drug-induced toxicity [liver, kidney, nervous system, muscle]
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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
DRUG-INDUCED HEPATOTOXICITY
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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
DRUG-INDUCED RENAL TOXICITY
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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
DRUG-INDUCED NEUROTOXICITY
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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.
DRUG-INDUCED NEUROTOXICITY
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3C. MechanismPharmacodynamic of Microtubule Disruption by Vinca Alkaloids
DRUG-INDUCED NEUROTOXICITY
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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)
DRUG-INDUCED SKELETAL MUSCLE TOXICITY
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.
DRUG-INDUCED SKELETAL MUSCLE TOXICITY
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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