clinical pharmacology for second years

7/31/2019 Clinical Pharmacology for Second Years

1/55

Click to edit Master subtitle style

5/24/12

Clinical Pharmacology for

Second Years


2/55


5/24/12

Heart Failure


3/55

5/24/12

Compensatory physiological responses inCHF


4/55

5/24/12

If these mechanisms adequately restore cardiac output,

the

heart failure is said to be compensated.

However, these compensations increase the work of

the

heart and contribute to further decline in cardiac

performance. If the adaptive mechanisms fail to maintain cardiac

output,

the heart failure is termed decompensated.

Decompensated heart failure


5/55

5/24/12

Drugs commonly used in management of HF

1. Angiotensin-Converting Enzyme (ACE) Inhibitors: Captopril

3. Diuretics: Thiazides (eg, hydrochlorothiazide) and

furosemide

4. Inotropic-cardiotonic drugs: Digoxin, Inamrinone andNesiritide

5. Aldosterone Antagonist:Spironolactone

6. Vasodialators: Nitrates, hzdralayine and isosorbide

dinitrate7. Beta adrenergic blocking agents: Propranolol, atenolol,metoprolol

2. Angiotensin II receptor blockers: Losartan, candesartan, irbesartan

8. Adrenergics : Dopamine or dobutamine


6/55

5/24/12

Angiotensin- Converting Enzyme

(ACE) Inhibitors


7/55

5/24/12

Introduction

Treatment of hypertension and heart failure

Captopril and enalapril the fore-runners, followed by several

others such as perindopril, lisinopril, cilazapril, quinapril,

fosinopril, ramipril, trandolapril and zofenopril

Angiotensin Converting Enzyme Inhibitors (ACE-I)


8/55

5/24/12

Mechanism of action of ACE -I


9/55

5/24/12

ACE inhibitors inhibit the conversion of Angiotensin I to

Angiotensin II, which results in vasodilation and less sodium

and water retention via the kidneys.

Angiotensin converting enzyme inhibitors work best when the

renin-angiotensin system is activated

Mechanism of action of ACE -I


10/55

5/24/12

IndividualMembers

1.Captopril

- Was the first ACE-inhibitor to become available

- Characterized by a much shorter half-life than other ACE inhibitors (2 hs)

2.Enalapril

-.Differs from captopril in that it is a prodrug, converted to the

active enalaprilic acid during its first passage through the liver.

- enalaprilic acid has a half life of approximately 10 hours compared with two

hours for captopril.More recently released ACE-inhibitors

.longer elimination half-lives.

.Otherwise, similar in terms of their clinical properties and side effects.



11/55

5/24/12

Pharmacokinetics

Poor relationship between plasma concentration of ACE inhibitor and its

action action dependent to large extent on the state of activation of the

renin-angiotensin system (RAS)

Bioavailability varies between 25 and 80%

All excreted via the kidneys but some also undergo hepatic metabolism,

such as fosinopril, perindopril, ramipril, spirapril and trandolapril

Captopril has a short half-life, therefore dosing 2-3 times daily is required.

Most others have half-lives in excess of 10 hours.

Captopril bioavailability is reduced by 30-40% if co-administered with food.



12/55

5/24/12

Clinical Uses

Hypertension

Cardiac Failure Diabetes

Myocardial infarction

1. Cardiac Failure Prolong survival as well as improve exercise tolerance and quality of life

Reduce the mortality of moderate to severe cardiac failure by 20-30%

Delay progression of heart failure in those with asymptomatic left

ventricular dysfunction

Introduce with caution to avoid hypotension, test dose and monitor BP,

increase dose slowly if tolerated.



13/55

5/24/12

Clinical Uses

2. Hypertension

Relatively weak anti-hypertensive effect when administered alone.Synergistic when administered with diuretics or vasodilators.

First-line agents in those with concomitant heart failure or type I diabetes

3. Diabetes

Reduce proteinuria and slow the progression of nephropathy in diabetes

Used as first-line therapy in diabetics with hypertension

Increasingly as first-line therapy in diabetics with early renal disease

who are normotensive

4. Myocardial Infarction

ACE inhibitors improve survival after MI in those with left ventricular failure

(even if transient) - Study - 26% reduction in mortality



14/55

5/24/12

Adverse Effects

First dose hypotension -more likely if RAS activated i.e. elderly, sodium

and water depletion, diuretic use, renal artery stenosis.

Initiate therapy with a test dose.

Exacerbation of hypotension

Renal failure - 0.5-1% Cough -20%

Rash, taste disturbance, neutropenia

Angioedema - rare but life-threatening

Reproductive effects -oligohydramnios, delayed fetal growth and decreased

fetal survival



15/55

5/24/12

DRUG INTERACTIONS

Potassium-sparing diuretics - Severe hyperkalaemia may result if these

drugs are used in combination with potassium sparing diuretics

(eg amiloride) especially if the patient has some pre-existing degree of

renal insufficiency.

Beta-blockers : because beta blockers suppress renin release, they

reduce sensitivity to the effect of ACE-inhibitors.

Diuretics : potentiate the hypotensive activity of ACE inhibitors.



16/55

5/24/12

Mode of Action

Competitively block binding of Angiotensin II (AT II) to ATII receptors

Blocks the vasoconstrictor and growth-promoting effects of AT II

Reduce sodium reabsorption and aldosterone release.

Available agents

Losartan, candesartan, irbesartan

Pharmacokinetics

Oral bioavailability of losartan 33%, therefore considerable FPM

Undergoes hepatic metabolism so reduce dose in hepatic dysfunction

Once daily dosing with all agents


17/55

5/24/12

Clinical uses

Hypertension

Similar efficacy to ACE inhibitors and beta-blockers

Reduces blood pressure without any change in heart rate

Synergistic with thiazides

Alternative to those who have ACE inhibitor intolerance

CHF, post-MI, diabetic nephropathy - studies ongoing

Adverse Effects

Similar to ACE inhibitors but cough less frequent

Avoid during pregnancy


18/55

5/24/12


2. Diuretics

Diuretics are used in treating both acute and chronic HF.

Thiazides (eg, hydrochlorothiazide) can be used for mild

diuresis in clients with normal renal function;

loop diuretics (eg, furosemide) should be used in clients who

need strong diuresis or who have impaired renal function.


19/55

5/24/12

3. Cadiotonic-inotropicdrugs


20/55

5/24/12

What are cadiotonic-inotropic drugs?

Inotropics and cardiotonics are medications that increase the strength

of the muscle contractions that pump blood from the heart.They are mainly used for treatment for heart failure.

What are the different classes of inotropics?1.Digitalis glycosides (Mainly Digoxine)

2.Phosphodiestrase inhibitors e.g Inamrinone (Inocor), and milrinone IV

(Primacor)

3. Human Natriuretic Peptide B-type e.g Nesiritide (Natrecor)

4. Endothelin Receptor Antagonists

A Di i


21/55

5/24/12

Pharmacology of digoxin on CVS: Positive inotropic action - inhibits Na+/K+ ATPase Suppression of sympathetic nervous system activity Increase of parasympathetic activity. Negative chronotropic effect

Actions in Heart Failure In HF, digoxin exerts a cardiotonic or positive inotropic effect that improves

the pumping ability of the heart. Increased myocardial contractility allows the ventricles to empty more

completely with each heartbeat. Improved cardiac output leads to decrease in all the following:

heart size, heart rate, end-systolic and end-diastolic

pressures, vasoconstriction, sympathetic nerve

stimulation, and venous congestion.

A. Digoxin(Lanoxin)


22/55

5/24/12 Digoxin indirectly increases intracellular calcium levels by binding

to the Na-K-ATPase

Mechanism of action of digoxin

(Na-K-ATPase), an enzyme in cardiac cellmembranes that stimulates the movementof sodium out of myocardial cells aftercontraction.

Cardiac cellmembraneNa-K-ATPase


23/55

5/24/12

Mechanism of action of digoxin in arrhythmia

In atrial dysrhythmias, digoxin slows the rate of ventricular contraction

(negative chronotropic effect). This effect is caused by several factors:

1. First, digoxin has a direct depressant effect on cardiac conduction

tissues, especially the atrioventricular node. This action decreases

the number of electrical impulses allowed to reach the ventricles from

supraventricular sources.

2. Second, digoxin indirectly stimulates the vagus nerve.

3. Third, increased efficiency of myocardial contraction and vagal stimulation

decrease compensatory tachycardia that results from the sympathetic

nervous system in response to inadequate circulation.


24/55

5/24/12

Medium lipid solubility and is relatively water soluble

Oral availability 70%

Protein-binding 20-40% Large volume of distribution and high concentrations are found in the

myocardium, brain, liver, and skeletal muscle

It also crosses the placenta, and serum levels in neonates are similar to

those in the mother. 20% metabolized - renal excretion 60%, largely unchanged

Dosage must be reduced in the presence of renal failure to prevent drug

accumulation and toxicity.

Half-life 36-40 hours with normal renal function Narrow therapeutic range 0.8-2.0 ng/ml

Therapeutic serum levels of digoxin are 0.5 to 2 ng/mL; toxic serum levels

are above 2 ng/mL. However, toxicity may occur at virtually any serum

level.

Pharmacokinetics of digoxin


25/55

5/24/12

Digoxin Dosages

Oral or intravenous

Loading dose for rapid "digitalization" only if patient can be monitored

closely for toxicity.

Steady-state plasma levels take about 7 days to achieve due to slow

elimination, longer if renal impairment.

Usual maintenance dose 0.125-0.25 mg/day Trough plasma levels to monitor for toxicity

Therapeutic Uses of Digoxin

Management of HF,

Atrial fibrillation, and atrial flutter.


26/55

5/24/12

Contraindications to Digoxin use

Digoxin is contraindicated in:

Severe myocarditis, ventricular tachycardia, or ventricular fibrillation and

must be used cautiously in clients with acute myocardial infarction, heart

block, Wolff-Parkinson-White syndrome (risk of fatal dysrhythmias),

electrolyte imbalances

(hypokalemia, hypomagnesemia, hypercalcemia), and renal impairment

Administration and Digitalization


27/55

5/24/12

Administration and Digitalization

Digoxin is given orally or intravenously (IV).

I.M route is not recommended because pain and muscle necrosis may occur

at injection sites.

When given orally, onset of action occurs in 30 minutes to 2 hrs, and peak

effects occur in approximately 6 hrs.

When given IV, the onset of action occurs within 10 to 30 minutes, and peak

effects occur in 1 to 5 hours.

In the heart, maximum drug effect occurs when a steady-state tissue

concentration has been achieved. This occurs in approximately 1 week

unless loading doses are given for more rapid effects.

Traditionally, a loading dose is called a digitalizing dose.


28/55

5/24/12

Narrow therapeutic range 0.8-2.0 ng/ml

Risk of toxic effects at levels above 2.0 ng/ml

Severe toxicity at levels above 3.5 ng/ml

GIT and CNS S/E are commonest and include anorexia, nausea, vomiting,

diarrhoea, abdominal cramps, visual disturbance, disorientation,

hallucinations and convulsions

Cardiac toxicity includes bradycardia, heart block and ventricular

tachyarrhythmias

Others - gynaecomastia, allergic skin reactions


29/55

5/24/12

Mild to moderate toxicity without serious arrhythmia

Withdrawal of digoxin

Correction of electrolyte disturbance

Moderate to severe toxicity with arrhythmia

Withdrawal of digoxin

Correction of electrolyte disturbance (K+, Ca++ and Mg++)

Cardiac pacing for bradyarrhythmias

Antiarrthymic drugs, lidocaine, phenytoin and propranolol

Digoxin antibodies (Digibind)


30/55

5/24/12

Inamrinone (Inocor), and milrinone IV (Primacor)

Cardiotonic-inotropic agents used in short-term management of acute, severeHF that is not controlled by digoxin, diuretics, and vasodilators.

Mechanism of action

- The drugs increase levels of cyclic adenosine monophosphate (cAMP) in

myocardial cells by inhibiting phosphodiesterase, the enzyme that

normally metabolizes cAMP.

- They also relax vascular smooth muscle to produce vasodilation and

decrease preload and afterload.

B. Phosphodiesterase Inhibitors

cAMP & cGMP Positive inotropiceffect

Vasodialationcyclic nucleotidephosphodiesterases

Degradation

Inamrinonemilrinone


31/55

5/24/12

Inamrinone (Inocor), and milrinone IV (Primacor)

Kinetics and Toxicity

- There is a time delay before the drugs reach therapeutic serum levels as

well as inter-individual variability in therapeutic doses.

- Both drugs are given IV by bolus injection followed by continuous infusion.

- Dose-limiting adverse effects of the drugs include tachycardia, atrial or

ventricular dysrhythmias, and hypotension.

B. Phosphodiesterase Inhibitors

C Human Natriuretic Peptide B type


32/55

5/24/12

Nesiritide (Natrecor)

The first in this class of drugs to be used in the management of acute HF.

Nesiritide is identical to endogenous human B-type natriuretic peptide,

which is secreted primarily by the ventricles in response to fluid and

pressure overload.

Mechanism of action

This drug acts to compensate for deteriorating cardiac function by:

1. Reducing preload and afterload,

2. Increasing diuresis and secretion of sodium,

3. Suppressing the reninangiotensinaldosterone system, and

4. Decreasing secretion of the neurohormones endothelin and

norepinephrine.

Onset of action is immediate with peak effects attained in 15 minutes with

a

C. Human Natriuretic Peptide B-type

D E d th li R t A t i t


33/55

5/24/12

This new class of drugs relaxes blood vessels and improves blood flow by

targeting endothelin-1 (a neurohormone) that is produced in excess in HF.

Endothelin-1 causes blood vessels to constrict, forcing the ailing heart to work

harder to pump blood through the narrowed vessels.

Studies indicate that endothelin antagonist drugs improve heart function,

as measured by cardiac index; animal studies indicate that structural

changes of heart failure (eg, hypertrophy) may be reversed by the drugs.

Currently, one endothelin receptor antagonist, bosentan

(Tracleer), is Food and Drug Administration (FDA) approved

but only for treatment of pulmonary hypertension. Additional data are being collected to support specific indications for these

drugs in the management of heart failure

D. Endothelin Receptor Antagonists


34/55

5/24/12


Adrenergics : Dopamine or dobutamine may be used in acute, severe

heart failure (HF) when circulatory support is required, usually in a critical

care unit.

Aldosterone Antagonist

Increasingly, spironolactone is also being added for clients with moderate to

severe HF.

Spironolactone is an aldosterone antagonist that reduces the aldosterone-

induced retention of sodium and water and impaired vascular function.

Although ACE inhibitors also decrease aldosterone initially, this effect istransient.

Spironolactone is given in a daily dose of 12.5 to 25 mg, along with standard

doses of an ACE inhibitor, a loop diuretic, and usually digoxin.



35/55

5/24/12

Vasodilators

Vasodilators are essential components of treatment regimens

for HF, and the beneficial effects of ACE inhibitors and angiotensin

receptor antagonists stem significantly from their vasodilating effects .

Other vasodilators may also be used.

Venous dilators (eg, nitrates) decrease preload

Arterial dilators (eg, hydralazine) decrease afterload.

Isosorbide dinitrate and hydralazine may be combined to decrease both

preload and afterload. The combination has similar effects to those of an

ACE inhibitor or an ARB, but may not be as well tolerated by clients.

Oral vasodilators usually are used in clients with chronic HF and parenteral

agents are reserved for those who have severe HF or are unable to take oral

medications.



36/55


5/24/12

HYPERTENSION


37/55

5/24/12

Cardiovascular Pharmacology


38/55


5/24/12

Cardiovascular PharmacologyManagement of hypertension

Hypertension is a major health problemwithprevalence rate of 25% among adults,increasing to 50% among those above

60years.Hypertension causes dangerous

complications(Target Organ Damage [TOD]) such

asmyocardial infarction, heart failure,

aorticaneurysm, stroke and renal failure.

These


39/55

5/24/12

The cause of hypertension is unknownand only less than 5% of cases are

secondary to renal diseases,pheochromocytoma, hyperaldosteronism,aortic coarctation, or secondary to drugs

(drug-induced hypertension) such as:- Vasoconstrictors, e.g. phenylephrine or flu

medicine

- Volume expanders, e.g. glucocorticoids,NSAIDs and oral contraceptives.


40/55

Target Blood Pressure


41/55

5/24/12

Lifestyle Modification(Nonpharmacological Management of

Hypertension)

Beneficial in reducing high blood pressureand its complications.

Reduces the dose requirement ofantihypertensive drugs.

Recommended in all hypertensives

initially and with drug therapy.

Lifestyle modification includes :-


42/55

5/24/12

Lifestyle modification includes :

(1). Reduced dietary intake of Na+ andfat, increased Ca2+ and K+ intake,together with diet rich in fruits andvegetables and low-fat dairy products.

(2). Weight reduction for overweightpatients.

(3). Regular physical exercise.

(4). Stopping smoking and reducingalcohol

intake

I Diuretics


43/55

5/24/12

I. Diuretics

Mechanism of Action

Initially, they act by reducing plasmavolume and COP, followed byvasodilation and reduction in peripheral

vascular resistance.

Advantages Reduce mortality, stroke and

cardiovascular complications of

hypertension.

Indications


44/55

5/24/12

Indications 1st choice in uncomplicated hypertension.

Specially indicated in:

1. Systolic hypertension.

2. Hypertension in elderly, black and obesepatients (salt-sensitive).

3. Hypertension complicated with heart failure.

Combined with other antihypertensives topotentiate their effect:

1. Control edema of vasodilators.

2. Reduce plasma volume increase renin andpotentiate the hypotensive action of ACEIs and bblockers, especially in black old patients.

Thi id th f d di ti f


45/55

5/24/12

Thiazides are the preferred diuretics forhypertension because in single dailydose they cause persistent volumedepletion which is required to lower BP;whereas once daily dose of frusemide isinadequate as it causes temporary Na+

loss.

Thiazides tend to retain Ca2+ risk of bone fracture in the elderly.

Side Effects :


46/55

5/24/12

Side Effects-:

1. Metabolic Side Effects

Hyperuricemia - hyperglycemia-hyperlipidemia.

2. Electrolyte Disturbances

Hypokalemia - hyponatremia-hypomagnesemia.


47/55

5/24/12

These side effects can be minimized

by:-a. Low-sodium and high-potassium diet.

b. Using low dose of thiazide especiallywhen combined with b blockers to avoidunfavorable additive metabolic effects.

c. Combination with spironolactone in

cardiac patients to avoid the dangerouseffects of hypokalemia andhypomagnesemia.

d. Combination with ACEIs which ma


48/55

5/24/12

3. Impotence (common).

4. Sulfonamide hypersensitivity reactions(rare) as jaundice, pancreatitis and blood

disorders.

II B Adrenergic Blockers


49/55

5/24/12

II. B-Adrenergic Blockers

Mechanism of Action-: Initially, they decrease COP without

effective drop in BP due to reflex

vasospasm with early increase in TPR. Later, they decrease TPR and BP through:

a. Renin release.

b. NA release by central and peripheraleffects.

c. Prostaglandins causing vasodilation.

Advantages


50/55

5/24/12

Advantages

Decrease cardiovascular mortality &morbidity and protect against coronaryheart disease.

Relatively not expensive.

Indications

Alternative to diuretics as 1st line

treatment of uncomplicated hypertension. Used in young hypertensives where COP is

high.


51/55

5/24/12

Side Effects (Less with B1-selective):

1. Bronchospasm, cold extremities.

2. Metabolic: glucose intolerance,dyslipidemia.

3. Bradycardia, heart block.

4. CNS depression, sense of fatigue.

5. Impotence.


52/55

, ,Adverse Reactions of Calcium Channel


53/55

Adverse Reactions of Calcium ChannelBlockersClass Actions Uses Adverse Reactions

I. Dihydropyridine(DHP)

A. Short-acting

Nifedipine

B. Long-acting

Amlodipine

(5-10 mg once daily)

Vessels > Myocardium > SAN,AVN

DHP induce strong coronary& peripheral vasodilation withless cardiac effect.

Lower BP with reflexsympathetic activation:

- Marked with nifedipine HR.

- Less with amlodipine minimal HR change

1. Hypertension.

2. Peripheralvascular disease(e.g., Raynaud'sphenomenon).

1. Markedtachycardia &

acute myocardialischemia incoronary disease(nifedipine).

2. Hypotension.

3. Headache, flushing,lower limb edema.

II. Non-DHP

A. Phenylalkylamines

Verapamil

(240 mg SR once daily)B. Benzothiazepines

Diltiazem

(Heart-Rate Lowering)

SAN, AVN > Myocardium =Vessels

Inhibition of SAN & AVN HR.

-ve inotropic effect.

Less VD effect lower BPwith mild reflex sympatheticactivation, partially offsettingthe direct cardiac effect

(especially verapamil).

1. SV arrhythmia:

- Prophylaxis of PSVT (nodal reentry).

- HR control in chronicAF.

2. HOCM ( outflowobstruction).

3. Angina pectoris (effortor vasospastic).

4. Hypertension.

1. Bradycardia &heart block.

2. HF (especially with

diltiazem).3. Constipation (only

with verapamil).

Calcium Channel Blockers for


54/55

5/24/12

Calcium Channel Blockers forHypertension

Mechanism of Action

Peripheral VD and TPR.

Diuretic action secondary to renal blood

flow. Aldosterone secretion.

Advantages

No metabolic side effects (no changes inglucose, lipid or uric acid levels).

No affection of sexual activity.

Indications :


55/55

2nd Choice after diuretics in elderlyhypertensives or in isolated systolic

hypertension. 2nd Choice after b blockers in

hypertensives with coronary heart

disease. Hypertension with peripheral vascular

disease (PVD).

Hypertension with renal impairment.

Preparations and Dosage:

clinical pharmacology for second years

Documents