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Acute De-compensated Heart Failure (ADHF)

A. Initial therapy includes the following:
Supplemental O2: for ADHF with decreased O2 saturation.
IV loop diuretic 1: for ADHF + pulmonary edema (except in severe
hypotension or cardiogenic shock).
Vasodilators: e.g. IV nitroglycerin (in non hypotensives). Nitroprusside
may be used if significant afterload reduction is needed 2.
Morphine: in patients with MI (avoid in ADHF without acute MI3)
B. Positive notropes4 : dobutamine or milrinone.
C. Venous thromboembolism prophylaxis: in hospitalized patients.
D. IV vasopressors (eg, phenylephrine): in diastolic HF (i.e. preserved
systolic function) with hypotension or shock (do not give an inotrope).

1
IV bolus dosing, if inadequate, give continuous infusion of loop diuretic & add a
thiazide.
2
Hypertensive emergency, acute aortic or mitral regurgitation.
3
Limited evidence of benefit & increased need for ventilatory support.
4
In systolic HF (e.g. documented low ejection fraction) severe ADHF, hypotension or
shock. Severe cases require mechanical cardiac assistance & ultrafiltration if refractory to
diuretics

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DRUG THERAPY OF SHOCK

Shock occurs when the circulation of arterial blood is inadequate to meet the
tissue metabolic needs (diminished tissue perfusion).

Types
1. Hypovolemic shock: intravascular volume is depleted due to
Hemorrhagic shock (loss of blood).
Burns (loss of plasma)
Vomiting, diarrhea or excessive sweating (loss of fluids &
electrolytes).
2. Cardiogenic shock: mostly due to acute myocardial infarction.
3. Distributive shock: systemic vascular resistance as in:
Septic shock
Anaphylactic
Neurogenic: during spinal anesthesia & psychic trauma.

Hemodynamic profiles of the types of shock

Physiologic
Preload Pump function Afterload Tissue perfusion
variable
Pulmonary Systemic
Clinical Mixed venous
capillary wedge Cardiac output vascular
measurement O2 saturation
pressure resistance
Hypovolemic

Cardiogenic

Distributive or

N.B. : Obstructive shock: a subtype where there is obstruction of a main

channel of blood flow, e.g. massive pulmonary embolism, dissecting aortic
aneurysm.

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Management of different types of shock

A. Hypovolemic shock:
1. Rapid volume repletion: delayed therapy can lead to ischemic injury
& to irreversible shock and mult-iorgan system failure:
At least 1-2 liters of isotonic saline 5 to restore tissue
perfusion are initially given rapidly & continued at rapid rate if BP
remains low.
Patients with non-hemorrhagic shock: isotonic crystalloid
solution
rather than a hyperoncotic starch or albumin-containing solution.
Patients with hemorrhagic shock: Red blood cell transfusions.
N.B.: efficacy of IV bicarbonate in patients with marked
hypoperfusion who develop lactic acidosis is uncertain.

B. Septic shock6
1. Secure airway and correct hypoxemia.
2. Restoration of tissue perfusion
Intravascular volume repletion: boluses of IV fluids : crystalloid
solution rather than a hyperoncotic starch solution or albumin.
Vasopressors: if patient remains hypotensive: norepinephrine preferred.
Inotropic therapy or blood transfusions: For patients whose
ScvO2 remains <70 % after intravenous fluid and vasopressor
therapy.
3. Identification and treatment of the site of infection
Antibiotics after appropriate cultures.
Empiric broad spectrum antibiotics if source of infection is unidentified.
Abscesses should be drained & extensive soft tissue infections excised.
5
For large volume lactated-Ringers solution or 0.45% saline solution with
75 mmol/L of sodium bicarbonate may be used instead of isotonic saline to avoid
hyperchloremic metabolic acidosis.
6
Syndrome of systemic inflammation & widespread tissue injury due to infection. Ranges from
mild sepsis to septic shock. Termed systemic inflammatory response syndrome in absence of
infection .

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4. Glucocorticoids.
5. Nutritional support and glucose control.
C. Cardiogenic shock: (mostly 2 ry to MI ,50% mortality)
1. Ventilation support to correct hypoxemia and, in part, acidosis
2. Early Aspirin + heparin
3. Sympathomimetic inotropes (e.g. DA, dobutamine (in normotensives).
4. Norepinephrine (for refractory hypotension)
5. Reperfusion should be attempted in all patients:
Revascularization is the best for all patients (PCI or CABAG)
Fibrinolytics for ST elevated MI if revascularization is not feasible
6. Antiplatelets: in addition to early aspirin, a thienopyridine e.g. clopidogrel
& a GP IIb/IIIa e.g. eptafibatide may be added for high risk patients.
7. Withhold beta blockers & calcium channel blockers.

D. Anaphylactic shock7:
1. Epinephrine: (1st & most important) IM8 or IV if not responding.
2. Airway: intubation if signs of impending obstruction from angioedema.
3. Place patient in recumbent position, and elevate lower extremities.
4. Oxygen: via facemask, or up to 100 percent oxygen as needed.
5. Normal saline: for hypotension, rapid IV infusion of 1 to 2 litres9
Additional Drugs
Salbutamol: For bronchospasm resistant to IM epinephrine.
H1 antihistamine: IV diphenhydramine for relief of urticaria & itching.
H2 antihistamine: IV ranitidine.
Glucocorticoid: Consider giving methylprednisolone 125 mg IV.
Treatment of refractory symptoms:
Epinephrine IVI10: if inadequate response to IM epinephrine & IV saline.
Vasopressors11: in addition to epinephrine.
7
Anaphylaxis: serious allergic reaction, rapid onset & fatal cardiorespiratory arrest.
8
Epinephrine (1 mg/mL preparation): Give 0.3 to 0.5 mg IM, can repeat every 5 to 15
9
Repeat as needed; massive fluid shifts with severe loss of intravascular volume can occur.
10
Epinephrine 2 to 10 mcg/ minute by infusion pump titrated according to BP, HR &O2.
11
Vaspressors are given by infusion pump titrated according to BP, HR &O2.

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Glucagon IV: Patients on beta-blockers may not respond to epinephrine

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Newer Oral Anticoagulants

Rivaroxiban - Dabigatran
Advantages over warfarin
2. No monitoring is required More rapid onset and offset. .1

.Less drug interactions with CYP450 interacting drugs .3

Comparison of Oral Anticoagulants

Warfarin Rivaroxiban Dabigatran

Mechanism Hepatic synthesis Direct competitive Direct competitive
of clotting factors reversible inhibitor reversible inhibitor
(II VII - IX X). of factor Xa of Thrombin
Onset 36-72 hours Within 30 min Within 30 min
Duration Up to 6 days 24 hours 24-36 hours
Monitoring INR No No
Antidote Vitamin K NONE NONE
Interaction Significant Low potential Low potential
Liver failure Contraindicated Contraindicated Possibly safe
Renal No dose adjustment Contraindicated Contraindicated

impairment
Pregnancy Category D Unknown Unknown

N.B.: Dabigatran is a prodrug with very low bioavailability12. Its absorption depends
.on acid environment absorption is decreased by proton pump inhibitors
Reversal of new oral anticoagulants action in toxicity
.Activated charcoal absorption (if given within few hours of ingestion) .1

.Prothrombin complex concentrate (PCC): reverses rivaroxaban effect .2

.Dialysis: for dabigatran (low plasma protein binding) .3

12
Bioavailability of dabigatran is 6.5%, rivaroxaban: 80% and warfarin: 100%.
Tartaric acid in capsules helps absorption.
Dose: rivaroxaban 10-20mg once / d, dabigatran. 150mg Po bid if creatinine clearance > 30ml /min.

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Indications of Anticoagulants
Aim of Therapy (limits propagation & prevents formation of new thrombi)
.Deep venous thrombosis & pulmonary embolism (treatment & prophylaxis) .1
.,Arterial thrombosis: coronary, cerebral .2
.Prophylactic in persistent atrial fibrillation .3
.Cardiac & vascular surgery (heparin) .4
.Hemodialysis (heparin) .5
Knee & hip replacement to decrease risk of thrombosis (rivaroxaban , .6
.dabigatran)

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ANTIPLATELET DRUGS

Platelet Aggregation

Damage of vessel wall exposure of collagen in subendothelium

platelet adhesion (enhanced by factor VIII and von Willebrand factor)
.followed by activation release reaction (ADP, fibrinogen TXA2, etc. )

ADP binds to its receptor on platelets g exposure of glycoprotein GP

gIIb/IIIa receptor on platelet membrane

Fibrinogen binds to the GP IIb/IIIa receptor linking adjacent platelets

gg aggregation

.Steps of Platelet Aggregation

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Classification of antiplatelets according to mechanism of Action

I. Drugs Acting on Platelet COX Enzyme

Acetylsalicylic acid (Aspirin)
Prototype antithrombotic
Low-dose aspirin (75 - 325 mg/day oral): inhibits platelet thromboxane A2

synthesis by inhibiting (irreversible acetylation) of COX -1 enzyme13.

Aspirin is the main antiplatelet drug used. Clopidogrel or dypiridamole
may be combined to it or given to patients intolerant to it.

II. Drugs Increasing cAMP

PGI2 analogue (epoprostenol) gg

Stimulates adenyl cyclase cAMP.
Potent antiplatelet & vasodilator.
Very short duration (minutes) given by IVI.

Dipyridamole & Cilostazol (oral) .2

Inhibit phospho-diesterase cAMP breakdown.
Vasodilator & antiplatelet.
Dipyridamole is a weak antiplatelet combined with warfarin
or aspirin.
Dipyridamole: prefered to aspirin for combination with
warfarin ( less bleeding).

13
Low dose aspirin is selective on platelets because platelets are exposed to aspirin in the
portal circulation before its acetylation by first pass metabolism. Since platelets are
nonnucleated,they cannot resynthesize new COX. Thus antiplatelet effect of aspirin remains
for 7-10 days (life span of platelet) after which new platelets are formed with new COX.
Vascular endothelial cells are nucleated thus can regenerate COX. Thus prostacyclin
synthesis recovers rapidly.

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III. Drugs acting on platelet ADP & fibrinogen Receptors

Drugs blocking ADP receptors ginhibit expression of fibrinogen receptors . 1

Clopidogrel & Prasugrel (oral )

Drugs blocking GP IIb/IIIa Fibrinogen Receptor .2

Tirofiban , eptifibatide , abciximab (mono-clonal antibody)
.(All are given IVI; short term therapy)

14
Therapeutic uses of antiplatelet drugs (mainly in arterial thrombosis)
.High risk of myocardial infarction (AMI): e.g., previous attack or angina (aspirin) .1
.Acute coronary syndrome (aspirin +clopidogrel or abciximab) .2
Coronary artery bypasses grafting, angioplasty & stent insertion (aspirin .3

.plus clopidogrel or abciximab)

Prosthetic heart valves: thrombo-embolism (dipyridamole plus .4
.warfarin)

.Transient ischemic attacks-thrombotic stroke (dipyridamole plus aspirin) .5

.Hemodialysis- cardiopulmonary bypass- pulmonary hypertension (epoprostenol) .6
.Intermittent claudication (cilostazol) .7

Side effects of antiplatelet drugs :

1. Aspirin: oral once /day
1. GIT: gastric irritation, bleeding ulcers. 3. Hypersensitivity
2.Risk of bleeding. 4. Hyperurecemia.

2. Clopidogrel15: oral once /day

Bleeding- rash
GIT: gastric irritation, dyspepsia, diarrhea
Clopidogrel is a prodrug avoid with omeprazole as it inhibits its activation in
liver.

14
Antiplatelets may be also given in atrial fibrillation if anticoagulants are
contraindicated.
15
Preferred to ticlopidine: rarely induces neutropenia, less GIT irritation.

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3. Dipyridamole (oral): Steal phenomena dizziness- headache- GIT disturbance.

4. Epoprostenol (IVI): Flushing, headache, hypotension.

5. Abciximab (IVI): bleeding, thrombocytopenia, arrhythmia.

6. Cilostazol (oral):
Headache ,dizziness.
Palpitations , tachycardia ,peripheral edema .
GIT upset: diarrhea , nausea, dyspepsia .

Indications of Fibrinolytics
1. Acute myocardial infarction (most effective if given early within 6
hours).
2. Pulmonary embolism.
3. Deep venous thrombosis.
4. Thrombotic stroke (tPA within 3 hours).
5. Obstructed arterio-venous shunt & occlusion of intravascular catheter

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CHEMOTHERAPY
Antipseudomonal penicillins, e.g. indanyl carbenicillin.
Broad-spectrum including Pseudomonas & many Gram-ve bacilli.
Stable to gastric acidity (oral).
Inactivated by -lactamase.

CEPHALOSPORINS & CEPHAMYCINS

-Lactams: similar mechanism to penicillins but more resistant to -
lactamase.

Classification according to Antibacterial Spectrum

1st Generation (Cephalexin, Cefazolin)

Spectrum:
G +ve cocci (Strept - Staph).
Some G -ve organisms (E coli - Klebsiella).

Special features
Cephalexin: oral, broad spectrum. in upper respiratory & urinary infections.
Cefazolin : 1st choice in surgical Prophylaxis& Orthopedic surgery:
Parentral
Penetrates bone well.
Penicillinase resistant (Staph).

2nd Generation ( cefuroxime, cefaclor, cephamycins)

Spectrum:
Less active on G +ve than 1st generation.
Extended spectrum on G -ve organisms.
Cephamycins: aerobic & anerobic G ve bacilli.

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Special features
Oral agents are used in sinusititis - otitis.
Cefuroxime: also used in community acquired pneumonia (H. influenza).
Cephamycins (cefoxitin - cefotetan cefmetazole): structurally related to
cephalosporins, parentral in mixed anerobic infections , B. fragillis,
peritonitis.

3rd Generation (cefoperazone, cefotaxime, ceftriaxone)

Spectrum: g Activity against resistant G -ve organisms (e.g. Pseudomonas).

Special features:
Used in serious infections.
Most agents can cross BBB ( used in meningitis)
Ceftriaxone (Parenteral , longest t.)
.Used in gonorrhea (single injection) - typhoid (resistant cases)

.Bone: good penetration into bone

.BBB: crosses BBB, so can be used in meningitis

Bile: excreted in bile (40%), used in biliary infection & in renal

.dysfunction

4th Generation (Cefepime; parentral)

Similar spectrum to 3rd gen. on gram negative & crosses BBB well.
Effective on penicillin resistant strepto & staph.
5th Generation (Ceftarolene fosamil )
Broad spectrum pro-drug of active metabolite ceftarolene.
Sectrum: MRSA, VRSA, H influenza, gram negative (plus amino
glycosides).
Used in: skin infections and community acquired pneumonia.
Requires dose adjustment in renal impairment.
Side effects: diarrhoea- nausea- headache- hypersensitivity

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Pharmacokinetics
.Some members are absorbed orally but most are given parentrally
Agents of 1st & 2nd generations cannot cross BBB while 3rd-generation
gagents (except cefoperazone) can cross g useful in meningitis
gElimination is mainly renal g adjust dose in renal dysfunction
Cefoperazone & ceftriaxone are excreted mainly in bilegg g can be used in
gbiliary infection & patients with renal dysfunction

Adverse effects
Hypersensitivity: avoid in pts with serious penicillin allergy (cross- gg

gallergy)

gNephrotoxicity especially if used with aminoglycosides gg

3. Local irritation g severe pain after IMI and thrombophlebitis after IVI.
4. Hypoprothrombinemia & bleeding (cefoperazone).
5. Intolerance to alcohol g disulfiram-like reaction.
6. Cross-resistance with penicillins: avoided in penicillin- resistant
infections.

MONOBACTAMS: Aztreonam (Given IV & IM)

Relatively non-toxic:
Similar to -lactams with less risk of hypersensitivity

TIGECYCLINE (structurally similar to tetracycline)

.Similar to tetracycline in mechanism of action & adverse effects
Effective against gram positive, gram negative & anerobes
.Given by slow iv infusion (adjust dose in liver impairment)

16
Cefoperazone (75 %) & ceftriaxone (40 %) are excreted in bile

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TELAVANCIN (synthetic derivative of vancomycin)

Mechanism of action (bactericidal)
.Inhibits bacterial cell wall synthesis

.Disruption of cell membrane

Spectrum (gram positive)

.MRSA,VRSA, daptomycin & linezolid resistant infections

Adverse effects
1. Metallic taste. 3. Nephrotoxic.
2. Red man syndrome, allergy. 4. Prolongs QT interval

:Antimicrobials against ORSA (or MRSA)

.Vancomycin & Rifampicin

.Daptomycin (if resistant to vancomycin & can be given IM)
.Quinupristin / Dalfopristin (if resistant to vancomycin (VRSA)
.Linezolid (if resistant to vancomycin (VRSA); can be given orally)
.Telavancin (MRSA & VRSA, daptomycin & linezolid resistant cases)
.Ceftarolene fosamil (MRSA & VRSA)
:TB therapy
2. Treatment for a minimum of 6 months up to 2 years) to prevent relapse.
3. Poor compliance when multidrug therapy lasts for 6 months or more
to ensure completion of therapy use directly observed therapy
(DOT) in which patients take drugs under supervision & observation.
2. Treatment involves 2 phases :
a- Initial intensive phase: For 2 months
4 drugs are used to the number of bacilli to avoid resistance.
Drugs used: Rifampicin + INH + pyrazinamide + ethambutol or
streptomycin.
b- Continuation phase: minimum of 4 months.

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2 drugs are used: INH & rifampicin.

DAPTOMYCIN

Mechanism of action
.Binds to & depolarizes cell membrane causing rapid cell death

Spectrum
Similar to vancomycin on Gram +ve organisms

Advantages
.More rapidly bactericidal
.Effective against vancomycin resistant organisms
Uses (IV & IM)

Skin & soft tissue infections .1

.Bacteremia & endocarditis .2

Adverse effects
.GIT upset & elevated liver enzymes .1
.Myopathy avoid with statins .2

STREPTOGRAMINS
Quinupristin / Dalfopristin17

MECHANISM OF ACTION
Complex with bacterial 50S ribosomal subunits to inhibit protein
synthesis

Spectrum & Uses (iv infusion )

Serious infections with resistant Gram +ve organisms e.g. MRSA
& streptococcus pneumonia when vancomycin cannot be tolerated

Adverse Effects
.Arthralgia & myalgia .1
.Thrombophlebitis .2
17
Given in combination as they are less active if given separately: 7.5 mg/Kg every 8-
12hrs.

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Enzyme inhibitor g drug interactions (similar to erythromycin) .3

OXAZOLIDINONES

Linezolid
MECHANISM OF ACTION
Binds to a unique site on the 50S subunit g inhibits initiation
.complex inhibits protein synthesis

Spectrum & Uses (iv = oral18)

Restricted to serious infections with Gram +ve organisms resistant to

vancomycin or MRSA in patients intolerant to vancomycin or if iv access is
.unavailable

Adverse Effects
.Thrombocytopenia. 2. GIT: Nausea, vomiting & diarrhea .1

3. Mild MAOI avoid with SSRIs & pseudoephedrine in cold remedies BP

18
100% bioavailability: 600mg twice daily oral or iv

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Diabetes
IV. Alpha Glucosidase Inhibitors
Acarbose - Miglitol

V. Dipeptidyl peptidase (DPP)-4 Inhibitors

Incretin Enhancers
Sitagliptin - Saxagliptin - Linagliptin

Mechanism of Action
Inhibit DPP-4 (enzyme responsible for rapid degradation of "incretins19"
e.g. GLP-1 incretins plasma level gpostprandial hyperglycemia
through:

1. Increase in glucose- dependent insulin secretion.

2. Suppression of glucagon secretion.

Indications:
Type 2 diabetes: monotherapy or combined with metformin or TZDs.
Advantage: Given orally once daily

Adverse effects (well tolerated)

Nasopharyngitis & upper respiratory infections.

Incretin Mimetics

Exenatide - Liraglutide
.Synthetic analogues of GLP-1 that are more stable than natural GLP-1
Administered by SC injection, exenatide: twice/day and liraglutide
.once/day

19
Incretins (e.g. GLP-1) are released from GIT in response to meal to lower blood sugar.
Natural GLP-1 is rapidly degraded in few minutes by DPP-4.

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Mechanism of Action
.Enhance glucose-dependent insulin secretion .1
.Suppress inappropriately elevated postprandial glucagon secretion .2
.Slow gastric emptying, and reduces food intake .3
.Restore the acute responsiveness of the -cell to secrete insulin .4

:Adverse effects
.Nausea (most common , especially with high doses)

Management of Diabetes
:The Four Cornerstones of Treatment of Diabetes are
Life style (diet regulation &exercise ginsulin receptors) education
.medication
Diet Regulation: g Total caloric intake
Carbohydrates: 50-60% (complex as starch to delay absorption).
Fat Low: < 20% (mostly unsaturated to avoid hyperlipidemia).
Protein: 20%.
Diet rich in fibres, fresh fruits & vegetables.

N.B.: Caloric restriction is not initially required in patients with IDDM

(underweight), but is necessary when insulin therapy results in
.weight

Drug Therapy

A. Drug Therapy of Type 1 DM:

Insulin therapy
.Intensive therapy20: multiple doses or insulin pump
Conventional therapy: 2 injections (mixture of intermediate & regular
.insulin; 2/3 of dose in the morning & 1/3 in the evening)

20
Intensive insulin for tight control is prescribed to all type 1 DM. & for type-2 patients
requiring tight control. Long or intermediate insulins are used to cover basal insulin
requirements. Short or ultrashort insulins are taken before each meal according to
carbohydrate in meal & pre-meal blood glucose.

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.Insulin dose should be increased during stress (infection, surgery )

B. Drug Therapy of Type 2 DM:
:Step 1: lifestyle modification + metformin
Step 2: lifestyle + metformin + basal insulin or a sulfonylurea (e.g.
.glipizide)
Step 3: lifestyle + metformin + intensive insulin

N.B.:
If initial therapy with metformin is CI give a sulfonylurea (e.g. glipizide )
.or insulin (if A1C >8.5%)
If sulfonylurea is CI give repaglinide or pioglitazone, if CI give
.sitagliptin
.Combinations of these drugs are often necessary to achieve optimal results

20