Drug Toxicity & Pharmacogenomics Review PDF

Drug Toxicity and Pharmacogenomics Review 701 Dental Pharmacology Hua Zhang, MD, PhD Email: [email protected]  Drug Toxicity Learning Objectives Describe factors that contribute to the ability of drug to cause harm. Describe sources of drug toxicity. Describe contexts o...

Drug Toxicity and Pharmacogenomics Review 701 Dental Pharmacology Hua Zhang, MD, PhD Email: [email protected]  Drug Toxicity Learning Objectives Describe factors that contribute to the ability of drug to cause harm. Describe sources of drug toxicity. Describe contexts of drug toxicity and give examples of each context. Describe the cellular mechanisms of drug toxicity. Describe the different types of hypersensitivity reactions. Give examples of different types of drug-induced organ toxicities. Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems. The effects of drugs are dose-dependent Quantal dose-response curves TI = TD50/ED50  Relationship of Dose to Differential Effect Concentration dependence of barbiturate and benzodiazepine effects MECHANISMS OF DRUG TOXICITY The ability of a drug to harm depends on Patients age: very young or elderly Genetic makeup Pre-existing conditions The dose of drug administered Other drugs the patient may be taking Sources of Drug Toxicity “On-target“ adverse effects: The drug binding to its intended receptor, but at an inappropriate concentration, with suboptimal kinetics, or in the incorrect tissue. "Off-target“ adverse effects The drug binding to a target or receptor for which it was not intended. Immune system mediated adverse effects: Hypersensitivity reactions Idiosyncratic toxicities: Unpredictable, in a small fraction of patients, for unknown reasons Pharmacogenetic contributions On-target and off-target adverse drug effects. On-Target Effects Correct receptor, correct tissue, exaggeration of the desired pharmacologic action due to overdose or increased sensitivity Correct receptor, but unintended tissue Diphenhydramine (Benadryl): H1-antihistamines cross blood-brain barrier, lead to somnolence Cholinesterase inhibitors: peripheral cholinergic effects, SLUDGE  Off-Target Effects A drug interacts with unintended targets Terfenadine: H1-antihistamine, is cardiotoxic at higher doses by blockage of potassium channel Unintended activation of different receptor subtypes β2-selective agonists are used as inhalers to treat asthma. At high doses may result in cardiac stimulation and tachycardia (β1 effects) Harmful Immune Responses and Immunotoxicity Some drugs may be recognized by the immune system as foreign substances usually occurs with large drugs Once the immune system is activated, hypersensitivity (allergic) responses or autoimmune reactions can result Skin rashes are common adverse effects of drug administration, and these likely involve immune system activation Immunotoxicity: injury to the immune system, either as an adverse effect of therapy or as the specific intent of therapy, increased risk of infection Cytotoxic cancer chemotherapy Inhaled corticosteroid: chronic obstructive pulmonary disease Immunotherapies: Rituximab (CD20+ B cell) Hypersensitivity Responses  Toxic, Idiosyncratic and Allergic Responses to Drugs OCCURRENCE: TOXIC IDIOSYNCRATIC ALLERGIC Incidence in In all subjects, if Only in genetically, or From a few per cent to 100 population dose high enough otherwise abnormal subjects percent, depending on drug Incidence All drugs Few drugs Many drugs among drugs CIRCUMSTANCES: Prior exposure Prior exposure unnecessary Prior exposure essential unnecessary RELATIONSHIP: Dose related Dose related Independent of dose MECHANISM: Drug-receptor Drug-receptor Antigen-antibody (immune) interaction interaction reaction EFFECT: Determined by Determined by Independent of eliciting drug; specific receptor; specific receptor; determined by endogenous characteristic of drug characteristic of drug mediators TREATMENT: Specific antagonists Specific antagonists Immunological antagonists (epinephrine, anti-inflammatory, 16 steroids, antihistamines) CONTEXTS OF DRUG TOXICITY Drug Overdose Drug-Drug Interactions Pharmacokinetic Pharmacodynamic Drug-Herb Cellular Mechanisms of Toxicity: Apoptosis and Necrosis Organ and Tissue Toxicity Pharmacokinetic Drug-Drug Interaction Antifungal drug ketoconazole is a potent inhibitor of CYP 3A4 Most drugs are metabolized through 3A4 Therefore, if a patient is taking a drug metabolized by 3A4 and you add ketoconazole, that first drug might build up to toxic levels Pharmacodynamic Drug-Drug Interactions Erectile dysfunction drug sildenafil increases cGMP in vascular smooth muscle Nitroglycerin sometimes used to prevent angina attacks also increases cGMP in vascular smooth muscle Using nitroglycerin too soon after using sildenafil can increase the risk for dangerous hypotension Drug-Herb Interactions Ginkgo biloba is an herb sometimes used for its memory promoting abilities It also inhibits platelet aggregation Concomitant use of NSAIDs (Nonsteroidal anti- inflammatory drugs) can increase the risk for bleeding  Cellular Mechanisms for Toxicity Apoptosis Necrosis programmed cell death uncontrolled cell death beneficial when occurs if toxic insult is so damaged cells are severe that programmed eliminated without cell death cannot be damage to surrounding accomplished tissue results in attraction of apoptotic cells undergo inflammatory cells and cell death with minimal can damage nearby inflammation and healthy cells disruption of adjacent tissue Organ and Tissue Toxicity Drug-Induced Hepatotoxicity Many drugs are metabolized in or excreted by the liver, and some of these metabolism can cause liver damages Acetaminophen metabolism normally results in toxic metabolite When the glutathione excretion pathway for this toxic metabolite is overwhelmed (such as an alcoholism), the toxic metabolite can accumulate and result in necrotic hepatic damage Mechanism of acetaminophen poisoning. Drug-Induced Renal Toxicity The kidney is the major route of excretion of many drugs and their metabolites Drug classes that can cause renal injury NSAIDs Antineoplastic agents Immunomodulators Angiotensin converting enzyme (ACE) inhibitors Antibiotics Aminoglycoside antibiotic Gentamicin: inhibition of lysosomal hydrolases, cause acute renal tubular necrosis Antifungal agent amphotericin B: bind to sterols, damage the membranes of renal tubular epithelial cells Drug-Induced Neurotoxicity Many cancer agents interfere with microtubule assembly and as a result are particularly neurotoxic, especially to the peripheral nervous system Vinca alkaloids: vincristine, vinblastine Drug-Induced Skeletal Muscle Toxicity Statins HMG-CoA reductase inhibitors, used to decrease cholesterol levels In some patients, statins also inhibit geranyl-geranylation of several muscle proteins, result in muscle toxicity Glucocorticoids Oral glucocorticoids are used to suppress the immune system Natural function of glucocorticoids is to mobilize glucose Corticosteroids do this, in part, by breaking down proteins in muscle Thus, prolonged oral corticosteroid use can lead to skeletal muscle wasting Drug-Induced Cardiovascular Toxicity Many drugs interact with cardiac potassium channels to cause QTc prolongation, delayed repolarization, and cardiac arrhythmias Some drugs are directly toxic to cardiac myocytes Some drugs are toxic to heart valves Drug-Induced Pulmonary Toxicity Aspirin can exacerbate asthma symptoms Drug-induced pulmonary fibrosis Chemotherapeutic agents: Bleomycin Antiarrhythmic drug: Amiodarone  Carcinogenesis Due to Drug Toxicity Tamoxifen is an estrogen receptor modulator that acts as an antagonist in breast, but agonist in the endometrium Thus, tamoxifen prevents breast cancer but promotes uterine cancer Cytotoxic alkylating agents used in cancer chemotherapy can cause acute myeloid leukemia (AML) due to damaging to normal blood cell progenitors Teratogenesis Due to Drug Therapy Many drugs are teratogenic to the fetus Chloramphenicol: gray baby syndrome Renin-Angiotensin-Aldosterone System (RAAS) drugs: ACE inhibitors, ARBs (angiotensin II receptor blockers) Principles for Treating Patients with Drug-Induced Toxicity Reduce or eliminate exposure to the drug Administer antagonists naloxone block opioid overdose flumazenil blocks benzodiazepine overdose Alter the metabolism of the drug give patients with acetaminophen overdose a precursor to glutathione to promote safe excretion Providing supportive measures giving cancer patients drugs that stimulate leukocyte production  Early Detection and Prediction of Drug Toxicity Identifying toxicity early in drug development Providing markers to monitor toxicity in patients  Learning Objectives Define the promise of the field of pharmacogenetics. Describe sources of genetic variation. Give examples of pharmacokinetic and pharmacodynamic genetic variations. Give an example of how pharmacokinetic and pharmacodynamic genetic variation can interact. Define idiosyncratic drug reaction and describe the role of pharmacogenetics in determining the mechanisms of idiosyncratic reactions. Describe SNP-array can be used to prevent statin-induced myopathy.  Introduction There are large individual differences in response to drug therapy Genetic variation play an important role Pharmacogenomics is the study of the impact of genetic polymorphisms on drug response, is a modern term for pharmacogenetics The promise of pharmacogenomics is the possibility that knowledge of a patient’s DNA sequence could be used to enhance pharmacotherapy The purpose of pharmacogenomics is to personalize or individualize drug therapy Genomic Variation and Pharmacogenomics The human genome contains three billion nucleotides and 25,000 genes that encode about 100,000 proteins Any two people differ in about 1 nucleotide per every 1,000 nucleotides Inter-individual variation is about 3 million base pairs Most of these are single nucleotide polymorphisms (SNPs), SNPs are the most common gene variations associated with drug response. There may also be insertions, deletions, duplications or reshufflings of a few nucleotides or a whole gene These modifications can occur in the gene, or in the promoters, enhancers, splice sites, or sites that control gene transcription or mRNA stability Genetic Variations Associated with Drug Response Variation in Enzymes of Drug Metabolism: Pharmacokinetics Variation in Transporters: Pharmacokinetics Variation in Drug Targets: Pharmacodynamics Pharmacodynamic and Pharmacokinetic Interactions: Polygenic effect Variation in Immune System Function: HLA (human leukocyte antigen) Polymorphisms  Variation in Enzymes of Drug Metabolism: Pharmacokinetics Phase I (Oxidation/Reduction) enzymes and Phase II (Conjugation) enzymes Can lead to toxic drug concentrations or alter the production of active or toxic metabolites CYP2D6: Codeine converted to morphine. Increased function associated with increased toxicity; decreased function associated with decreased analgesia Thiopurine S-methyltransferase (TPMT): Reduced function associated with increased thiopurine (azathioprine, 6-mercaptopurine, 6-thioguanine) toxicity CYP2D6 pharmacogenetics. Tamoxifen pharmacogenetics.  Genetic Variation in Transporters: Pharmacokinetics Genetic differences in transporter genes can dramatically alter drug disposition and response, may increase risk for toxicities Example: Organic anion transporter (OATP)1B1 encoded by the SLCO1B1 gene, responsible for the hepatic uptake of many drugs, eg. Statins. Some SNPs are associated with reduced functions, result in elevated concentrations of some statins, and increase risk of skeletal muscle myopathy  Variation in Drug Targets: Pharmacodynamics Genetic variations in drug receptors Example: b2-adrenergic receptor Genetic variations in target enzymes Example: Some asthma patients do not response to 5- lipoxygenase inhibitor Zileuton  Pharmacodynamic and Pharmacokinetic Interactions: Polygenic Effects Interactions between pathways may contribute to individual differences It is difficult to predict warfarin an idea dosing because of genetic variations in both the drug receptor and drug metabolism  Warfarin Pharmacokinetics and Pharmacodynamics Warfarin >50% on interindividual variation is caused by genetic variation in CYP2C9, vitamin K epoxide reductase (VKORC1 complex), or CYP4F2 Polymorphisms in CYP2C9 lead CYP4F2 to warfarin sensitivity phenotype Hydroxyvitamin K1 Polymorphism in VKORC1 leads to warfarin resistance or warfarin sensitivity phenotype Genetic Variation in Immune System Function Human leukocyte antigen (HLA) polymorphisms are associated with drug-induced hypersensitivity reactions Severe hypersensitivity reaction associated with the HLA-B*5701 allele in HIV patients taking abacavir, a reverse transcriptase inhibitor Predrug testing for HLA-B*5701 has been shown to nearly eliminate such hypersensitivity reactions Stevens-Johnson syndrome TABLE 5–4 Polymorphisms in HLA genes associated with Stevens-Johnson syndrome, toxic epidermal necrosis, or drug-induced liver injury. Variant of HLA Gene Drug and Adverse Effect Human Leukocyte Antigen (HLA) HLA-B*57:01 HLA-B*58:01 Abacavir-induced skin toxicity Allopurinol-induced skin toxicity Polymorphisms HLA-DRB1 *15:01, DRB5 *01:01, DQB1 *06:02 haplotype Amoxicillin-clavulanate-induced liver injury HLA-B*15:02 Carbamazepine-induced skin toxicity HLA-B *57:01 Flucloxacillin-induced liver injury HLA-DQB1 *06, *02, HLA-DRB1 Various drugs, subgroup analysis for cholestatic or other types of *15, *07 liver injury HLA-DRB1 *07, HLA-DQA1 *02 Ximelagatran, increased ALT  Modern Pharmacogenetics Translating genomic knowledge into clinical practice with application of modern genomic assay techniques SNPs analysis through genome-wide association studies (GWAS ) can be used to predict patients who will have altered metabolism of statins, increasing the frequency of statin- induced myopathy Genome-Wide Association Study (GWAS): Analysis of the complete genomes of a population of individuals with regard to the frequency of association of specific allelic variations with a specific phenotype Genome-wide association study of statin-induced myopathy (SNP: rs4363657 in SLCO1B1 gene) References Principles of Pharmacology, The pathophysiologic Basis of Drug Therapy, 4e Katzung & Trevor's Pharmacology: Examination & Board Review, 12e (Access Pharmacy) Basic & Clinical Pharmacology, 14e (Access Medicine or Access Pharmacy) Goodman and Gilman’s Manual of Pharmacology and Therapeutics, 2e (Access Pharmacy) Dowd, Pharmacology and Therapeutics for Dentistry, 7e Reference Slides (FYI) Poisoning Poisoning: damaging physiological effects result from exposure to pharmaceuticals, illicit drugs, or chemicals. A poison is any substance, including any drug, that has the capacity to harm a living organism. Absorption, distribution, metabolism, and elimination (ADME) may differ significantly after poisoning - Toxicokinetics Potential Scenarios for the Occurrence of Poisoning Top Five Agents Involved in Drug- Related Deaths Therapeutic drug toxicity Cocaine Exploratory exposure by young children Opioids Environmental exposure Benzodiazepines Occupational exposure Recreational abuse Alcohol Medication error Antidepressants Prescribing error Dispensing error Source: U.S. DHHS. Administration error Purposeful administration for self-harm Purposeful administration to harm another AccessPharmacy>Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016 Prevention of Poisoning Reduction of medication errors Right drug, right patient, right dose, right route, right time Poisoning prevention in the home Passive prevention strategies Best Practice Recommendations to Reduce Medication Administration Errors Short Term Maintain unit-dose distribution systems for non-emergency medications Have pharmacies prepare intravenous solutions Remove inherently dangerous medications (e.g., concentrated KCl) from patient care areas Develop special procedures for high-risk drugs Improve drug-related clinical information resources Improve medication administration education for clinicians Educate patients about the safe and accurate use of medications Improve access of bedside clinicians to pharmacists Long Term Implement technology-based safeguards: Computerized order entry Computerized dose and allergy checking Computerized medication tracking Use of bar codes or electronic readers for medication preparation and administration AccessPharmacy>Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016  Passive Poisoning Prevention: Strategies and Examples Reduce manufacture/sale of poisons Withdrawal of phenformin from U.S. market Decrease amount of poison in a consumer product Limiting of pills in bottle of baby aspirin Prevent access to poison Use of child-resistant packaging Change product formulation Removing ethanol from mouthwash AccessPharmacy>Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016 Management of the Poisoned Patient Maintenance of vital functions Identification of Poisons Decontamination Enhancement of elimination Antidotes TABLE 58–1 Toxic syndromes caused by major drug groups Drug Group Clinical Features Key Interventions Antimuscarinic drugs (anticholinergics) Delirium, hallucinations, seizures, coma, Control hyperthermia; physostigmine may be tachycardia, hypertension, hyperthermia, helpful, but not for tricyclic overdose mydriasis, decreased bowel sounds, urinary retention Cholinomimetic drugs (carbamate or Anxiety, agitation, seizures, coma, bradycardia or Support respiration. Treat with atropine and organophosphate cholinesterase inhibitors) tachycardia, pinpoint pupils, salivation, sweating, pralidoxime. Decontaminate hyperactive bowel, muscle fasciculations, then paralysis Opioids (eg, heroin, morphine, methadone) Lethargy, sedation, coma, bradycardia, Provide airway and respiratory support. Give hypotension, hypoventilation, pinpoint pupils, cool naloxone as required skin, decreased bowel sounds, flaccid muscles Salicylates (eg, aspirin) Confusion, lethargy, coma, seizures, Correct acidosis and fluid and electrolyte hyperventilation, hyperthermia, dehydration, imbalance. Alkaline diuresis or hemodialysis to aid hypokalemia, anion gap metabolic acidosis elimination Sedative-hypnotics (barbiturates, Disinhibition initially, later lethargy, stupor, coma. Provide airway and respiratory support. Avoid fluid benzodiazepines, ethanol) Nystagmus is common, decreased muscle tone, overload hypothermia. Small pupils, hypotension, and Consider flumazenil for benzodiazepine overdose decreased bowel sounds in severe overdose Stimulants (amphetamines, cocaine, Agitation, anxiety, seizures. Hypertension, Control seizures, hypertension, and hyperthermia phencyclidine [PCP]), bath salts tachycardia, arrhythmias. Mydriasis, vertical and horizontal nystagmus with PCP. Skin warm and sweaty, hyperthermia, increased muscle tone, possible rhabdomyolysis SSRIs Mild: shivering, hyperreflexia, and diarrhea. Stop offending drug, supportive management, and Severe: muscle rigidity, fever seizures, and antidote with cyproheptadine cardiovascular instability Tricyclic antidepressants Antimuscarinic effects (see above). The “3 Cs” of Control seizures. Correct acidosis and coma, convulsions, cardiac toxicity (widened QRS, cardiotoxicity with ventilation, sodium bicarbonate, arrhythmias, hypotension) and norepinephrine (for hypotension). Control hyperthermia  TABLE 58–3 Important antidotes. Antidote Poison(s) Acetylcysteine Acetaminophen; best given within 8–10 h of overdose Atropine Cholinesterase inhibitors, rapid-onset mushroom poisoning with muscarinic effects Bicarbonate, sodium Membrane-depressant cardiotoxic drugs (eg, quinidine, tricyclic antidepressants) Calcium Fluoride; calcium channel blockers Deferoxamine Iron salts Digoxin antibodies Digoxin and related cardiac glycoside Esmolol Caffeine, theophylline, sympathomimetics Ethanol Methanol, ethylene glycol (fomepizole is better tolerated by patient) Flumazenil Benzodiazepines, zolpidem (note: flumazenil can trigger seizures) Fomepizole Methanol, ethylene glycol Glucagon Beta-adrenoceptor blockers Glucose Hypoglycemics Hydroxocobalamin Cyanide Naloxone Opioid analgesics Oxygen Carbon monoxide Physostigmine Suggested antidote for muscarinic receptor blockers when effect needed in CNS, NOT as antidote for tricyclics Pralidoxime (2-PAM) Organophosphate cholinesterase inhibitors. Most effective if used within 24 hours of exposure Environmental Toxicology Heavy Metals Heavy metals Lead, arsenic, mercury, iron - frequently cause toxicity in humans Interaction with sulfhydryl groups of enzymes and regulatory proteins Chelators Organic compounds with 2 or more electronegative groups that form stable bonds with cationic metal atoms These stable complexes lack the toxicity of the free metals and often are excreted readily. Function as chemical antagonists, are used as antidotes in the treatment of heavy metal poisoning. TABLE 57–1 Important characteristics of the toxicology of arsenic, iron, lead, and mercury. Route of Target Organs for Metal Form Entering Body Treatmenta Absorption Toxicity Lead Inorganic lead oxides and Gastrointestinal, Hematopoietic Dimercaprol, salts respiratory, skin system, CNS, EDTA, succimer, (minor) kidneys unithiol Tetraethyl lead Skin (major), CNS Seizure control gastrointestinal Arsenic Inorganic arsenic salts All mucous Capillaries, Dimercaprol, surfaces gastrointestinal unithiol, succimer, tract, hematopoietic penicillamine system Arsine gas Inhalation Erythrocytes Supportive Mercury Elemental Inhalation CNS, kidneys Succimer, unithiol Inorganic salts Gastrointestinal Kidneys, Succimer, unithiol, gastrointestinal tract penicillamine, dimercaprol Organic mercurials Gastrointestinal CNS Supportive Iron Ferrous sulfate Gastrointestinal Gastrointestinal, Deferoxamine, CNS, blood deferasirox a In all cases, removal of the person from the source of toxicity is the first requirement of management. Basic & Clinical Pharmacology, 13e, 2015