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D. DRUG-INDUCED TOXICITY4gro

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Pavitra Krishnan ∙Eshwari

Gunasegaran ∙Annisa

Hayatunnufus ∙Durga Devi ∙

Varisha Priyaa ∙

Bachelor of Pharmacy (Hons), Principles of Medical Pharmacology

Christine Shalin ∙Hong Tshun Kuan ∙

M. Reza Alfathiansyah ∙

M. Haidir ∙Yeoh Chun Siong ∙

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CONTENT1. Drug-induced

Hepatotoxicity 2. Drug-

inducedRenal Toxicity

3. Drug-induced

Neurotoxicity 4. Drug-induced

Skeletal Muscle toxicity

1A. TYPES & RISK

FACTORS1B.

MECHANISM1C.

PREVENTION

3A. INTRO 3B. EXAMPLE BY VINCA ALKALOIDS

3C. MECHANISM

4A. CLASSIFICATION &

MECHANISM

4C. CLINICAL PRESENTATIONS

4B. CAUSES

2A. INTRO & MECHANISM

2B. DRUGS THAT CAUSE

2C. PREVENTION

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4D. PREVENTION

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1A. Types & Risk Factors

Types of Liver Injury

Risk Factors

Genetic Predisposition Sex Age

Alcohol Consumption

Overdose of Certain Drugs

Chronic Viral Infection

Exposure to Chemical Agents

Pharmacokinetic/Pharmacodynami

c InteractionsIllicit Drug Use

(Ex: Cocaine)

FATTY LIVER NECROSIS APOPTOSIS CHOLESTASIS

DRUG-INDUCED HEPATOTOXICITY

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1B. Mechanism (Part 1)DRUG-INDUCED HEPATOTOXICITY

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1B. Mechanism (Example: Rifampin)DRUG-INDUCED HEPATOTOXICITY

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1C. Prevention

?Recognition and rapid discontinuation of agent

Patient with risk factors should not receive hepatotoxic agents if & when

alternative agents are available

Monthly monitoring liver

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12A. Introduction & Mechanism

Mechanism?

1. Altered intraglomerular hemodynamics2. Tubular cell toxicity3. Inflammation 4. Crystal nephropathy5. Rhabdomyolysis 6. Thrombotic microan-giopathy

One of the most common kidney problems & occurs when the body is exposed to a drug or toxin that causes damage to the kidneys. kidney damage occurs unable to rid of excess urine + wastes in the body blood electrolytes (ie. K & Mg) elevated

Nephrotoxicity?

DRUG-INDUCED RENAL TOXICITY

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2B. Drugs That CauseDRUG-INDUCED RENAL TOXICITY

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2B. Drugs That Cause (Ex: Aminoglycocides)

DRUG-INDUCED RENAL TOXICITY

AMINOGLYCOSIDES(AMG)

Concentrated in renal cortex and proximal tubular cells

AMG bind to lysosomes with formation of myeloid bodies

Release of AMG interferes phosphatidyl-inositol pathway.

Clinical Features:Proximal tubular dysfunction, glycosuria, hypokalemia, hypomagnesemia

Mechanism:

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2E. Prevention

Lowest dose Shortest course of therapy

Avoid giving nephrotoxic drugs

concurrently

Make interval between aminoglycoside courses

as long as possible

Patients on aminoglycoside should

be monitored

Use aminoglycosides as an once daily dose rather than divided

dose

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3A. Introduction

Drug-induced neurotoxicity most often associated with the use of cancer chemotherapeutic agents

Peripheral neuropathy has been associated with:

In most cases, neurotoxicity manifests in the peripheral nerves, but the central

nervous system may be affected as well.

Vinca Alkaloids• Vinchristine• Vinblastine

Platinum Compounds

• CisplatinTaxanes

• Paclitaxel

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3B. Example by Vinca Alkaloids

Originally to treat…• leukemia• lymphomas • sarcomas• brain tumors

How does it induce neuropathy?

Disruption of microtubules within axons & interference with axonal transport neuropathy of sensory & motor fibers

Virtually all patients have some degree of neuropathy The clinical features resemble those of other axonal

neuropathies (ex: diabetic neuropathies)

Signs & Symptoms• Loss of ankle

jerks• Profound

weakness• Neuropathies

• Abdominal pain• Constipation• Impotence• Postural hypotension

• Retinal damage• Night blindness• Jaw and parotid

pain.

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3C. MechanismPharmacodynamic of Microtubule Disruption by Vinca Alkaloids

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4A. Classification & Mechanism

Drug-induced Skeletal Muscle Toxicity

MYALGIAMYOSITIS MYOPATHY

RHABDOMYOLISIS

MechanismInjured muscle tissue causes…

INCREASED MYOGLOBIN

INCREASED SERUM

CREATINE KINASE

INCREASED OTHER

INTRACELLULER

CONSTITUENTS (ie. Fluid,

intracellular K & Ca)

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Cholesterol synthesis: The Mevalonate Pathway

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4B. Causes (Ex: Statin)DRUG-INDUCED SKELETAL MUSCLE TOXICITY

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4C. Clinical Presentations• Muscles of patients with rhabdomyolysis may be

tender, stiff, or weak.

• However, most patients with drug-induced rhabdomyolysis do not complain of swelling or tenderness at the time of admission. They may develop a “second wave phenomenon” in which a delayed increase in fascial compartment pressure causes compression neuropathies, swelling, and tenderness.

• Compartment syndromes in drug-induced rhabdomyolysis usually occur secondary to prolonged immobilization or coma, which can result in contractures and amputations.

• Acute cardiomyopathy can present from direct toxic effects of drugs on the cardiac muscle.

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4D. Prevention• Use the lowest dose possible, avoid or minimize concomitant risk factors, and monitor

carefully for onset of symptoms when drugs known to cause myopathy cannot be avoided

• Moderate amounts of exercise and physical activity (extremely vigorous or prolonged periods of exercise may increase the risk for drug-induced myopathies)

• Avoid combining drugs when each has a risk of myopathy, when possible (ex: statin + fibrates or statin + cyclosporine)

• Consider genetic screening when drug-induced myopathy occurs

DRUG-INDUCED SKELETAL MUSCLE TOXICITY

• Consider measuring a baseline creatine kinase in patients with multiple risk factors of causing myopathy

• Educate patients regarding signs and symptoms: discoloured urine Weakness in addition to pain Symptoms in more than one muscle system