase, that leads to an increase in intracellular calcium

DobutamineDobutamine

• given as an IV infusion

• primarily used in the management of acute heart failure in the hospital setting

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors

• MOA: inhibits the enzyme phosphodiesterase which hydrolyses cAMP , thereby prolonging the action of protein kinase

• Amrinone

• Milrinone

UnloadersUnloaders• ACE Inhibitors & ARBs

– preload and afterload unloaders– vasodilating effect– Captopril, Enalapril

• Beta Blockers– vasodilating effect– Metoprolol, Misoprolol, Carvedilol

• Diuretics– preload unloaders– Spironolactone

• Vasodilators– Hydralazine, Nitroprusside

1. Drugs that have been found to be useful in one 1. Drugs that have been found to be useful in one or more types of heart failure include all of the or more types of heart failure include all of the following EXCEPTfollowing EXCEPT

A. Na+/K+ ATPase inhibitors

B. Alpha-adrenoceptor agonists

C. Beta-adrenoceptor agonists

D. ACE inhibitors

2. The mechanism of action of digitalis is 2. The mechanism of action of digitalis is associated withassociated with

A. A decrease in calcium uptake by the sarcoplasmic reticulum

B. An increase in ATP synthesis

C. A modification of the actin molecule

D. An increase in systolic intracellular calcium levels

E. A block of cardiac B adrenoceptors

4. A 65-year old woman has been admitted to the 4. A 65-year old woman has been admitted to the coronary care unit with a left ventricular myocardial coronary care unit with a left ventricular myocardial infarction. If this patient develops acute severe infarction. If this patient develops acute severe heart failure with mark pulmonary edema, which heart failure with mark pulmonary edema, which one of the following would be most useful?one of the following would be most useful?

A. Digoxin

B. Furosemide

C. Minoxidil

D. Propanolol

E. Spironolactone

6. Drugs associated with clinically useful or 6. Drugs associated with clinically useful or physiologically important positive inotropic effects physiologically important positive inotropic effects include all of the following EXCEPTinclude all of the following EXCEPT

A. Amrinone

B. Captopril

C. Digoxin

D. Dobutamine

E. Norepinphrine

7. Successful therapy of heart failure with digoxin 7. Successful therapy of heart failure with digoxin will result in which one of the following?will result in which one of the following?

A. Decreased heart rate

B. Increased afterload

C. Increased aldosterone

D. Increased renin secretion

E. Increased sympathetic outflow to the heart

8. Which of the following has been shown to 8. Which of the following has been shown to prolong life in patients with chronic congestive prolong life in patients with chronic congestive failure but has a negative inotropic effect on failure but has a negative inotropic effect on cardiac contractility?cardiac contractility?

A. Carvedilol

B. Digoxin

C. Dobutamine

D. Enalapril

E. Furosemide

10. Which of the following is the drug of choice in 10. Which of the following is the drug of choice in treating suicidal overdose of digitoxin?treating suicidal overdose of digitoxin?

A. Digoxin antibodies

B. Lidocaine

C. Magnesium

D. Phenytoin

E. Potassium

Coronary Artery Diseases Coronary Artery Diseases (CAD)(CAD)

ororIschemic Heart Diseases Ischemic Heart Diseases

(IHD)(IHD)

Coronary Artery DiseasesCoronary Artery Diseases

Coronary Artery DiseasesCoronary Artery Diseases• occur when the

coronary arteries become so narrowed by atherosclerosis that they are unable to deliver sufficient blood to the heart muscle– Localized areas of

thickened tunica intima associated with accumulation of smooth muscle cells and lipids, principally cholesterol

Coronary Artery DiseasesCoronary Artery Diseases• Angina Pectoris

– episodic, reversible oxygen insufficiency– severe chest pains generally radiating to the left shoulder and

down the inner side of the arm– usually precipitated by physical exertion or emotional stress

• Myocardial Ischemia– deprivation of oxygen to a portion of the myocardium (reversible)

• Myocardial Infarction– severe, prolonged deprivation of oxygen to a portion of the

myocardium that leads to myocardial tissue necrosis (reversible)

Risks FactorsRisks Factors

• Smoking• Hypertension• Diabetes Mellitus• Males >45 yo; Females >55 yo• Dyslipidemia• Obesity• Family history of CAD• Others:

– sedentary lifestyle, hx of chronic inflammation

EtiologyEtiology• Decreased blood flow

– Atherosclerosis – most common cause– Coronary artery spasm – sustained contraction of 1 or

more coronary arteries Prinzmetal’s angina or MI– Traumatic injury – that interferes with blood flow in the

heart– Embolic events – can abruptly restrict oxygen supply

• Increased oxygen demand– Exertion and emotional stress sympathetic

stimulation increase HR• Reduced blood oxygenation

– Reduced O2-carrying capacity (anemia)

Angina PectorisAngina Pectoris

• chest pain

• a symptom of myocardial ischemia in the absence of an infaction

• Types:– Stable Angina

• aka: Classical Angina• develops on exertion and lasts for < 5 min• relieved with rest or drugs• 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

• Types:– Angina Decubitus

• nocturnal angina• occurs in recumbent position

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

Drugs for Angina PectorisDrugs for Angina Pectoris

• Nitrates

• Beta Blockers

• Calcium Channel Blockers

NitratesNitrates

• MOA: metabolized into NO in the body, leading to peripheral vasodilation

• examples– amyl nitrite– nitroglycerin– isosorbide dinitrate (ISDN)– isosorbide mononitrate (ISMN)

• SE:– throbbing headache, tolerance

• drug of choice for stable angina

• MOA: decreases HR & contractility reduce oxygen demand (rest and during exertion) reduce arterial BP

CCBsCCBs• MOA

– inhibits calcium influx into vascular smooth muscle & heart muscles increased blood flow enhance oxygen supply prevent and reverse coronary spasm

– dilates peripheral arterioles & reduce contractility reduce total peripheral vascular 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 AgentsOther Agents

• Morphine– Unstable angina with no CI; IV doses given

after 3 sublingual nitroglycerin 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 InfarctionMyocardial Infarction

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

Cellular ischemia

Tissue injury

Tissue necrosis

Note:Damage on myocardial tissue is not reversible myocardial tissue dies

Myocardial Infarction (MI)Myocardial Infarction (MI)

• persistent, severe chest pain or pressure “crushing”, “squeezing” or heavy “an elephant sitting on the chest”

Signs and Symptoms of MISigns and Symptoms of MI

• Compared to angina – Pain persists longer– Not relieved by rest or nitroglycerin– Sense of impending doom, sweating, nausea,

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

Drugs for MIDrugs for MI

IMMEDIATE TREATMENT FOR

MYOCARDIAL INFARCTION

MORPHINE

OXYGEN

NITROGLYCERINE

Drugs for MIDrugs for MI

• Nitrates

• Oxygen

• Morphine

• Thrombolytic Agents

NitratesNitrates• 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

OxygenOxygen

• for patients who have chest pain and who may be ischemic

• improve oxygenation of myocardium

MorphineMorphine

• MOA– causes venous pooling and reduces preload,

cardiac workload, and oxygen consumption– IV until pain is relieved

• Indication– DOC for MI pain and anxiety

• Precautions– can produce orthostatic hypotension and fainting– monitor for hypotension & signs of resp depression– GI SE: nausea and vomiting; constipation

Thrombolytic AgentsThrombolytic Agents

• MOA:– Lysis of thrombus clot

• The following are given IV within 12 h to restore normal blood flow in an acute MI:– Recombinant t-PA (recombinant tissue-type

plasminogen activator alteplase)– Streptokinase– Anisoylated plasminogen streptokinase activator

complex (APSAC)– Reteplase– Tenecteplase

Post thrombolysis adjunctive Post thrombolysis adjunctive therapytherapy• Aspirin

– prevents platelet aggregation; shown to reduce post-infarct mortality

– also: dipyridamole, ticlopidine, clopidogrel

• Heparin– prevent re-occlusion once a coronary artery has

been opened– not used with streptokinase increased risk of

hemorrhage

• Warfarin– reduce mortality, prevent recurrent MI

Post thrombolysis adjunctive Post thrombolysis adjunctive therapytherapy• Beta Blockers

– if administered early reduce ischemia, reduce potential zone of infarction, decrease oxygen demands, preserve left ventricular function, decrease cardiac workload

• ACE Inhibitors– improve exercise capacity and reduce mortality

in px with CHF; aid in the prevention of progressive ventricular remodelling

• “Statins”– reduced mortality due to MI when used by px to

aggressively lower cholesterol

Post thrombolysis adjunctive Post thrombolysis adjunctive therapytherapy

• Lidocaine– used for px who develop ventricular

arrhythmia

• Calcium Channel Blockers– decrease incidence of reinfarction in px

with non-Q-wave infarcts; not for acute mgt.

Items 1-3. Mr. Green, 60 years old, has Items 1-3. Mr. Green, 60 years old, has severe chest pain when he attempts to carry severe chest pain when he attempts to carry parcels upstairs to his apartment. The pain parcels upstairs to his apartment. The pain rapidly disappears when he rest. A decision rapidly disappears when he rest. A decision is made to treat him with nitroglycerin.is made to treat him with nitroglycerin.

2. In advising Mr. Green about the adverse effects 2. In advising Mr. Green about the adverse effects he may notice, you point out that nitroglycerin in he may notice, you point out that nitroglycerin in moderate doses often produces certain symptoms. moderate doses often produces certain symptoms. These toxicities result from all of the following These toxicities result from all of the following EXCEPTEXCEPT

A. Meningeal vasodilation

B. Reflex tachycardia

C. Hypotension

D. Methemoglobinemia

3. 2 years later, Mr. Green returns complaining 3. 2 years later, Mr. Green returns complaining that his nitroglycerin works well when he takes it that his nitroglycerin works well when he takes it for an acute attack but that he is having frequent for an acute attack but that he is having frequent attacks now and would like something to prevent attacks now and would like something to prevent them. Useful drugs for the prophylaxis of angina of them. Useful drugs for the prophylaxis of angina of effort include which one of the following?effort include which one of the following?

A. Amyl nitrite

B. Diltiazem

C. Sublingual isosorbide dinitrate

D. Sublingual nitroglycerin

4. The antianginal effect of propanolol may be 4. The antianginal effect of propanolol may be attributed to which one of the following?attributed to which one of the following?

A. Block of exercise-induced tachycardia

B. Decreased end-diastolic ventricular volume

C. Dilation of constricted coronary vessels

D. Increased cardiac force

E. Decreases heart rate

5. The major common determinant of myocardial 5. The major common determinant of myocardial oxygen consumption isoxygen consumption is

A. Blood volume

B. Cardiac output

C. Diastolic blood pressure

D. Heart rate

E. Myocardial fiber tension

6. You are considering therapeutic options for a 6. You are considering therapeutic options for a new patient who presents with hypertension and new patient who presents with hypertension and angina. In considering adverse effects, you note angina. In considering adverse effects, you note that an adverse effect which nitroglycerin, that an adverse effect which nitroglycerin, prazosin, and ganglion blockers have in common prazosin, and ganglion blockers have in common isis

A. Bradycardia

B. Impaired sexual function

C. Lupus erythematosus syndrome

D. Orthostatic hypotension

E. Throbbing headache

7. A patient is admitted to the emergency 7. A patient is admitted to the emergency department following a drug overdose. He is noted department following a drug overdose. He is noted to have severe tachycardia. He has been receiving to have severe tachycardia. He has been receiving therapy for hypertension and angina. A drug that therapy for hypertension and angina. A drug that often causes tachycardia isoften causes tachycardia is

A. Diltiazem

B. Guanethidine

C. Isosorbide dinitrate

D. Propanolol

E. Verapamil

ArrhythmiasArrhythmias

• deviations from normal heartbeat pattern– abnormalities in impulse formation

– conduction disturbances

ArrhythmiasArrhythmias

• The heart is endowed with a specialized electrogenic system for:– Generating rhythmical impulses to

cause rhythmical contraction of the heart muscle

– Conducting these impulses rapidly throughout the heart

Cardiac Conduction SystemCardiac Conduction System

• Sinoatrial node – Pacemaker of the heart– 60 – 100 beats/min– Location: posterior wall of the right atrium near the

entrance of the superior vena cava

• Atrioventricular node– Location: posterior septal wall of the right atrium

immediately behind the tricuspid valve– Connects the atrial and ventricular conduction

systems

Cardiac Conduction SystemCardiac Conduction System• Bundle of His (AV bundle)

– Delayed transmission• Delays in transmission provide mechanical

advantage atria complete ejection of blood before initiating ventricular contraction

• Purkinje system– 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

Cardiac Conduction SystemCardiac Conduction System

Myocardial Action PotentialMyocardial 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 PotentialResting Membrane Potential• membrane is

relatively permeable to K+

• charges of opposite polarity become aligned along the membrane

(+) outside

(-) inside

DepolarizationDepolarization• cell membrane

suddenly becomes selectively permeable to current-carrying ions such as Na+

• Na+ enters cell sharp rise of intracellular potential to positivity while K+ migrate outside

RepolarizationRepolarization• re-establishment of the

resting potential• slower process;

increased permeability to K+ K+ ions move outward removes (+) charges inside the cell– The Na-K pump helps

to preserve the intracellular negativity by moving 3 Na+ ions out of the cell in exchange for 2 K+ ions.

• Five Phases:Phase 0: Rapid Depolarization

Phase 1: Early Rapid Repolarization

Phase 2: Plateau Phase of Repolarization

Phase 3: Final Rapid Repolarization

Phase 4: Slow Depolarization

Electrocardiography (ECG)Electrocardiography (ECG)

• A recording of the electrical activity of the heart during depolarization-repolarization– P wave

• SA node and atrial depolarization

– QRS complex• Ventricular depolarization

– T wave• Ventricular repolarization

– Isoelectric line between P wave & Q wave• Depolarization of the AV node, bundle

branches, Purkinje system

– ST segment• Absolute refractory period; part of ventricular

repolarization

– Atrial repolarization occurs during ventricular depolarization and is hidden in the QRS complex.

Cardiac arrhythmia may Cardiac arrhythmia may cause the heart tocause the heart to• To beat too slowly

• To beat too rapidly

• To respond to impulses originating from sites other than the SA node

• To respond to impulses travelling along extra pathways

CAUSES OF ARRHYTHMIACAUSES OF ARRHYTHMIA

• Abnormal automaticity

• Effect of drug

• Abnormalities in impulse conduction

Action Potential & ECGAction Potential & ECG

Classification of ArrhythmiasClassification 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 PatternNormal ECG Pattern

ECG Patterns of ArrhythmiasECG Patterns of Arrhythmias

Anti-arrhythmic AgentsAnti-arrhythmic Agents

AntiarrhythmicsAntiarrhythmicsSodium Channel Blockers

Class IA

Class IB

Class IC

•Quinidine•Procainamide•Disopyramide

•Lidocaine•Tocainide•Mexiletine•Phenytoin

•Flecainide•Propafenone•Moricizine

Beta Adrenergic Blockers Class II•Propranolol•Esmolol•Acebutolol

Potassium Channel Blockers Class III•Amiodarone•Sotalol•Bretylium

Calcium Channel Blockers Class IV•Verapamil•Diltiazem

CLASS 1ACLASS 1A

• Slows phase 0 depolarization

• Prolong action potential

• Slow conduction

CLASS 1BCLASS 1B

• Shortens phase 3 repolarization

• Decrease duration of action potential

CLASS 1CCLASS 1C

• Markedly slow phase 0 depolarization

CLASS IICLASS II

• Suppresses phase 4 depolarization

CLASS IIICLASS III

• Prolongs phase 3 repolarization

CLASS IVCLASS IV

• Slows phase 4 spontaneous depolarization

• Shorten action potential

Miscellaneous AgentsMiscellaneous Agents

• Adenosine

• MgSO4

TYPE OF ARRHYTHMIA TYPE OF ARRHYTHMIA AND DRUGSAND DRUGS• Atrial flutter

• Class 1 – quinidine

• Class II - propranolol

• Class IV – verapamil

• Others - digoxin

• Atrial fibrillation

• 1- quinidine

• 2- propranolol

• 3- amniodarone

• 4 – anticoagulant

• AV –NODAL REENTRY

• PROPRANOLOL

• VERAPAMIL

• DIGOXIN

• ACUTE SUPRAVENTRICULAR TACHYCARDIA

• Verapamil

• adenosine

• ACUTE VENTRICULAR TACHYCARDIA

• Lidocaine

• Sotalol

• Amniodarone

• VENTRICULAR FIBBRILLATION

• Lidocaine

• Bretylium

• Amnidarone

• epinephrine

ProcainamideProcainamide

• can cause SLE (Systemic Lupus Erythematosus)

QuinidineQuinidine

• drug interaction with digoxin

• can increase serum levels of digoxin by at least 2x

LidocaineLidocaine

• anesthetic

• DOC for digitalis-induced arrhythmias

PropafenonePropafenone

• for acute atrial fibrillation

AmiodaroneAmiodarone

• iodine-containing molecule

• first-line treatment for almost all types of Ventricular Tachycardia and Atrial Fibrillation

VerapamilVerapamil

• alternative for acute SVT (Supraventricular Tachycardia)

AdenosineAdenosine

• first-line drug for acute SVT

Drugs for Coagulation Drugs for Coagulation DisordersDisorders

Clotting MechanismClotting Mechanism• inciting event: epithelial vascular injury• followed by:

– migration of platelets to the site of injury– platelet aggregation

• aka: primary hemostasis• white thrombus• platelet plug• unstable clot

– deposition of fibrin over the plug– attachment of other blood cells

• aka: secondary hemostasis• red thrombus• stable clot

Clotting MechanismClotting Mechanism

• thrombus– clot that adheres to a blood vessel wall

• embolus– detached thrombus

Clotting MechanismClotting Mechanism

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

Coagulation CascadeCoagulation Cascade

Drugs for Coagulation Drugs for Coagulation DisordersDisorders

Anticoagulants

Anti-Platelet Drugs

Fibrinolytic Agents

Pro-coagulant Drugs

AnticoagulantsAnticoagulants

• Site of action– synthesis of or directly against clotting factors (II,

• Types:– Parenteral

• Hirudin, Heparin

– Oral• Dicumarol, Warfarin

Parenteral AnticoagulantsParenteral Anticoagulants

HirudinHirudin

• obtained from medicinal leeches (Hirudo medicinalis)

• used in the management of HIT (Heparin-Induced Thrombocytopenia)

• Lepirudin – produced by recombinant DNA technology

HeparinHeparin• heterogeneous mixture of sulfated

mucopolysaccharides– Regular or Unfractionated heparin

• activates antithrombin III which in turn inactivates thrombin (IIa); Ixa, Xa, Xia

• SQ/IV

– Low MW Heparin• Inactivates IIa and Xa• Enoxaparin,fraxiparin,dalteparin• SQ

HeparinHeparin• Clinical use

– initiation of anticoagulant therapy– mgt of MI or unstable angina– tx & prevention of pulmonary embolism & DVT– anticoagulation in pregnancy (APAS)

• SE:– hemorrhage (monitor aPTT – activated partial

thromboplastin time) 2-2.5x or delay of 50 – 80 secs except SQ

– Thrombocytopenia– osteoporosis– antidote: protamine sulfate

CONTRAINDICATIONSCONTRAINDICATIONS

• Hypersensitivity

• Active bleeding

• Thrombocytopenia

• Severe HPN

• Active TB

Oral AnticoagulantsOral Anticoagulants

• DICUMAROL

• aka: bis-hydroxycoumarin

• high incidence of GI side-effects

• PHENPROCOUMON

• INDANEDIONES ex: anisindione,phenindione

• WARFARIN

• MOA: blocks carboxylation of X, IX,VII,II

• ONSET: 8 – 12 hrs maximum after 1 to 3days

• delay in the anticoagulant effect• Clinical use

– 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• Antidote: Vit K, FFP

SE:SE:

• Hemorrhagic dse of the newborn

• Teratogenic: abnormal bone formation

• Cutaneous necrosis

• Purple toe syndrome

• Alopecia, urticaria,dermatitis

Anti-Platelet DrugsAnti-Platelet Drugs

• Thromboxane Synthesis Inhibitors

• Phosphodiesterase Inhibitors

• ADP Inhibitors

• Glycoprotein IIb/IIIa Inhibitors

Thromboxane Synthesis Thromboxane Synthesis InhibitorsInhibitors• Irreversibly acetylates COX- inhibition

of TXA2 synthesis, lasts for 8 – 10 days

• Aspirin– primary prophylaxis for MI

– secondary prophylaxis for MI and stroke

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors

• Dypiridamole– given together with antiplatelet;

ineffective when alone

– Inc CAMP

– SE: coronary steal phenomenon

ADP Inhibitors - ADP Inhibitors - ThienopyridinesThienopyridines• Ticlopidine

– SE: thrombocytopenia purpura,neutropenia,

– n/v,diarrhea

• Clopidogrel– safer than ticlopidine

Glycoprotein InhibitorsGlycoprotein Inhibitors

• Abciximab

• Eptifibatide

• Tirofiban

Fibrinolytic AgentsFibrinolytic Agents

Fibrinolytic Agents / Fibrinolytic Agents / ThrombolyticsThrombolytics• MOA

– catalyse activation of plasminogen to plasmin(serine protease)

• Use– mgt of severe pulmonary embolism– 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 DrugsPro-coagulant Drugs

• Mgt of bleeding disorders– Vitamin K

• K1 – phytonadione (in plants, useful 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)

• used to decrease risk of post surgery & post dental bleeding

Drugs for DyslipidemiaDrugs for Dyslipidemia

DyslipidemiaDyslipidemia

• Hypercholesterolemia (inc LDL, dec HDL)

• Hypertriglyceridemia (inc TG, ~ inc VLDL, chylomicrons)

• Liver– Only organ in the body that efficiently

uses cholesterol• Converts it to bile salts

Cholesterol SynthesisCholesterol Synthesis

HMG-CoA Mevalonate Cholesterol

HMG-CoA Reductase

Cholesterol Source–Diet (exogenous)–Endogenous

hydroxymethylglutaryl- Coenzyme A (HMG-CoA)

AtherosclerosisAtherosclerosis

Condition associated with cholesterol deposition in vascular smooth muscles (arthroma) with consequent narrowing of the lumen of the affected blood vessels

• Could lead to…– CAD

– Cerebrovascular disease

– Aortic disease

– Renal artery disease

• Major Risk factors– Age (males: > 45;

females: > 55)– Smoking– DM– HPN– Dyslipidemia– Obesity– Family history of

premature heart attack

• Minor Risk Factors– Chronic infection– Sedentary lifestyle

• Modifiable Risk Factors– By therapy– By lifestyle change

Drugs for DyslipidemiaDrugs for Dyslipidemia

• HMG-CoA Reductase Inhibitors

• Nicotinic Acid

• Bile Acid Sequesterants

• Fibric Acid Derivatives

• Probucol

HMG-CoA Reductase HMG-CoA Reductase InhibitorsInhibitors• “-statins”

• MOA: inhibit the enzyme HMG-CoA Reductase, thereby inhibiting the first step (rate-limiting step) in cholesterol synthesis

• first-line drugs for dyslipidemia

• Diurnal Pattern of Cholesterol Synthesis– means that the biosynthesis of

cholesterol in the body occurs at night

– thus most statins are given at bedtime (esp the short-acting ones)

HMG-CoA Reductase HMG-CoA Reductase InhibitorsInhibitors

HMG-CoA Reductase HMG-CoA Reductase InhibitorsInhibitors• Short-acting

– simvastatin– lovastatin– fluvastatin

• Long-acting– atorvastatin– rosuvastatin Long-acting statins can

be given any time of the day.

• SE:– hepatotoxicity

– myositis

– rhabdomyolysis (muscle wasting)

HMG-CoA Reductase HMG-CoA Reductase InhibitorsInhibitors

Nicotinic AcidNicotinic Acid

• unknown MOA

• used in the management of hypertriglyceridemia

• SE: flushing (due to percutaneous vasodilation), myositis

Bile Acid SequesterantsBile Acid Sequesterants

• aka: Bile Acid – Binding Resins

• MOA: Inhibit reabsorption of bile acid

• since liver must maintain a certain amount of bile, it will synthesize bile from endogenous cholesterol when bile levels go low

Bile Acid SequesterantsBile Acid Sequesterants

• Cholestyramine

• Colestipol

• SE:– constipation– impaired absorption of certain drugs– may increase incidence / risk of biliary

stone formation

Fibric Acid DerivativesFibric Acid Derivatives

• MOA: stimulate lipoprotein lipase which decreases triglycerides

• first-line drug in hypertriglyceridemia

• Gemfibrozil• Fenofibrate• Clofibrate (withdrawn)

Fibric Acid DerivativesFibric Acid Derivatives

• SE:– myositis

– rhabdomyolysis

– increase risk of bile stone formation

– hepatobiliary cancer (Clofibrate)

ProbucolProbucol

• MOA: anti-oxidant

• SE: – increase risk of arrhythmia

– produces fetid odor

Ok, before we end our Ok, before we end our lecture, quiz muna tayo… lecture, quiz muna tayo…

Question 1:Question 1:

• Which enzyme is responsible for the conversion of Angiotensin I into the active form Angiotensin II?

A. Renin

B. ACE

C. HMG-CoA

D. StreptokinaseB

Question 2:Question 2:• A 55 y/o male patient was diagnosed to

have uncomplicated HTN. Which of the following drugs would most likely be given to him?

A. Thiazide diuretic + Beta Blocker

B. ACE Inhibitor

C. CCB + ACE Inhibitor

D. ACEi + ARBA

• From the list of anti-hypertensive drugs below, select the one most likely to lower blood sugar:

A. Prazosin

B. Nifedipine

C. Propranolol

D. Hydralazine

E. Labetalol C

• Which of the following conditions predisposes a patient taking digitalis into arrhythmia?

A. hypocalcemia

B. decreased heart rate

C. hyponatremia

D. hypokalemia D

• All of the following mechanisms of action correctly match a drug, EXCEPT:

A. Quinidine: blocks Na+ channels

B. Bretylium: blocks K+ channels

C. Propranolol: blocks β-receptors

D. Procainamide: blocks K+ channelsD

• Which of the following adverse effects is associated with nitrates?

A. nausea

B. throbbing headache

C. sexual dysfunction

D. anemiaB

• A patient experienced orthostatic hypotension after taking the first dose of her drug. She most likely took:

A. Labetalol

B. Valdesartan

C. Prazosin

D. DigoxinC

• Mrs. G. R. is a hypertensive patient under therapy. After some time, she developed Lupus-like symptoms. Which of the ff drugs may have cause this?

A. Hydralazine

B. Losartan

C. Furosemide

D. Metoprolol A

• Which of the following antagonizes the co-factor functions of Vitamin K?

A. Tranexamic acid

B. Heparin

C. Warfarin

D. HirudinC

• The following drugs for dyslipidemia can cause rhabdomyolysis, EXCEPT:

A. simvastatin

B. atorvastatin

C. colestipol

D. fenofibrateC

““The only thing greater The only thing greater than the power of the than the power of the

mind is the courage of the mind is the courage of the heart.”heart.”

- from the movie, - from the movie, A Beautiful MindA Beautiful Mind

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