What kind of edema results from left ventricular heart failure?

From right?

Pulmonary congestion/edema

Systemic edema

In a pressure volume loop, decreased contractility, increased end systolic volume, and increased end diastolic volume indicates what

What about increased diastolic pressure with normal contractility?

Left sided heart failure

Right sided heart failure

What are the 3 main diuretics?  What is their mechanism of action?

Which drugs have a risk of hypokalemia?

• Furosemide – inhibits the Na-K-2Cl- co-transporter

in the TALH

• Thiazide – inhibits Na-Cl-co-transporter in the

distal tubule

• Spironolactone – inhibits aldosterone receptor in the

collecting tubules. Also classed as aldosterone

antagonist. It is potassium sparing.

All aim to DECREASE preload

Furosemide (loop diuretic)

Thiazides

A patient who was referred to you is experiencing palpations ever since she started her new drug regimen which includes a thiazide diuretic and digitalis.  How could these drugs cause her problem?

What is commonly seen on EKG in such patients?

Arrhythmias are caused by the relative hypokalemia generated from the diuretic and the inhibition of the Na⁺/K⁺ transporter in the heart.  This action causes an effective hypokalemic crisis, enhancing the duration of the stay of calcium in the cardiomyocytes allowing for extensive contraction.

low or inverted T, decreased ST segment; increased PR interval & U waves, prominent R, atrial or vent. arrhythmia.

What is the mechanism of action of isosorbide dinitrate (nitroglycerin)?

Where does this action prodominantly take place?

What is one adverse effect that affects dosing?

What is the most COMMON side effect?

Enhance the formation of NO

Moreso in veins and venules than arterioles

Tolerance may develop because of loss/saturation of

sulfhydryl groups - decreased release of NO

Headaches

At the correct dosage, what can digitalis do that can aid a patient in CHF (besides acting as a positive inotrope).

What is the most common adverse effect?

Decreased sympathetic activity and increased parasympathetic activity helping the heart work less and demand less oxygen.

Decrease plasma renin concentration due to better perfusion of the renal vessels.

Arrhythmias; causes premature ventricular contractions

Name the bipyridines and describe their mechanism of action.

What results can be seen clinically from this activity?

What are the uses of these drugs, and what are the most concerning adverse effects?

Amrinone and Milrinone

Phosphodiesterase inhibitors; increase cardiomyocyte intracellular cAMP levels, thereby increasing Ca⁺² levels.  Also, appears to have a vasodilation efect.

Incrased cardiac output and reduced peripheral vascular resistance.

• Should not be used in long term therapy

• Used i.v. only in acute heart failure or when chronic heart failure has been exacerbated

Most concern is thrombocytopenia and liver abnormalities, arrhythmias

• Milrinone less likely to cause liver toxicity but still can cause arrhythmias

How and when is dobutamine administered?

What is its mechanism of action?

Given IV and is useful in emergency heart failure where BP is low and renal blood flow is poor.

Produces renal arteriolar vasodilation (via D1 receptors) and thus increases urinary output and relieves edema Positive inotropic effect on cardiac muscle (b1 agonism).

Increase cardiac output and decreased ventricular filling pressure

• Tachyphylaxis can occur.

• With Dobutamine use, angina and

arrhythmias can occur in patients with

coronary artery disease.

What are the contraindications when using beta blockers?

What are the adverse effects?

Heart block, bradicardia, and severe airway disease.  Relatively contraindicated in patients with pulmonary congestion.

Bradycardia, fatigue, exacerbation of preexisting

asthma or diabetes, decreased HDL

cholesterol

• Psychological problems such as nightmares,

depression, memory loss

• GI disturbances and sexual dysfunction may

also occur

What ending on drug names do ACE inhibitors have?

What about ARBs?

What are the seperate and collective effects of these drugs?

-pril

-tan

• ACE inhibitors decrease levels of Angiotensin II

• ARBs inhibit action of Angiotensin II at level of receptor

• Decrease total peripheral resistance and afterload

• Reduce salt and water retention and thus reduce venous return and preload.

• Reduces long-term ventricular remodeling

What are the most common adverse effects seen in patients on ACE inhibitors?

What are the main contraindications of these drugs?

Dry cough and angioedema

• Contraindicated in pregnant women

• Contrainidcated in bilateral renal stenosis or 1-kidney with renal stenosis. (these patients have kidneys which soley rely on the renin pathway)

• Used with caution in patients with renal failure

(creatinine levels > 2.5 mg/dl, GFR < 30 ml/min)

• Hyperkalemia

What drug can be used to decrease the afterload in a patient that cannot tolerate diuretics or ACE inhibitors?

What kind of drug is this?

Hydralazine

Arteriolar vasodilator

What are the 4 classes and criteria of heart failure?

What are the 4 symptomatic criteria?

• Class I: No limitation of physical activity

• Class II: Slight limitation (dyspnea and fatigue present with moderate activity)

• Class III: Marked limitation of activity (dyspnea with minimal activity)

• Class IV: Severe limitation of activity

• Asymptomatic (NYHA class I)

• Symptomatic without history of rest dyspnea

(NYHA class II)

• Symptomatic with history of rest dyspnea

(NYHA class III)

• Symptomatic with rest dyspnea (class IV)

In the management of chronic heart failure, which drug class should be used as a first line?

What if the patient has atrial fibrillation as well?

What about in a patient who has vascular congestion as a result of the chronic heart failure?

ACE inhibitors

Digitalis

Diuretics

In a patient with forward heart failure (SBP less than 100mmHg), what drug is a good idea to use? (Hint, this patient could not tolerate ACE inhibis. or ARBs)

What about in a patient with high filling pressures and symptoms of dyspnea, pulmonary congestion and fatigue?

Hydralazine

Isosorbide dinitrate (nitroglycerin)

What are the typical psychotic drugs?

What is the most typical disorder following long term use of these agents?

Phenothiazines including:
Chlorpromazine[Thorazine]
Thioridazine[Mellaril]
Trifluoperazine[Stelazine]
Fluphenazine[Prolixin]
Perphenazine[Trilafon]
Mesoridazine[Serentil]
Prochlorperazine[Compazine]

Thioxanthene
[More potent]
Thiothixene[Navane]

Butyrophenone
[More potent but more EPS]
Haloperidol [Haldol]

Tardive diskinesia

What is a very dangerous and acutely life threatening possible complication when administering typical antipsychotics?

What treatment must be administered when a patient comes down with this?

Neuroleptic Malignant Syndrome (AKA Malignant hyperthermia)

Diazapam (dantrolene) and a cooling blanket

What are the atypical antipsychotics?

What are the common side effects seen with their usage?

Dibenzapines
Clozapine[Clozaril]
Olanzapine[Zyprexa]
Loxapine[Loxitane]
Quetiapine[Seroquel]

Dihydroinolone
Molindone[Moban]

Benzisoxazoles
Risperidone[Risperdal; Risperdal Consta]
Ziprasidone[Geodon]
Paliperidone[Invega]
Iloperidone[Fanapt]

–Weight gain [olanzapine, clozapine]
–Development of diabetes and risk of hyperglycemia [black box warning]
•Metabolic monitoring as per ADA and APA
–Skin eruptions

Quinolinone (newest)
Aripiprazole[Abilify]

What are the 5 most common antipsychotics in use today?

Which has the highest risk for EPS?

Which has the highest risk for drowsiness and weight gain?

Which has the LOWEST risk for drowsiness?

Neuroleptics

Schizophrenia

What medication is very commonly used in bipolar disorder, and how long does it take to have an effect?

How does this drug work?

Lithium

Takes 2 weeks to lyse an episode.

Mechanism is unclear, but may have to do with ion transport.

When on lithium therapy, what must be carefully monitored?

Why?

Must monitor lithium serum levels.

The blood levels are directly correlated to side effects and efficacy of the drug.

What are the side effects of lithium treatment?

What are some important considerations regarding drug interactions?

–Cardiovascular –widening of QRS
–Renal –diabetes insipidus
–Endocrine –hypothyroidism
–Dermatologic –rash, alopecia
–Hematologic –leukocytosis(without left shift)
–Teratogenic

–NSAIDs, ACE-I will ↑ lithium levels
–Theophylline will ↓ lithium levels
–Diuretics will ↑ levels (any loss of sodium)

What is the first line treatment for bipolar disorder considered to be by many?  (hint: this is a newer treatment)

What are the side effects of this treatment?

antiepileptics, specifically sodium valproate (depakote)

Weight gain, nausea (with a dose that is too high), and abnormal liver function tests (LFTs) if used over long term.

Angina of effort: Caused most often by a fixed obstruction which causes narrowing of coronary artery. When exercise causes an increased demand for myocardial oxygen, there is an episode of myocardial ischemia and angina results. Also called stable angina.

Variant angina (Prinzmetal angina) : Coronary insufficiency caused localized vasospasm of large coronary vessels. Angina occurs at rest or with exercise.

Unstable angina: Complicated pathology. Unstable angina is when angina occurs at rest or when there is a change in the nature of the angina which had previously been stable, or when patients whitout history of angina show frequent and severe angina, Usually caused by thrombosis or ruptured plaque.

Unstable angina possibly due to clot rupture.

Thrombolytic agents; long term therapy should include low dose asprin.

Orally active agents which inhibit the L-type calcium channel, reduce intracellular Ca.

Affects impulse generation in SA node, AV node or calcium dependent action potentials.

Cardiac contractility is reduced
Reduces contractile responses of vascular smooth muscle.  Reduces peripheral vascular resistance and relax/dilates coronary arteries.

Dihydropyridines (Nifedepine, Amlodepine, Nicardepine)

Vascular selective, decreasing afterload. Dilates

coronaries.

Side effects: Hypotension, peripheral edema, flushing, reflex tachycardia.

Uses: For Variant angina - dilatation of coronary arteries (reduce coronary vasospasm).
For Angina of effort to reduce afterload, reduces myocardial oxygen demand.

Verapamil-cardioselective.  Reduces calcium current in AV node and SA node. Blocks calcium current of cardiac cells with slow response action potentials.

Adverse effects: Constipation (most commonly), peripheral edema, bradycardia, hypotension, heart block, heart failure.

Uses: In both angina of effort as well as variant angina
Advantageous in angina with atrial fibrillation, tachycardia or flutter

Diltiazem

 Vasodilates coronary vessels without as much negative inotropic effects as Verapamil.

Cardioselective. (similar to Verapamil).

Adverse effects: Bradycardia, hypotension, peripheral edema, heart block, heart failure.  Will not cause as much reflex tach. as dihydropyradines.

Used in both variant angina as well as angina of effort

Bepridil

Similar cardiac effects as Verapamil but it also blocks potassium channels which results in much greater risk of inducing arrhythmias

Limited usefulness.

A patient in the ER presents with a cocaine overdose.  Although other symptoms are obviously present, you notice him clutching his chest in pain.  What drug should you administer to alleviate his chest pain?

What would you NOT use?

Nitrates, or perhaps Ca⁺² channel blockers due to his vasospastic angina.

Any kind of Beta Blocking agent.

Mr. D has coronary artery disease with 50% occlusion of his LAD. He has chest pains when he walks up the stairs. He also has pulmonary edema secondary to left ventricular systolic failure.

What drugs can be used to alleviate his symptoms?

Major adverse effects of diuretics are

hypokalemia and hyperlipoproteinemia

• High-risk patients who have symptomatic

coronary heart disease, CHF and those taking

digitalis must be protected from hypokalemia.

• The increase in LDL and VLDL cholesterol

caused by Thiazide diuretics may be of

consequence in the incidence of coronary

heart disease. Such adverse effects dosedependent

– less when administered at 12.5

or 6.25 mg/day.

Monotherapy or in conjunction with other

antihypertensive drugs of a different class.

• If used in monotherapy may be best to be used with a

potassium sparing diuretic (e.g amiloride orotassium

spironolactone) or K+ supplementation.

• Given alone, Thiazides can cause a decrease in blood

pressure with as little as 12.5 mg/day. The dose

should not be >25 mg/day, to avoid hypokalemia.

• Should not be given if patients on drugs for ischemic

ventricular fibrillation or polymorphic ventricular

tachycardia (e.g. quinidine).

Thiazide as antihypertensive therapy is

probably best in elderly patients (> 65)

with low renin levels with no overt signs of

renal insufficiency.

Principal toxicity of propranolol is from the blockade

of b-receptors. Important in patients with asthma,

peripheral vascular insufficiency and diabetes.

• Can cause fatigue and bradycardia

• Low incidence of G.I tract disturbances; diarrhea,

constipation, nausea and vomiting.

• Can increase plasma triglycerides and decrease

HDL-cholesterol.

• Does not cause postural hypotension, reflex

tachycardia or salt and water retention

• mild hypertension with high plasma renin, post

myocardial infarction patients and young

hypertensives (<50) with rapid heart rate

• Also used in hypertensives with angina of effort

• moderate or severe hypertension - given with a

thiazide diuretic

• if used alone, less effective than diuretic alone for

treatment of hypertension in elderly

metoprolol (LOPRESSOR), atenolol (generic,

TENORMIN) : b1-selective blocker. Advantageous in

treating hypertensive patients who also suffer from

asthma, diabetes or peripheral vascular disease.

• nadolol (CORGARD), carteolol (CATROL):Nadolol and

carteolol are non-selective b-receptor antagonists.

They can be given once daily because of their

relatively long half-lives.

what are 3 partial beta agonists? 

What are their uses?

Pindolol, Acebutolol and Penbutolol are partial

agonists of b-receptors, i.e. have intrinsic

sympathomimetic activity. Lower BP by decreasing

peripheral vascular resistance but depress cardiac

output or heart rate less than other b-blockers.

• Do not increase serum triglyceride or decrease HDL

• May be beneficial to patients with cardiac failure,

brady-arrhythmias or peripheral vascular disease.

• Preferred in patients who develop symptomatic

bradycardia or postural hypotension with other betablockers.

Adverse effects and toxicity

• Can cause variable amount of postural hypotension

which occurs in first 90 min (first dose effect).

• Causes salt and water retention..

• Can cause positive test for antinuclear factor in serum

Uses

• Hypertensive patients with dyslipidemia

• Moderate hypertension with diuretic and/or b-blocker

• Hypertensives with prostatism

• Decreases peripheral resistance. Reduces

renal vasular resistance. Its mode of action is

through the activation of centrally located a2

receptors (ACTIVATES them!). Thus, it reduces release of

presynaptic norepinephrine. Cardiovascular

reflexes remain intact.

• Its half-life is approximately 2 hrs. Maximal

antihypertensive effect can persist for up to

24 hrs.

moderate hypertension in combination with

thiazide diuretic

hypertension associated with pre-eclampsia

• Long-term use may result in autoantibodies

against Rh locus and positive Coombs test.

• Decreases sympathetic and increases

parasympathetic tone, resulting in blood

pressure lowering and bradycardia. Mode

of action is through activation of a2-

receptors.

• Reduces CO due to decreased heart rate

and relaxation of capacitance vessels.

Reduces blood pressure in the supine

position and rarely causes postural

hypotension. May cause initial increase in

BP

• Dry mouth and sedation are frequent and

may be severe. Concomitant treatment with

tricyclic antidepressants may block

antihypertensive effect of clonidine. Rapid

withdrawal of clonidine may result in lifethreatening

hypertensive crisis.

Use

• Moderate hypertension with thiazide diuretic

Causes direct relaxation of arteriolar smooth

muscle.

• Mechanism is unclear and may be related to

the release of nitric oxide and/or

hyperpolarization of smooth muscle (K+

channel opening).

• Dilates arterioles more than veins. Decrease in

BP is associated with a decrease in vascular

resistance in the coronary, cerebral and renal

circulation.

What are the adverse effects and possibe toxicity of hydralazine?

What are its uses?

Hydralazine-induced vasodilatation is

associated with reflex stimulation of the

sympathetic system - increased heart rate and

contractility, increased plasma renin activity

and fluid retention.

• Adverse effects include headache, nausea,

flushing, hypotension, palpitation, tachycardia,

dizziness and angina.

• If the drug is used alone, there might be salt

and water retention.

• may also cause postural hypotension

• The second type of side effect is caused

by activation of the immune system. Lupus

syndrome is the most common but

symptoms which resemble serum

sickness, hemolytic anemia, vasculitis and

glomerulonephritis occur infrequently.

Drug fever is an uncommon but serious

side effect.

• As 3rd drug in moderate or severe

hypertension

• hypertension associated with pre-eclampsia

What are the side effects of sodium nitroprusside?

What is its most successful use?

• The short-term side effects of nitroprusside are due

to excessive vasodilatation with hypotension and the

consequences thereof.

• Less commonly, toxicity may result from conversion

of nitroprusside to cyanide and thiocyanate.

Concomitant administration of sodium thiosulfate

can prevent accumulation of cyanide in patients who

are receiving higher than usual doses of sodium

nitroprusside. Signs and symptoms of thiocyanate

toxicity include anorexia, nausea, fatigue,

disorientation and toxic psychosis.

Drug of choice in hypertensive emergency

what are the side effects of diazoxide?

When is it best used?

• The two most common side effects are

salt and water retention and

hyperglycemia. Retention of fluid can be

avoided by restriction of salt and water.

• Hyperglycemia results from diazoxide's

capacity to inhibit the secretion of insulin

from pancreatic b-cells.

Drug of choice in hypertensive emergencies

IF accurate infusion pumps are not

available

• especially efficacious in low-renin

hypertension.

• do not cause salt and water retention.

Only the dihydropyridines cause a

mild reflex tachycardia.

Diltiazem 3 2 5 4

Nicardipine 5 0 1 0

Nifedipine 5 1 1 0

Nimodipine 5 1 1 0

Verapamil 4 4 5 5

vasodilation, the suppression of contractility, SA node suppression, and AV node suppression from left to right.

• The dihydropyridines cause the most vascular

side effects including headache, flushing,

dizziness and peripheral edema. The edema

is probably caused by vasodilatation of the

capillaries and increased hydrostatic

pressure.

• Apart from excessive hypotension, verapamil

and diltiazem may cause bradycardia while

verapamil may cause constipation as well

• Verapamil and Diltiazem must be given

with caution to patients who are also

receiving a b-blocker because of the

possible development of AV block or heart

failure.

• They are usually safe to be given to mild

to moderate hypertensive patients with

asthma, hyperlipidemia, diabetes mellitus

and renal dysfunction.

• Variant angina and angina of effort

• Hypertension with high plasma renin

• Congestive heart failure

• Acute MI with left ventricular dysfunction

• Ischemic heart disease

• Diabetic nephropathy

What are the adverse effects of ACE inhibitors?

What type of drug must NEVER be used with ACE inhibitors?

• A substantial fall in blood pressure may occur

in patients with severe hypertension who have

been treated with multidrug regimens that

include diuretics (first dose effect). Less severe

side effects include skin rash and loss of taste

sensation.

• Dry cough is a common side-effect of some

ACE inhibitors.

• Angioedema of the face, extremeties, lips,

glottis and larynx.

• 2 rare but major side effects of ACE

inhibition are proteinuria and neutropenia.

Metabolic side effects are not

encountered. Does not alter carbohydrate

metabolism or plasma concentrations of

uric acid, lipoproteins and cholesterol.

 ACE inhibitors can cause fetal and

neonatal morbidity when administered to

pregnant women especially in the 2nd or

3rd trimesters. Contraindicated in patients

with bilateral renal stenosis.

• The drugs are not to be taken with K+

sparing diuretics.

Advantage of these compounds is that (i) it is

potentially a more selective inhibitor of angiotensin II

metabolism

(ii) cough and angioedema have not

been associated with the Angiotensin receptor

antagonist.

b-adrenergic antagonists should be considered for young

hypertensives and patients with angina pectoris, a history of myocardial infarction and cardiac arrhythmias.

• Ca channel blockers should be considered for

patients who cannot tolerate diuretics or b-

adrenergic antagonists. In general, calcium

channel blockers can be used in patients with

low renin hypertension. Hypertensive patients

with underlying bronchospastic pulmonary

disease are good candidates for this drug.

Patients with a history of cardiac arrhythmias

and those with peripheral vascular disease can

safely be given a Ca2+-channel blocker. Also

patients with variant angina and angina of

effort.

Patients who do not respond to a single

drug can be switched to another drug with

a different mechanism of action. If

treatment with a single drug is not

successful, addition of a second drug from

a different class is appropriate. If two drugs

do not control the blood pressure

adequately, a third drug of a different class

can be added to the existing regimen.

What ion causes phase 0 (rapid upstroke) in the cardiac myocytes of the SA node?

What about in myocytes of the ventricles?

Why is this important?

Ca+2

Na+

This shows how calcium channel blockers work to slow the heart rate.  By acting on the rapid upstroke of the SA node, total heart rate decreases.

Class I action: Sodium channel block 

Class IA: (Quinidine, Procainamide, Disopyramide) 

Class IB: (Lidocaine, Mexiletine, Tocainide)

 Class IC: (Flecainide)

Class II action: Sympathetic drugs (beta blockers)

Class III action: Blocks potassium channel

Class IV action: Block calcium currents.

Out of class IA, IB and IC, which blocks Na⁺ channels the LEAST?

Which blocks these channels the MOST?

Which causes PROLONGED repolarization, and how is this accomplished?

Class IB

Class IC

Class IA by blocking K⁺ channels

What are the class IA antiarrhythmic drugs, and what is each typically used for?

Which causes a very serious complication called "lupus-like syndrome"?

Quinidine

Most common indications are atrial fibrillation and flutter and occasionally ventricular tachycardia.

Procainimide (can cause lupus like syndrome)

Electrophysiologic effects are similar to that of Quinidine. Less anti-muscarinic effects than Quinidine. Does not alter plasma Digoxin levels. Can cause peripheral dilatation due to inhibition of neurotransmission at sympathetic ganglia. Effective for sustained atrial and ventricular arrhythmias 

Can be used during and/or immediately after MI to prevent reentrant arrhythmias.

Disopyramide

Approved only for the treatment of ventricular arrhythmias, although it has been shown to be useful in atrial arrhythmias.  More antimuscarinic effects than quinidine!

Lidocaine

Very effective for suppressing arrhythmias associated with depolarization (e.g. diseased myocardium) but relatively ineffective in normally polarized tissues.  This is because class Ib drugs can act on both activated and de-activated sodium channels. Useful for emergent ventricular arrhythmias.

Can also use Tocainide and Mexiletine as adjuvant therapies with quinidine or sortalol to increase antiarrhythmic efficacy.

Flecainide (only one went over in class)

Effective in suppressing premature ventricular contractions

Life-threatening situations such as paroxysmal supraventricular tachycardias 

Verapamil and diltiazem

Used in reentrant supraventricular tachycardia because these arrhythmias involve the AV node.

Used to suppress both early and delayed after depolarizations.

Has peripheral dilatory activity which may decrease myocardial oxygen demand.

Most common cardiac manifestations of glycoside toxicity include, premature ventricular depolarizations and second degree AV blockade.

Quinidine displaces digoxin from tissue binding sites (minor effect) and reduces renal clearance of digoxin (major effect). Net effect is to raise plasma levels of digoxin and increase possibility of toxicity

NSAIDS also may reduce digoxin clearance.

Other drugs that can reduce clearance

Alprazolam (Xanax) 

Amiodarone (Cordarone) 

Verapamil (Calan)

Which drugs decrease the absorption of digoxin? 

Which drugs speed up its clearance?

Drugs that decrease the serum digoxin concentration by decreasing absorption: 

Antacids 

Cholestyramine (Questran) 

Metoclopramide (Reglan) 

Neomycin 

Drugs that decrease the serum digoxin concentration by increasing nonrenal clearance: 

Rifampin (Rifadin)

A white thrombus (mostly platelets) can form in high pressure arteries. Can reduce blood flow.

A red thrombus can form around a white thrombus in low pressure veins (the red coloring is from red blood cells).

What platelet binding step is KEY in the initiation of thrombus formation?

What binding causes platelet to platelet adhesion?

von Willebrand factor of the endothelium to the GP Ib site on platelets.

GPIIb/IIIa (platelet to platelet)

How can you measure the effacacy of the intrinsic coagulation pathway?

What about the extrinsic?

activated partial thromboplastin time (aPTT)

Prothrombin time

1) Prostacyclin (PGI2)

2) Antithrombin III

3) Proteins C and S

4) Tissue factor pathway inhibitor (TFPI)

5) Tissue-type plasminogen activator (t-PA)

What coagulation factors are inhibited by antithrombin III?

How is this activated?

What is its mechanism of action?

Antithrombin III (ATIII) inhibits factors VIIa, IXa, Xa and thrombin.

Intact endothelium activates ATIII.

ATIII forms a complex with the coagulation factors and inhibits their activity.

i) endothelial injury

ii) abnormal blood flow

iii) hypercoagulability

What 2 types of heparin are commercially availible?

What is the difference between each?

Unfractionated Heparin (Standard heparin): 5 - 30 kD (more commonly used)

Cheap

Low molecular weight heparin (LMWH): 1-5 kD

Expensive!

What is the mechanism of action of Heparin?

Which coagulation factors does this affect?

Antithrombin III circulates in the plasma where it inhibits coagulation factors (thrombin, Xa, IXa, and VIIa). 

Inhibition is due to binding of heparin to ATIII where it induces a conformational change producing a complex with greater affinity for the clotting factors than ATIII alone.

This results in prolongation of the activated partial thromboplastin time (aPTT). 

This affects VIIa, IXa, and Xa

More bioavailability

No need to monitor with labs such as aPTT

subcutaneous injection only

Decreased bleeding risk

Higher anticoagulant effect

Prevention and treatment of deep vein thrombosis

Used to prevent propagation of pulmonary embolism because of its rapid onset of action.

Can be used initially after acute myocardial infarction to prevent systemic thromboembolism

Used to maintain patency in indwelling arterial and venous catheters

Used in initial treatment of unstable angina

Prevention of deep vein thrombosis.

Enoxaparin and Dalteparin: Treatment of acute coronary syndromes

A patient on anticoagulant therapy is shown to have thrombocytopenia.  What is the drug that this patient is on?

How can this be treated?

Heparin (heparin induced thrombocytopenia)

discontinue use or use protamine sulfate. Switch with direct thrombin inhibitors (Lepirudin and Bivalirudin).

What is a major contraindication of LMW heparin?

What other drug has this contraindication?

Renal insufficiency

Fondaparinux (selective Xa inhibitor)

What is the MoA of Warfarin?

How long does it take to be effective?

What is its halflife, and what accounts for this?

blockade is coupled to metabolism of vitamin K

there is an 8-12 h delay (not useful in emergent situations!) in action of warfarin because of the dependence on the degradation rate in the circulation of vitamin K dependent clotting factors

Relatively long half-life (36h). Metabolized by P450 enzymes in liver. Highly bound to albumin. 

Used in conjunction with heparin for prevention as well as treatment of venous thrombosis, pulmonary embolism,

Also MAY be used with aspirin for prevention of venous thrombosis, pulmonary and systemic emboli after MI.

Used to prevent thrombosis and emboli formation in patients with atrial fibrillation (Very common use!)

Warfarin crosses the placenta readily and can cause hemorrhagic fever in the fetus

Bleeding risk

can cause serious birth defects characterized by abnormal bone formation

cutaneous necrosis with reduced activity of protein C sometimes occurs in first weeks of therapy.

Rarely, the above process can cause hemorrhagic infarction of various tissues and venous thrombosis

What are the effects on warfarin with clopidogrel (plavix), amiodarone, broad-spectrum antibiotics, or fluconazole treatment?

What about a high dose of vitamin K?

Increased prothrombin time (increased warfarin effect)

Decreased prothrombin time (decreased warfarin effect competitively)

A patient recovering from an acute MI would benefit from what to prevent clots?

What about long term?

Thrombolytics. Of greater benefit if used in conjunction with aspirin.

Beta-blockers and ACE inhibitors are used for long term treatment AFTER thrombolytic treatment

What is the mechanism of action of streptokinase, what factors does it inhibit, and what are its uses?

How should discontinuation of therapy be achieved?

Combines with plasminogen. Enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin, and hydrolyzes fibrin plugs

Catalyzes the degradation of fibrinogen as well as clotting factors V and VII

Approved for use in acute pulmonary embolism, deep venous thrombosis, acute myocardial infarction, arterial thrombosis. MI therapy instituted within 4h of MI and continued for 1-3 days.  

On discontinuation of treatment, either heparin or oral anticoagulants are administered to prevent rethrombosis

What are the adverse effects of streptokinase?

What is one drug that is more effective, has a similar mechanism of action, and has less of these adverse effects?

Bleeding disorders 

Hypersensitivity reactions (rashes, fever and rarely anaphylaxis) allergic reactions occur in 3 % of cases.

Can result in systemic fibrinolysis

Urokinase (expensive)

What is the most commonly used type of fibronolytic?

What is the benefit of these drugs?

tPA-like drugs:

Alteplase - unmodified  human t-PA

Reteplase – genetically engineered t-PA from which several aminoacids have been deleted.

Longer half-life and increased specificity for thrombus-bound fibrin. 

Tenecteplase – similar to Reteplase.

Anisetreplase -  complex of purified human plasminogen and streptokinase

Long half-life – single iv bolus is effective in achieving reperfusion.

Which drugs act to inhibit the ADP receptor, thereby preventing platelet aggrogation?

What are these drugs useful for?

Ticlopidine and clopidogrel-plavix (more common)

Can be used in conjunction with or as a substitute for asprin.  clopidogrel has generally less side effects

What drug combination can be used to prevent thrombisis in prosthetic heart valves?

What about to prevent thrombotic diathesis?

Phosphodiesterases With Warfarin, used in prevention of thrombosis in prosthetic heart valves.

Phosphodiesterases With Aspirin, used in patients with thrombotic diathesis.

What is the problem in "coronary steal phenomenon"

What drugs have been shown to cause this phenomenon?

Abciximab - humanized monoclonal Ab directed against IIb/IIIa complex. Approved for use in acute coronary syndromes

Eptifibatide and Tirofiban are fibrinogen analogs which reversibly inhibit binding of fibrinogen to receptor

Useful because the specifically target the platelets

Unstable angina or non ST elevation MI: 

Can add Heparin to a low dose asprin regimen. If at high-risk add GPIIb/IIIa inhibitor and/or Clopidogrel. Thrombolytics are NOT used in non ST elevation MI. 

ST elevation MI: 

Thrombolytics added to an asprin regimen or angioplasty. If thrombolytics used, can add Heparin and Clopidogrel. GP IIb/IIIa inhibitor is NOT used (never use with thrombolytics). After angioplasty, Heparin and GPIIb/IIIa inhibitor and/or Clopidogrel can be added. 

1. Low dose aspirin (75-325mg/day)reduces risk of secondary coronary thrombosis. 

2. Nitrates as antianginals are useful to decrease preload.

3. Beta-blockers and 

4. ACE inhibitors can reduce mortality when used after fibrinolytics.

5. Aldosterone antagonist –Spironolactone for patients with ejection fraction < 40%. 

A: Aspirin, ACE inhibitors, antianginals, aldosterone antagonists

B: Beta blockers, blood pressure

C. Cholesterol lowering (and cigarettes)

D: Diet and diabetes control

E: Education and exercise

Mr. J. is 56 year-old man with a history of coronary artery disease. He is awakened at night with chest pains, sweating and shortness of breath. After being taken to ER, he is shown to have ST elevated MI. He is given asprin, alteplase and nitroglycerin 

How does nitroglycerin, aspirin, alteplase help Mr. J?

Asprin prevents thrombi formation (platelets)

alteplase (tPA) is thrombinolytic and degrades fibrin (activates plasmin)

nitroglycerin is for pain and reduced preload