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Drug-induced Toxicity [Liver, Kidney, Nervous System, Muscle]
- 1. 2 3 4 1 D. DRUG-INDUCED TOXICITY PavitraKrishnan ∙ Eshwari Gunasegaran∙ Annisa Hayatunnufus ∙ DurgaDevi ∙ VarishaPriyaa ∙ Bachelor of Pharmacy (Hons), Principles of Medical Pharmacology Christine Shalin∙ Hong Tshun Kuan∙ M. Reza Alfathiansyah ∙ M. Haidir ∙ YeohChun Siong ∙ 1/19
- 2. 1A. TYPES & RISK FACTORS 1B. MECHANISM 1C. 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 2/19 4D. PREVENTION
- 3. 2 3 4 1A. Types & Risk Factors RiskFactors Genetic Predisposition Sex Age Alcohol Consumption Overdose of Certain Drugs Chronic Viral Infection Exposure to Chemical Agents Pharmacokinetic/ Pharmacodynamic Interactions Illicit Drug Use (Ex: Cocaine) FATTY LIVER NECROSIS APOPTOSIS CHOLESTASIS DRUG-INDUCED HEPATOTOXICITY 3/19
- 4. 2 3 4 1B. Mechanism (Part 1) DRUG-INDUCED HEPATOTOXICITY 4/19
- 5. 2 3 4 1B. Mechanism (Example: Rifampin) DRUG-INDUCED HEPATOTOXICITY 5/19
- 6. 2 3 4 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 6/19
- 7. 3 4 1 2A. Introduction & Mechanism Mechanism? 1. Altered intraglomerular hemodynamics 2. Tubular cell toxicity 3. Inflammation 4. Crystal nephropathy 5. 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 7/19
- 8. 3 4 1 8/19 2B. Drugs That Cause DRUG-INDUCED RENAL TOXICITY
- 9. 3 4 1 9/19 2B. Drugs That Cause (Ex: Aminoglycocides) DRUG-INDUCED RENAL TOXICITY 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:
- 10. 3 4 1 10/19 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
- 11. 2 4 1 11/19 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 • Cisplatin Taxanes • Paclitaxel DRUG-INDUCED NEUROTOXICITY
- 12. 2 4 1 12/19 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) • Loss of ankle jerks • Profound weakness • Neuropathies • Abdominal pain • Constipation • Impotence • Postural hypotension • Retinal damage • Night blindness • Jaw and parotid pain. DRUG-INDUCED NEUROTOXICITY
- 13. 2 4 1 13/19 3C. Mechanism Pharmacodynamic of Microtubule Disruption by Vinca Alkaloids DRUG-INDUCED NEUROTOXICITY
- 14. 2 3 1 14/19 4A. Classification & Mechanism MYALGIA MYOSITIS MYOPATHY RHABDOMYOLISIS Injured muscle tissue causes… INCREASED MYOGLOBIN INCREASED SERUM CREATINE KINASE INCREASED OTHER INTRACELLULER CONSTITUENTS (ie. Fluid, intracellular K & Ca) DRUG-INDUCED SKELETAL MUSCLE TOXICITY
- 15. Cholesterol synthesis: The Mevalonate Pathway
- 16. 2 3 1 16/19 4B. Causes (Ex: Statin) DRUG-INDUCED SKELETAL MUSCLE TOXICITY
- 17. 2 3 1 17/19 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
- 18. 2 3 1 18/19 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
Editor's Notes
- Nephrotoxicity can be temporary with a temporary elevation of lab values (BUN and/or creatinine). If these levels are elevated, these may be due to a temporary condition such as dehydration or you may be developing renal (kidney failure). If the cause of the increased BUN and/or creatinine levels is determined early, and your healthcare provider implements the appropriate intervention, permanent kidney problems may be avoided.
- The neuropathy cause by vinca alkaloids and taxanes is directly related to their primary mechanism of action, microtubule disruption. In peripheral nerves, microtubule disruption is thought to result in altered axonal trafficking and both sensory and motor neuropathy. Platinum- containing compounds may have direct toxic effects on peripheral nerves.
- Management: Dose reduction