Midterms Toxicants & Mechanism of Toxicity PDF

DISPOSITION OF TOXICANTS & MECHANISM OF TOXICITY OBJECTIVE: TO UNDERSTAND THE CONCEPT OF DIFFERING TOXIC EFFECTS DEPENDING ON THE ROUTE OF ADMINISTRATION AND THE PROCESSES INVOLVED IN LIBERATION AND ABSORPTION OF TOXICANTS INTO THE BODY; TO APPLY THE BASIC PRINCIPLES INVOLVED IN DISTRI...

DISPOSITION OF TOXICANTS & MECHANISM OF TOXICITY OBJECTIVE: TO UNDERSTAND THE CONCEPT OF DIFFERING TOXIC EFFECTS DEPENDING ON THE ROUTE OF ADMINISTRATION AND THE PROCESSES INVOLVED IN LIBERATION AND ABSORPTION OF TOXICANTS INTO THE BODY; TO APPLY THE BASIC PRINCIPLES INVOLVED IN DISTRIBUTION AND ELIMINATION OF TOXICANTS; TO UNDERSTAND THE DOSE-RESPONSE RELATIONSHIP AND VARIOUS MECHANISMS OF TOXICITY.  3 PHASES OF TOXICOLOGY 1. EXPOSURE PHASE THIS PHASE FOCUSES ON HOW AN ORGANISM COMES INTO CONTACT WITH A TOXIC SUBSTANCE. IT INVOLVES UNDERSTANDING THE ROUTE OF EXPOSURE, DOSE, AND FREQUENCY. ROUTES OF EXPOSURE INCLUDE: INHALATION (E.G., GASES, AEROSOLS) INGESTION (E.G., CONTAMINATED FOOD, DRUGS) DERMAL ABSORPTION (E.G., CHEMICALS THROUGH THE SKIN) KEY FACTORS: DOSE-RESPONSE RELATIONSHIP: THE CORRELATION BETWEEN THE AMOUNT OF TOXIN AND ITS EFFECTS. BIOAVAILABILITY: THE EXTENT AND RATE AT WHICH THE TOXIN ENTERS THE CIRCULATION. 2. TOXICOKINETIC PHASE THIS PHASE EXAMINES HOW THE BODY HANDLES THE TOXIN, OFTEN SUMMARIZED USING ADME: ABSORPTION: ENTRY OF THE TOXIC SUBSTANCE INTO THE BODY. DISTRIBUTION: SPREAD OF THE SUBSTANCE TO VARIOUS TISSUES. METABOLISM: BIOTRANSFORMATION, PRIMARILY IN THE LIVER, WHERE TOXINS MAY BE CONVERTED TO MORE OR LESS HARMFUL FORMS. EXCRETION: REMOVAL OF TOXINS THROUGH URINE, FECES, SWEAT, OR EXHALATION. THIS PHASE HELPS DETERMINE THE TOXICOKINETICS (TIME COURSE) OF THE SUBSTANCE IN THE BODY. 3. TOXICODYNAMIC PHASE THIS PHASE EXPLORES HOW THE TOXIN INTERACTS WITH THE BODY'S CELLS, TISSUES, OR ORGANS TO CAUSE HARM. IT INVOLVES: MECHANISM OF ACTION: HOW THE TOXIN CAUSES CELLULAR OR SYSTEMIC EFFECTS (E.G., ENZYME INHIBITION, DNA DAMAGE). TARGET ORGANS: SPECIFIC ORGANS MOST AFFECTED BY THE TOXIN (E.G., LIVER FOR ALCOHOL, LUNGS FOR ASBESTOS). ADVERSE EFFECTS: ACUTE OR CHRONIC EFFECTS SUCH AS IRRITATION, ORGAN DAMAGE, CARCINOGENESIS, OR DEATH.  THREE FUNDAMENTAL LAWS IN TOXICOLOGY 1. THE DOSE-RESPONSE PRINCIPLE STATEMENT: "THE DOSE MAKES THE POISON.“ PARACELSUS: 15TH CENTURY GERMAN PHYSICIAN EXPLANATION: ANY SUBSTANCE CAN BE TOXIC DEPENDING ON THE DOSE; EVEN ESSENTIAL NUTRIENTS AND WATER CAN CAUSE HARM AT EXCESSIVE LEVELS. TOXIC EFFECTS INCREASE WITH DOSE, OFTEN FOLLOWING A PREDICTABLE RELATIONSHIP (LINEAR OR NON-LINEAR). IMPLICATION: DETERMINES THRESHOLDS FOR SAFE EXPOSURE AND HELPS ESTABLISH ACCEPTABLE DAILY INTAKE (ADI) AND PERMISSIBLE EXPOSURE LIMITS (PEL). 2. THE INDIVIDUAL SUSCEPTIBILITY PRINCIPLE STATEMENT: "TOXIC EFFECTS VARY BETWEEN INDIVIDUALS." EXPLANATION: INDIVIDUAL DIFFERENCES, SUCH AS GENETICS, AGE, SEX, HEALTH STATUS, AND ENVIRONMENTAL FACTORS, INFLUENCE A PERSON'S RESPONSE TO TOXIC SUBSTANCES. FOR EXAMPLE, CHILDREN, THE ELDERLY, OR INDIVIDUALS WITH PRE-EXISTING CONDITIONS MAY BE MORE SENSITIVE TO CERTAIN TOXINS. IMPLICATION: PERSONALIZES RISK ASSESSMENT AND GUIDES REGULATORY STANDARDS TO PROTECT VULNERABLE POPULATIONS. 3. THE CHEMICAL SPECIFICITY PRINCIPLE STATEMENT: "THE TOXIC EFFECT OF A SUBSTANCE DEPENDS ON ITS CHEMICAL NATURE AND INTERACTIONS." EXPLANATION: DIFFERENT CHEMICALS CAUSE TOXICITY THROUGH SPECIFIC MECHANISMS, TARGETING CERTAIN ORGANS OR SYSTEMS. TOXICITY ALSO DEPENDS ON FACTORS LIKE SOLUBILITY, BIOAVAILABILITY, METABOLISM, AND INTERACTIONS WITH OTHER SUBSTANCES. IMPLICATION: HIGHLIGHTS THE NEED FOR DETAILED ANALYSIS OF EACH CHEMICAL TO UNDERSTAND ITS UNIQUE TOXICOLOGICAL PROFILE.  TOXICOKINETICS AND TOXICODYNAMICS TOXICOKINETICS: HOW A SUBSTANCE IS ABSORBED, DISTRIBUTED, METABOLIZED, AND EXCRETED (ADME). TOXICODYNAMICS: HOW A SUBSTANCE INTERACTS WITH BIOLOGICAL SYSTEMS TO CAUSE HARM (MECHANISM OF ACTION).  IMPORTANT CONCEPTS FOR TOXICOLOGISTS A. ZERO-ORDER KINETICS DEFINITION: A FIXED AMOUNT OF A DRUG OR TOXIN IS ELIMINATED PER UNIT OF TIME, REGARDLESS OF ITS CONCENTRATION IN THE BODY. KEY CHARACTERISTICS: ELIMINATION RATE IS CONSTANT. OCCURS WHEN METABOLIC ENZYMES OR ELIMINATION PATHWAYS ARE SATURATED. EXAMPLES: ETHANOL AT HIGH DOSES. ASPIRIN AND PHENYTOIN (AT TOXIC LEVELS). B. FIRST-ORDER KINETICS DEFINITION: A CONSTANT PROPORTION (PERCENTAGE) OF A DRUG OR TOXIN IS ELIMINATED PER UNIT OF TIME. KEY CHARACTERISTICS: ELIMINATION RATE DEPENDS ON THE CONCENTRATION OF THE SUBSTANCE. MOST DRUGS FOLLOW FIRST-ORDER KINETICS AT THERAPEUTIC DOSES. EXAMPLE: ELIMINATION OF CAFFEINE OR MOST MEDICATIONS AT NORMAL DOSES. C. SERUM HALF-LIFE (T½) DEFINITION: THE TIME REQUIRED FOR THE CONCENTRATION OF A SUBSTANCE IN THE BLOOD TO DECREASE BY 50%. KEY CHARACTERISTICS: INDICATES HOW LONG A DRUG OR TOXIN STAYS IN THE BODY. AFFECTED BY FACTORS LIKE METABOLISM, RENAL FUNCTION, AND VOLUME OF DISTRIBUTION. USED TO DETERMINE DOSING INTERVALS AND DURATION OF TOXICITY. FORMULA: EXAMPLE: ACETAMINOPHEN HAS A HALF-LIFE OF 2-3 HOURS UNDER NORMAL CONDITIONS. D. FIRST-PASS EFFECT DEFINITION: THE METABOLISM OF A DRUG OR TOXIN BY THE LIVER AND GASTROINTESTINAL TRACT BEFORE IT REACHES SYSTEMIC CIRCULATION. KEY CHARACTERISTICS: REDUCES THE BIOAVAILABILITY OF ORALLY ADMINISTERED SUBSTANCES. DRUGS WITH SIGNIFICANT FIRST-PASS METABOLISM OFTEN REQUIRE ALTERNATIVE ADMINISTRATION ROUTES (E.G., IV, SUBLINGUAL). EXAMPLES: NITROGLYCERIN, PROPRANOLOL, AND MORPHINE. E. STEADY STATE DEFINITION: THE POINT AT WHICH THE RATE OF DRUG ADMINISTRATION EQUALS THE RATE OF ELIMINATION, RESULTING IN A CONSTANT PLASMA CONCENTRATION. KEY CHARACTERISTICS: ACHIEVED AFTER APPROXIMATELY 4-5 HALF-LIVES OF THE SUBSTANCE. IMPORTANT FOR MAINTAINING THERAPEUTIC LEVELS OF DRUGS. EXAMPLE: ADMINISTERING A DRUG LIKE DIGOXIN AT REGULAR INTERVALS TO REACH AND MAINTAIN THERAPEUTIC STEADY-STATE CONCENTRATIONS.  FACTORS THAT CHANGE PHARMACOKINETICS PHARMACOKINETICS INVOLVES THE PROCESSES OF ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) OF SUBSTANCES. VARIOUS FACTORS CAN ALTER THESE PROCESSES, INCLUDING: A. RENAL FUNCTION IMPACT ON PHARMACOKINETICS: THE KIDNEYS ARE ESSENTIAL FOR THE EXCRETION OF MANY DRUGS AND THEIR METABOLITES. IMPAIRED RENAL FUNCTION CAN LEAD TO REDUCED ELIMINATION, PROLONGED DRUG HALF-LIFE, AND INCREASED RISK OF TOXICITY. EFFECTS: DECREASED CLEARANCE: ACCUMULATION OF DRUGS EXCRETED VIA THE KIDNEYS (E.G., AMINOGLYCOSIDES, DIGOXIN, LITHIUM). ALTERED DRUG DOSAGE: DOSAGES OFTEN NEED ADJUSTMENT BASED ON CREATININE CLEARANCE (CRCL) OR ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). CHANGES IN PROTEIN BINDING: UREMIA CAN REDUCE PLASMA PROTEIN BINDING, INCREASING FREE DRUG LEVELS. EXAMPLES: ACCUMULATION OF RENALLY EXCRETED DRUGS LIKE VANCOMYCIN OR METFORMIN IN PATIENTS WITH CHRONIC KIDNEY DISEASE. B. HEPATIC FUNCTION IMPACT ON PHARMACOKINETICS: THE LIVER IS CRITICAL FOR DRUG METABOLISM, ESPECIALLY VIA PHASE I (OXIDATION, REDUCTION) AND PHASE II (CONJUGATION) REACTIONS. IMPAIRED LIVER FUNCTION CAN DECREASE DRUG METABOLISM AND INCREASE SYSTEMIC DRUG LEVELS. EFFECTS: REDUCED METABOLISM: DRUGS METABOLIZED BY THE LIVER (E.G., BENZODIAZEPINES, OPIOIDS) MAY ACCUMULATE IN PATIENTS WITH LIVER DISEASE. FIRST-PASS EFFECT ALTERATION: DRUGS WITH SIGNIFICANT FIRST-PASS METABOLISM (E.G., PROPRANOLOL) MAY EXHIBIT INCREASED BIOAVAILABILITY IN LIVER DYSFUNCTION. ALTERED PROTEIN BINDING: HYPOALBUMINEMIA IN LIVER DISEASE REDUCES BINDING OF PROTEIN-BOUND DRUGS, INCREASING FREE (ACTIVE) DRUG LEVELS. EXAMPLES: INCREASED SENSITIVITY TO DRUGS LIKE WARFARIN AND THEOPHYLLINE IN PATIENTS WITH CIRRHOSIS. C. SATURATION KINETICS IMPACT ON PHARMACOKINETICS: SOME DRUGS FOLLOW ZERO-ORDER KINETICS WHEN METABOLIC PATHWAYS OR ELIMINATION PROCESSES BECOME SATURATED. BEYOND THIS POINT, THE RATE OF ELIMINATION IS CONSTANT, REGARDLESS OF DRUG CONCENTRATION. EFFECTS: NONLINEAR PHARMACOKINETICS: SMALL INCREASES IN DOSE CAN LEAD TO DISPROPORTIONATE INCREASES IN PLASMA LEVELS, INCREASING THE RISK OF TOXICITY. DELAYED ELIMINATION: ONCE SATURATED, ELIMINATION TAKES LONGER, EVEN AFTER STOPPING THE DRUG. EXAMPLES: PHENYTOIN: EXHIBITS SATURATION KINETICS AT THERAPEUTIC DOSES; SMALL DOSE INCREASES CAN LEAD TO TOXICITY. ETHANOL: METABOLIZED AT A CONSTANT RATE DUE TO ENZYME SATURATION.  DISTRIBUTION IS THE PROCESS IN WHICH A CHEMICAL AGENT TRANSLOCATE THROUGHOUT THE BODY. -BLOOD CARRIES THE AGENT TO AND FROM ITS SITE OF ACTION, STORAGE DEPOTS, ORGAN OF TRANSFORMATION AND ORGANS OF ELIMINATION -RATE OF DISTRIBUTION (RAPID) DEPENDENT UPON: BLOOD FLOW CHARACTERISTICS OF TOXICANT (AFFINITY FOR THE TISSUE AND THE PARTITION COEFFICIENT) OVER TIME  PATHOLOGY OF DRUG TOXICITY THE STUDY OF DRUG TOXICITY INVOLVES UNDERSTANDING HOW DRUGS CAN CAUSE HARM TO VARIOUS TISSUES AND ORGANS OVER TIME. THE PATHOLOGY OF DRUG TOXICITY INCLUDES THE EFFECTS OF SUBSTANCES AT DIFFERENT TIMES, HOW THEY IMPACT CELLULAR INTEGRITY, AND THEIR EFFECTS ON SPECIFIC ORGANS AND TISSUES. 1. TEMPORAL ASPECTS OF TOXICITY (ACUTE VS. CHRONIC) ACUTE TOXICITY DEFINITION: TOXIC EFFECTS THAT OCCUR AFTER A SINGLE EXPOSURE OR MULTIPLE EXPOSURES OVER A SHORT PERIOD (TYPICALLY WITHIN 24 HOURS). MECHANISM: RESULTS FROM A HIGH DOSE OF A DRUG OR TOXIC SUBSTANCE OVERWHELMING THE BODY’S DEFENSE MECHANISMS. DAMAGE OCCURS RAPIDLY, AND SYMPTOMS APPEAR QUICKLY AFTER EXPOSURE. EXAMPLES: ACUTE OVERDOSE OF ACETAMINOPHEN: CAN LEAD TO LIVER DAMAGE OR FAILURE WITHIN HOURS. CARBON MONOXIDE POISONING: RAPID ONSET OF HYPOXIA LEADING TO NEUROLOGICAL AND CARDIOVASCULAR DAMAGE. CHRONIC TOXICITY DEFINITION: TOXIC EFFECTS THAT DEVELOP OVER A LONG PERIOD OF REPEATED EXPOSURE, TYPICALLY FROM LOW TO MODERATE DOSES. MECHANISM: LONG-TERM EXPOSURE TO A SUBSTANCE CAUSES CUMULATIVE DAMAGE TO ORGANS OR TISSUES, OFTEN DUE TO GRADUAL ACCUMULATION OR SLOW CELLULAR DAMAGE. CHRONIC TOXICITY MAY LEAD TO DISEASES SUCH AS CANCER, LIVER CIRRHOSIS, OR KIDNEY FAILURE. EXAMPLES: CHRONIC ALCOHOL CONSUMPTION: LEADS TO LIVER CIRRHOSIS, FATTY LIVER DISEASE, AND INCREASED CANCER RISK. CIGARETTE SMOKE: CHRONIC EXPOSURE LEADS TO LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND CARDIOVASCULAR DISEASES. 2. CELLULAR TOXICITY: APOPTOSIS AND NECROSIS APOPTOSIS (PROGRAMMED CELL DEATH) DEFINITION: A REGULATED PROCESS OF CELL DEATH WHERE THE CELL ACTIVELY PARTICIPATES IN ITS OWN DESTRUCTION. MECHANISM: OFTEN TRIGGERED BY SIGNALS LIKE DNA DAMAGE, OXIDATIVE STRESS, OR DRUG-INDUCED CELLULAR INJURY. CELLS SHRINK, FRAGMENT, AND ARE PHAGOCYTOSED BY NEIGHBORING CELLS WITHOUT CAUSING INFLAMMATION. APOPTOSIS HELPS TO ELIMINATE DAMAGED CELLS, PREVENTING FURTHER HARM OR MUTATIONS. EXAMPLES: CHEMOTHERAPY DRUGS LIKE CISPLATIN AND ETOPOSIDE INDUCE APOPTOSIS IN CANCER CELLS. TOXICANTS LIKE CYTOCHROME P450 METABOLITES CAN LEAD TO APOPTOSIS IN LIVER CELLS. NECROSIS (UNCONTROLLED CELL DEATH) DEFINITION: A FORM OF CELL DEATH CAUSED BY ACUTE DAMAGE TO THE CELL, OFTEN DUE TO EXCESSIVE INJURY OR EXPOSURE TO TOXIC SUBSTANCES. MECHANISM: INVOLVES SWELLING OF THE CELL, RUPTURE OF THE MEMBRANE, AND RELEASE OF INTRACELLULAR CONTENTS INTO THE SURROUNDING TISSUES, WHICH CAN LEAD TO INFLAMMATION. NECROSIS IS OFTEN ASSOCIATED WITH SIGNIFICANT TISSUE INJURY AND CAN EXACERBATE LOCAL INFLAMMATION. EXAMPLES: ISCHEMIA OR HYPOXIA LEADING TO NECROSIS IN TISSUES (E.G., MYOCARDIAL INFARCTION CAUSING HEART MUSCLE NECROSIS). ACETAMINOPHEN OVERDOSE: CAUSES LIVER CELL NECROSIS WHEN GLUTATHIONE STORES ARE DEPLETED. 3. ORGAN & TISSUE TOXICITY LIVER TOXICITY MECHANISM: THE LIVER IS HIGHLY INVOLVED IN DRUG METABOLISM AND DETOXIFICATION, MAKING IT A PRIME TARGET FOR DRUG TOXICITY. HEPATOTOXICITY CAN RESULT FROM DRUG-INDUCED LIVER INJURY (DILI) CAUSED BY METABOLITES, OXIDATIVE STRESS, OR DIRECT HEPATOCYTE DAMAGE. HEPATIC TOXICITY MAY MANIFEST AS FATTY LIVER, HEPATITIS, CIRRHOSIS, OR LIVER FAILURE. EXAMPLES: ACETAMINOPHEN OVERDOSE: THE LIVER METABOLIZES ACETAMINOPHEN INTO TOXIC METABOLITES, CAUSING NECROSIS AND LIVER FAILURE. METHOTREXATE: LONG-TERM USE CAN CAUSE LIVER FIBROSIS AND CIRRHOSIS. KIDNEY TOXICITY MECHANISM: KIDNEYS FILTER MANY DRUGS, AND TOXIC SUBSTANCES CAN ACCUMULATE IN RENAL TISSUE, LEADING TO NEPHROTOXICITY. CAN LEAD TO GLOMERULAR, TUBULAR, OR INTERSTITIAL INJURY. EXAMPLES: AMINOGLYCOSIDE ANTIBIOTICS (E.G., GENTAMICIN) CAN CAUSE ACUTE TUBULAR NECROSIS. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS): CHRONIC USE MAY CAUSE INTERSTITIAL NEPHRITIS OR GLOMERULONEPHRITIS.  CARDIOVASCULAR TOXICITY MECHANISM: DRUGS CAN AFFECT THE HEART MUSCLE, BLOOD VESSELS, OR CONDUCTION SYSTEM, LEADING TO ARRHYTHMIAS, HEART FAILURE, OR VASCULAR DAMAGE. EXAMPLES: DIGOXIN TOXICITY: CAN CAUSE ARRHYTHMIAS, BRADYCARDIA, AND HEART BLOCK. TRICYCLIC ANTIDEPRESSANTS (TCAS): OVERDOSE CAN LEAD TO CARDIAC ARRHYTHMIAS DUE TO SODIUM CHANNEL BLOCKADE. LUNG TOXICITY MECHANISM: SOME DRUGS CAN DAMAGE LUNG TISSUE BY INDUCING INFLAMMATION, FIBROSIS, OR DIRECT CELLULAR INJURY. EXAMPLES: AMIODARONE: LONG-TERM USE CAN LEAD TO PULMONARY FIBROSIS. METHOTREXATE: CAN CAUSE PNEUMONITIS AND FIBROSIS. NEUROTOXICITY MECHANISM: DRUGS CAN CAUSE DAMAGE TO NEURONS OR GLIAL CELLS, RESULTING IN DYSFUNCTION OF THE CENTRAL OR PERIPHERAL NERVOUS SYSTEM. EXAMPLES: LEAD POISONING: CAUSES PERIPHERAL NEUROPATHY AND BRAIN DAMAGE, ESPECIALLY IN CHILDREN. CHEMOTHERAPY-INDUCED NEUROPATHY: DRUGS LIKE VINCRISTINE CAN CAUSE SENSORY AND MOTOR NEUROPATHY. ENDOCRINE TOXICITY MECHANISM: SOME DRUGS INTERFERE WITH THE PRODUCTION, RELEASE, OR ACTION OF HORMONES, AFFECTING VARIOUS ENDOCRINE ORGANS. EXAMPLES: CORTICOSTEROIDS: LONG-TERM USE CAN SUPPRESS THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND CAUSE ADRENAL INSUFFICIENCY. THYROID TOXICITY: DRUGS LIKE AMIODARONE CAN ALTER THYROID FUNCTION, LEADING TO HYPOTHYROIDISM OR HYPERTHYROIDISM  UNDERSTANDING THE PATHOLOGY OF DRUG TOXICITY IS ESSENTIAL FOR DIAGNOSING, MANAGING, AND PREVENTING ADVERSE DRUG EFFECTS. IT INVOLVES RECOGNIZING THE TEMPORAL NATURE OF TOXICITY (ACUTE VS. CHRONIC), UNDERSTANDING HOW DRUGS IMPACT CELLULAR INTEGRITY (APOPTOSIS VS. NECROSIS), AND IDENTIFYING SPECIFIC ORGAN SYSTEMS AFFECTED BY TOXIC SUBSTANCES (LIVER, KIDNEY, CARDIOVASCULAR, ETC.).  MECHANISMS OF DRUG TOXICITY DRUG TOXICITY CAN OCCUR THROUGH VARIOUS MECHANISMS THAT AFFECT THE BODY IN DIFFERENT WAYS. UNDERSTANDING THESE MECHANISMS IS KEY TO PREDICTING, MANAGING, AND PREVENTING ADVERSE EFFECTS. HERE ARE THE PRIMARY MECHANISMS OF DRUG TOXICITY: 1. ‘‘ON-TARGET’’ ADVERSE EFFECTS DEFINITION: TOXIC EFFECTS THAT OCCUR WHEN A DRUG INTERACTS WITH ITS INTENDED TARGET IN THE BODY BUT CAUSES UNWANTED OR EXCESSIVE EFFECTS DUE TO THE DOSE OR THE SPECIFIC CIRCUMSTANCES OF THE PATIENT. MECHANISM: THE DRUG BINDS TO ITS PRIMARY RECEPTOR OR ENZYME, LEADING TO THE EXPECTED PHARMACOLOGICAL RESPONSE, BUT AT A LEVEL THAT CAUSES TOXICITY. DOSE-RELATED: THESE EFFECTS ARE OFTEN DOSE-DEPENDENT AND PREDICTABLE WHEN THE DRUG CONCENTRATION IS ABOVE A CERTAIN THRESHOLD. EXAMPLES: ANTICOAGULANTS: OVERDOSING WITH WARFARIN OR HEPARIN CAN LEAD TO BLEEDING COMPLICATIONS DUE TO EXCESSIVE INHIBITION OF CLOTTING FACTORS. BETA-BLOCKERS: EXCESSIVE DOSES MAY CAUSE BRADYCARDIA, HYPOTENSION, OR HEART BLOCK DUE TO OVERSTIMULATION OF THE BETA- ADRENERGIC RECEPTORS. 2. ‘‘OFF-TARGET’’ ADVERSE EFFECTS DEFINITION: TOXIC EFFECTS THAT OCCUR WHEN A DRUG INTERACTS WITH UNINTENDED TARGETS IN THE BODY, LEADING TO ADVERSE EFFECTS THAT ARE NOT RELATED TO ITS THERAPEUTIC ACTION. MECHANISM: THE DRUG BINDS TO RECEPTORS, ENZYMES, OR ION CHANNELS THAT ARE NOT ITS PRIMARY TARGET, RESULTING IN UNINTENDED BIOLOGICAL RESPONSES. THESE EFFECTS ARE OFTEN UNPREDICTABLE AND CAN VARY SIGNIFICANTLY BETWEEN INDIVIDUALS. EXAMPLES: ANTIPSYCHOTICS: DRUGS LIKE CHLORPROMAZINE OR HALOPERIDOL MAY INTERACT WITH HISTAMINE RECEPTORS (CAUSING SEDATION) OR MUSCARINIC RECEPTORS (LEADING TO DRY MOUTH, CONSTIPATION). ANTIBIOTICS: SOME ANTIBIOTICS (E.G., TETRACYCLINE) MAY AFFECT MITOCHONDRIAL RIBOSOMES, LEADING TO TOXICITY IN CELLS WITH HIGH MITOCHONDRIAL ACTIVITY. 3. PRODUCTION OF TOXIC METABOLITES DEFINITION: THE CONVERSION OF A DRUG INTO A TOXIC COMPOUND VIA METABOLIC PROCESSES IN THE LIVER, USUALLY BY CYTOCHROME P450 ENZYMES. MECHANISM: THE DRUG OR ITS METABOLITES MAY BIND COVALENTLY TO CELLULAR MACROMOLECULES (PROTEINS, LIPIDS, OR DNA), LEADING TO CELLULAR DAMAGE. THE METABOLITES CAN CAUSE OXIDATIVE STRESS, CELLULAR DAMAGE, AND INFLAMMATION. EXAMPLES: ACETAMINOPHEN (PARACETAMOL): WHEN TAKEN IN OVERDOSE, ACETAMINOPHEN IS METABOLIZED TO A HIGHLY REACTIVE METABOLITE (NAPQI) THAT CAN CAUSE LIVER CELL NECROSIS. ISONIAZID: A TUBERCULOSIS DRUG THAT CAN GENERATE TOXIC METABOLITES LEADING TO HEPATOTOXICITY. 4. PRODUCTION OF HARMFUL IMMUNE RESPONSES DEFINITION: TOXICITY THAT ARISES FROM THE IMMUNE SYSTEM’S REACTION TO THE DRUG OR ITS METABOLITES. THIS CAN MANIFEST AS HYPERSENSITIVITY OR AUTOIMMUNE RESPONSES. MECHANISM: THE DRUG OR ITS METABOLITES CAN ACT AS HAPTENS, BINDING TO PROTEINS AND TRIGGERING AN IMMUNE RESPONSE. THIS MAY RESULT IN TYPE I (IMMEDIATE HYPERSENSITIVITY), TYPE II (CYTOTOXIC), TYPE III (IMMUNE COMPLEX), OR TYPE IV (DELAYED-TYPE HYPERSENSITIVITY) REACTIONS. EXAMPLES: PENICILLIN: CAN TRIGGER AN ALLERGIC REACTION SUCH AS RASH, ANAPHYLAXIS, OR HEMOLYTIC ANEMIA. SULFONAMIDES: CAN CAUSE STEVENS-JOHNSON SYNDROME, A SEVERE SKIN REACTION, DUE TO IMMUNE SYSTEM ACTIVATION. 5. IDIOSYNCRATIC RESPONSES DEFINITION: UNPREDICTABLE AND ATYPICAL REACTIONS TO A DRUG THAT ARE NOT RELATED TO ITS KNOWN PHARMACOLOGICAL EFFECTS. THESE RESPONSES ARE OFTEN GENETIC IN ORIGIN AND MAY VARY GREATLY BETWEEN INDIVIDUALS. MECHANISM: THESE RESPONSES CAN BE DUE TO GENETIC POLYMORPHISMS THAT AFFECT DRUG METABOLISM, RECEPTOR BINDING, OR IMMUNE SYSTEM FUNCTION. THE MECHANISM IS USUALLY NOT WELL UNDERSTOOD, AND THE ADVERSE RESPONSE MAY NOT BE RELATED TO THE DOSE OR TYPICAL PHARMACOLOGICAL EFFECTS OF THE DRUG. EXAMPLES: CLOZAPINE: AN ATYPICAL ANTIPSYCHOTIC THAT CAN CAUSE AGRANULOCYTOSIS IN A SMALL NUMBER OF PATIENTS DUE TO IMMUNE SYSTEM DYSREGULATION. GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY: PATIENTS WITH THIS GENETIC DEFICIENCY CAN DEVELOP HEMOLYSIS WHEN EXPOSED TO CERTAIN DRUGS LIKE SULFONAMIDES OR PRIMAQUINE.  UNDERSTANDING THE VARIOUS MECHANISMS OF DRUG TOXICITY HELPS HEALTHCARE PROVIDERS ANTICIPATE AND MANAGE ADVERSE EFFECTS MORE EFFECTIVELY. THIS INCLUDES RECOGNIZING POTENTIAL ON-TARGET AND OFF- TARGET EFFECTS, IDENTIFYING TOXIC METABOLITES, UNDERSTANDING IMMUNE-MEDIATED TOXICITY, AND ACCOUNTING FOR IDIOSYNCRATIC RESPONSES. RECOGNIZING THESE MECHANISMS IS VITAL FOR SAFE DRUG USE, ADJUSTING DOSAGES, AND IDENTIFYING PATIENTS AT HIGHER RISK OF ADVERSE REACTIONS. TOXIC EFFECTS OF CHEMICALS (CLASSIFICATION) A. NON-THRESHOLD AND THRESHOLD EFFECTS  B. DURATION OF EXPOSURE 1. ACUTE EFFECTS IS A TERM DESCRIBING THE INITIAL EFFECTS OF EXPOSURE TO VERY HIGH DOSES OR THE EFFECTS THAT RESULT FROM A SINGLE EXPOSURE, NOT THE SEVERITY OF THE EFFECTS. 2. CHRONIC EFFECTS IS A TERM REFERRING EITHER TO LIFETIME EXPOSURES OR TO THE LONGEST PERIOD OF EXPOSURE TIME NEEDED TO PRODUCE AN EFFECT. IT DOES NOT REFLECT THE PERSISTENCE OR REVERSIBILITY OF THE EFFECT BUT SIMPLY THE LENGTH OF EXPOSURE. 3. SUBCHRONIC EFFECTS IS A TERM REFERRING TO ALL LENGTHS OF EXPOSURES BETWEEN ACUTE AND CHRONIC.  C. REVERSIBILITY OF EFFECTS 1. REVERSIBLE EFFECTS OCCUR WHEN NO PERMANENT CHANGE IS MADE IN THE BIOLOGIC SYSTEM. THE MECHANISM OF REVERSIBILITY DEPENDS ON THE CHEMICAL AND ITS TOXIC EFFECT. 2. IRREVERSIBLE EFFECTS OCCUR WHEN THE BIOLOGIC SYSTEM DOES NOT RETURN TO ITS FORMER STATE AFTER REMOVAL OF THE TOXIC INSULT; SOME PERMANENT CHANGE HAS OCCURRED AS A RESULT OF THE CHEMICAL INTERACTION. 3. CUMULATIVE EFFECTS OCCUR WHEN THE CHEMICAL IS SEQUESTERED (USU. IN A TARGET ORGAN) AND DOES NOT AFFECT THE ORGAN SYSTEM UNTIL A CRITICAL BODY BURDEN IS PRESENT. TOXIC EFFECTS MAY BE DELAYED OR IMMEDIATE, DIRECT OR INDIRECT, LOCAL OR SYSTEMIC. THEY MAY BE DESCRIBED AS GRADED OR “ALL OR NONE” (QUANTAL). EXAMPLES: 1. STRONG ACID MAY HAVE A DIRECT, LOCAL TOXIC EFFECT ON SKIN WHICH IS IMMEDIATE BUT REVERSIBLE. 2. PARACETAMOL HAS A DIRECT BUT SYSTEMIC EFFECT LEADING TO LIVER DAMAGE, WHICH IS SOMEWHAT DELAYED. 3. ALTERNATIVELY PENICILLIN HAS AN INDIRECT AND SOMETIMES IMMEDIATE SYSTEMIC EFFECT ON SEVERAL BODY SYSTEMS WHICH IS REVERSIBLE. 4. CANCER CAUSED BY CHEMICALS SUCH DIMETHYLNITROSAMINE OR BENZOPYRENE, IS A RESPONSE WHICH MAY BE LOCAL OR SYSTEMIC AND IS GENERALLY IRREVERSIBLE AND OFTEN MUCH DELAYED, BUT USUALLY IT IS THE RESULT OF A DIRECT EFFECT ON A PARTICULAR ORGAN  CLASSIFICATION OF TOXIC RESPONSES 1. ADDITIVE – WHEN 2 SUBSTANCES ARE GIVEN TO AN ANIMAL TOGETHER, THE RESULTING TOXIC RESPONSE MAY SIMPLY BE THE SUM OF THE TWO INDIVIDUAL RESPONSES. THIS SITUATION WHERE THERE IS NO INTERACTION IS KNOWN AS ADDITIVE EFFECT. 2. SYNERGISM – EXPOSURE TO 2 TOXIC COMPOUNDS IS GREATER THAN THE SUM OF THE INDIVIDUAL RESPONSES. EX: CCL4 AND ETOH TAKEN TOGETHER ARE MORE TOXIC TO THE LIVER THAN EACH IS SEPARATELY. 3. POTENTIATION – IS SIMILAR TO SYNERGISM EXCEPT THAT THE TWO SUBSTANCES IN QUESTION HAVE DIFFERENT TOXIC EFFECTS OR PERHAPS ONLY ONE IS TOXIC. EX: WHEN DISULFIRAM IS GIVEN TO ALCOHOLICS, SUBSEQUENT INTAKE OF ETHANOL CAUSES TOXIC EFFECTS TO OCCUR DUE TO INTERFERENCE IN THE METABOLISM OF ETHANOL BY DISULFIRAM. DISULFIRAM HAS NO TOXIC EFFECT AT THE DOSES ADMINISTERED HOWEVER. 4. COALITIVE – THE EFFECTS PRODUCED WHEN ADMINISTRATION OF TWO SUBSTANCES TO AN ANIMAL LEAD TO A TOXIC RESPONSE WHICH IS ENTIRELY DIFFERENT FROM THAT OF EITHER OF THE COMPOUNDS. 5. ANTAGONISM – OCCUR IN WHICH ONE SUBSTANCE DECREASES THE TOXIC EFFECT OF ANOTHER TOXIC AGENT. THUS THE OVERALL TOXIC EFFECT OF THE TWO COMPOUNDS TOGETHER IS LESS THAN ADDITIVE. *FUNCTIONAL ANTAGONISM – THE EFFECTS ARE OPPOSITE AND THEREFORE COUNTERBALANCED *CHEMICAL ANTAGONISM – A COMPLEX IS PRODUCED *DISPOSITIONAL ANTAGONISM – THE ADME OF THE TOXIC COMPOUND IS INFLUENCED *RECEPTOR ANTAGONISM – TWO SUBSTANCES INTERACT WITH THE SAME RECEPTOR AND THEREBY REDUCE THE TOXIC RESPONSE  COMMON TOXIC SYNDROMES 1. ANTICHOLINERGIC SYNDROME THE SIGNS AND SYMPTOMS OF ANTICHOLINERGIC TOXICITY RESULT FROM THE COMPETITIVE, REVERSIBLE BLOCKADE OF CENTRAL AND PERIPHERAL CHOLINERGIC NERVE FIBERS. A USEFUL MNEMONIC SUMMARIZES THESE CLINICAL FINDINGS IN PATIENTS IS: BLIND AS A BAT (MYDRIASIS); HOT AS A HARE (HYPERTHERMIA); RED AS A BEET (VASODILATATION); DRY AS A BONE (ANHIDROSIS); AND MAD AS A HATTER (DELIRIUM, PSYCHOSIS, HALLUCINATIONS), THE BLADDER LOSE THEIR TONE, AND THE HEART RUNS ALONE.  2. CHOLINERGIC SYNDROME ORGANOPHOSPHATES AND CARBAMATES ARE AMONG THE MOST COMMONLY USED CLASSES OF PESTICIDES AND ARE FOUND IN BOTH AGRICULTURAL AND HOUSEHOLD SETTINGS. THEIR WIDESPREAD USE HAS RESULTED IN A SUBSTANTIAL NUMBER OF HUMAN POISONINGS. THESE POTENT PESTICIDES ACT AS CHOLINESTERASE INHIBITORS, WHICH ALLOW THE ACCUMULATION OF ACETYLCHOLINE IN BOTH THE CENTRAL AND PERIPHERAL NEURAL SYNAPSES. MNEMONIC FOR CLINICAL SIGNS AND SYMPTOMS OF CHOLINERGIC POISONING (“SLUDGE”) SALIVATION LACRIMATION URINATION DEFECATION GASTROINTESTINAL SYMPTOMS EMESIS OR EYE FINDINGS (MIOSIS)  3. SYMPATHOMIMETIC SYNDROME IT IS CLASSICALLY BEEN ASCRIBED TO AMPHETAMINE (A-METHYLPHENYLETHYLAMINE) OR ITS STRUCTURAL ANALOGS. HOWEVER, MANY ADDITIONAL MEDICATIONS AND DRAGS Signs and OF ABUSE SHARE SIMILAR PHARMACOLOGICAL EFFECTS. THE ACTIVITY OF THESE Common cause Symptoms COMPOUNDS IS THOUGHT TO INVOLVE CATECHOLAMINE RELEASE FROM ADRENERGIC NERVE TERMINALS, INHIBITION OF REUPTAKE OF NEUROTRANSMITTERS, OR DIRECT STIMULATION OF ADRENERGIC RECEPTORS. THE CLINICAL PRESENTATION THEREFORE CONSISTS OF CNS STIMULATION, INCREASED SYMPATHETIC ACTIVITY, AND PROFOUND CARDIOVASCULAR EFFECTS.  4. DRESS SYNDROME A SEVERE ADVERSE CUTANEOUS DRUG REACTION THAT INCLUDED ABNORMALITIES OF BONE MARROW, LIVER AND RENAL FUNCTION. “DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS.” THE TRIAD OF RASH, FEVER AND INTERNAL ORGAN INVOLVEMENT ARE THE KEY FEATURES IN MAKING THIS DIAGNOSIS. IT IS USUALLY SEEN 2-8 WEEKS AFTER THE INITIATION OF A NEW DRUG OR WITHIN A DAY OF RE-EXPOSURE. THE RASH, WHICH CAN VARY IN APPEARANCE AND SEVERITY, IS MOST COMMONLY MORBILLIFORM (MEASLES-LIKE). THE ERUPTION OF THE RASH OFTEN PRECEDES OR COINCIDES WITH THE DEVELOPMENT OF A FEVER AND NON-SPECIFIC FINDINGS INCLUDING MALAISE, PHARYNGITIS, FACIAL EDEMA, AND LYMPHADENOPATHY. ANTICONVULSANTS AND SULFONAMIDES HAVE BEEN THE MOST COMMON DRUGS REPORTED TO CAUSE DRESS SYNDROME, WITH AN INCIDENCE RANGING FROM 1 IN 1,000 TO 1 IN 10,000 EXPOSURES. SOME OF THE OTHER DRUGS IMPLICATED IN THIS SYNDROME INCLUDE: PHENYTOIN, CARBAMAZEPINE, PHENOBARBITAL, LAMOTRIGINE, MINOCYCLINE, DAPSONE, ALLOPURINOL, NEVIRAPINE, AND ABACAVIR.  5. SEROTONIN SYNDROME THERE ARE NOW A LARGE NUMBER OF SEROTONERGIC AGENTS (E.G., SSRIS) USED THERAPEUTICALLY AND RECREATIONALLY. THIS SYNDROME INVOLVES MILD TO MODERATE NEUROMUSCULAR, COGNITIVE, AND AUTONOMIC ABNORMALITIES. SYMPTOMS INCLUDE CONFUSION, AGITATION, EUPHORIA/HYPOMANIA, RESTLESSNESS, SHIVERING, NAUSEA [SOMETIMES REFERRED TO AS A "HAPPY DRUNK" STATE]. PHYSICAL EXAM FINDINGS CAN BE MYOCLONUS, HYPERREFLEXIA, MUSCLE RIGIDITY, TREMOR, ATAXIA/INCOORDINATION, SWEATING, ELEVATED TEMPERATURE, NYSTAGMUS, UNREACTIVE PUPILS.  RECOMMENDED QUALITATIVE COLOR TESTS 1. SALICYLIC ACID – TRINDERS TEST 5. PARACETAMOL, PHENACETIN – O-CRESOL/AMMONIA TEST POSITIVE COLOR: VIOLET POSITIVE: STRONG BLUE TO BLUE BLACK 2. PHENOTHIAZINE – FPN TEST 6. PARAQUAT, DIQUAT – DITHIONITE TEST POSITIVE COLOR: FROM PINK TO RED, ORANGE, VIOLET OR POSITIVE COLOR: BLUE-BLACK (PARAQUAT) YELLOW- BLUE VARIATIONS GREEN (DIQUAT) 3. IMIPRAMINE AND RELATED COMPOUNDS (FORREST TEST ) 7. ETHANOL & OTHER VOLATILE REDUCING AGENTS – POSITIVE COLOR: YELLOW GREEN DEEPENING THROUGH DICHROMATE TEST DARK GREEN TO BLUE POSITIVE COLOR: ORANGE TO GREEN 4. TRICHLORO COMPOUNDS (INCLUDING CHLOROFORM, 8. CHLORATES & OTHER OXIDIZING AGENTS – CHLORAL HYDRATE, DIPHENYLAMINE TEST DICHLORALPHENAZONE,TRICHLOROETHYLENE) – FUJIWARA POSITIVE COLOR: STRONG BLUE TEST POSITIVE COLOR: INTENSE RED/PURPLE COLOR 9. FERROUS AND FERRIC ION – FERRICYANIDE / FERROCYANIDE TEST POSITIVE COLOR: DEEP BLUE PRECIPITATE  GENERAL APPROACH TO POISONED PATIENT: 1. HISTORY 2. PHYSICAL EXAM (VS, PULMONARY EDEMA, BREATH ODOR, SKIN FINDINGS, MOTOR TONE, BOWEL SOUNDS) 3. TOXIDROMES (CHOLINERGIC, ANTICHOLINERGIC, OPIOID DRUGS, SEDATIVE-HYPNOTICS, SYMPATHOMIMETICS, HALLUCINOGENS, EXTRAPYRAMIDAL, SEROTONERGIC, HEMOGLOBINOPATHIES, METAL FUME FEVER, WITHDRAWAL SYNDROMES) 4. MAJOR TOXIC SIGNS (CARDIAC DYSRHYTHMIAS, METABOLIC ACIDOSIS, COMA, HYPERTHERMIA, GI SYMPTOMS, SEIZURES) 5. DIAGNOSTIC STUDIES (ECG, CBC, LYTES, GLUCOSE, OSMOLALITY, BUN, CREATININE, CK, ABGS, SERUM LEVELS OF ASA, ACETAMINOPHEN & ETHANOL, ABDOMINAL X-RAYS, UA) 6. GENERAL TREATMENT MEASURES 7. LATENT COMPLICATIONS (HEPATOTOXICITY, GI HEMORRHAGE, RENAL FAILURE, DYSRHYTHMIAS, HYPERTENSION, HYPOTENSION, NEUROTOXICITY, RESPIRATORY PROBLEMS)  PHARMACISTS CAN HELP REDUCE MORBIDITY AND MORTALITY DUE TO POISONINGS AND OVERDOSES BY (1) RECOGNIZING THE SIGNS AND SYMPTOMS OF VARIOUS TYPES OF TOXIC EXPOSURE, (2) GUIDING EMERGENCY ROOM STAFF ON THE APPROPRIATE USE OF ANTIDOTES AND SUPPORTIVE THERAPIES, (3) HELPING TO ENSURE APPROPRIATE MONITORING OF PATIENTS FOR ANTIDOTE RESPONSE AND ADVERSE EFFECTS, AND (4) MANAGING THE PROCUREMENT AND STOCKING OF ANTIDOTES TO ENSURE THEIR TIMELY AVAILABILITY. STEP 1: SECURE THE - AIRWAY - BREATHING - CIRCULATION AND PERFORM A DIRECTED NEUROLOGICAL EXAMINATION A. DETERMINE LOC, GAG REFLEX, EFFECTIVENESS OF COUGH B. WHAT TO DO: ADMINISTER OXYGEN, MONITOR SAO2 & CARDIAC RHYTHM, ESTABLISH IV ACCESS, SUPPORT BP, AND CHECK BEDSIDE FINGERSTICK GLUCOSE.  STEP 2: CALL POISON CONTROL AND REVIEW MANAGEMENT - EFFECTS / COMPLICATIONS OF AGENTS - ANTIDOTES (IF ANY): - RECOMMENDED METHODS OF BLOCKING ABSORPTION AND ENHANCING ELIMINATION; - OTHER DEFINITIVE CARE A. GATHER INFORMATION B. BEGIN LABORATORY EVALUATION (ECG, GLUCOSE, ABG, CBC, ELECTROLYTES, BUN, CREATININE, UA  THE ABCDE APPROACH THE AIRWAY, BREATHING, CIRCULATION, DISABILITY, EXPOSURE (ABCDE) APPROACH IS A SYSTEMATIC APPROACH TO THE IMMEDIATE ASSESSMENT AND TREATMENT OF CRITICALLY ILL OR INJURED PATIENTS. THE APPROACH IS APPLICABLE IN ALL CLINICAL EMERGENCIES. IT CAN BE USED IN THE STREET WITHOUT ANY EQUIPMENT (FIGURE 7) OR, IN A MORE ADVANCED FORM, UPON ARRIVAL OF EMERGENCY MEDICAL SERVICES, IN EMERGENCY ROOMS, IN GENERAL WARDS OF HOSPITALS, OR IN INTENSIVE CARE UNITS.  STEP 3: ADMINISTER SPECIFIC ANTIDOTES (SEE LIST ON P.12) -FOR POISONING OF RAPID ONSET OR THAT MAY IMMEDIATELY THREATEN THE AIRWAY (E.G., CYANIDE, CHOLINERGIC POISONING WITH BRONCHORRHEA), ANTIDOTES SHOULD BE ADMINISTERED AS ART OF THE ABCS. -THIAMINE AND NALOXONE SHOULD BE ADMINISTERED ROUTINELY TO THE PATIENT WITH AN ALTERED LOC -GLUCOSE SHOULD BE ADMINISTERED TO ANY PATIENT WITH AN ALTERED LOC AND FINGERSTICK GLUCOSE ADMINISTRATION 1-2 HOURS POST- INGESTION) USUALLY ADMINISTERED AS AN INITIAL ORAL DOSE OF 50 G SUSPENDED IN 300 ML OF WATER FOLLOWED BY 50 G IN 300 ML OF WATER 4-HOURLY OR 25 MG IN 150 ML OF WATER 2-HOURLY, UP TO 200 G. MORE THAN 200 G MAY BE ADMINISTERED IF IT IS GIVEN WITH A CATHARTIC (E.G. SORBITOL) AND IT APPEARS IN THE STOOLS WITHIN 12 HR. EFFECTIVE IN THE TREATMENT OF SALICYLATE, QUINIDINE, QUININE, CHLOR-OQUINE, DAPSONE, DEXTROPROPOXYPHENE, DIGOXIN, MEPROBAMATE, BARBITURATES, CARBAMAZEPINE, TRICYCLIC ANTIDEPRESSANTS, PHENOTHIAZINES AND THEOPHYLLINE OVERDOSAGE. SIDE EFFECTS: CONSTIPATION/CHARCOAL IMPACTION; BRONCHIOLITIS OBLITERANS/PROGRESSIVE RESPIRATORY FAILURE CONTRAINDICATIONS: PHAIL (PESTICIDES, HEAVY METALS, ALKALIS/MINERAL ACIDS, ISOPROPYL ALCOHOL, LITHIUM)  -GASTRIC LAVAGE THIS IS PERFORMED USING 0.9% SALINE AND A 16 - 20 FRENCH GAUGE NASOGASTRIC TUBE (INSERTING THE TUBE TO A DISTANCE OF 10 CM GREATER THAN THE DISTANCE FROM THE XIPHISTERNUM TO THE BRIDGE OF THE NOSE OR INSERTING IT TO THE 55 CM MARK AT THE TIP OF THE NOSE IN AN ADULT), WITH THE PATIENT HEAD DOWN AND RIGHT SIDE UPPERMOST. WHEN THE PATIENT’S AIRWAY IS ASSESSED AS ‘PROTECTED’ (I.E. HAS EFFECTIVE GLOTTIC REFLEXES OR HAS AN ENDOTRACHEAL TUBE IN PLACE), THE STOMACH IS COMPLETELY ASPIRATED AND 50 ML OF SALINE IS INSTILLED AND ASPIRATED. THIS IS CONTINUED UNTIL THE GASTRIC ASPIRATE IS CLEAR, WHICH USUALLY OCCURS AFTER 500 ML OF SALINE HAS BEEN USE CONTRAINDICATED IN PATIENTS WHO HAVE INGESTED CORROSIVES (E.G. ACIDS OR ALKALIS) OR PETROLEUM DISTILLATES (E.G. KEROSENE, PETROL, EUCALYPTUS OIL, AS IT MAY CAUSE PERFORATION OF THE STOMACH OR ESOPHAGUS.  -WHOLE BOWEL IRRIGATION (USES: BODY PACKERS, ORAL OD WITH SUSTAINED RELEASE COMPOUNDS AND WITH AGENTS NOT ADSORBED BY ACTIVATED CHARCOAL) *DO NOT PERFORM GASTRIC EMPTYING PROCEDURE IF INGESTION IS A CAUSTIC SUBSTANCE OR A LOW VISCOSITY PETROLEUM DISTILLATE.  2. SYMPTOMATIC AND SUPPORTIVE CARE 3. ENHANCED POISON ELIMINATION -ALKALINE DIURESIS FORCED ACID DIURESIS HAS BEEN USED TO TREAT OVERDOSAGE OF PHENCYCLIDINE OR AMPHETAMINE, AND FORCED ALKALINE DIURESIS HAS BEEN USED TO TREAT PATIENTS WITH BARBITURATE OR SALICYLATE OVERDOSAGE. HOWEVER, UNLESS MANAGED VERY CAREFULLY, FORCED DIURETIC THERAPIES HAVE THE CAPACITY TO INCREASE RATHER THAN DECREASE MORTALITY DUE TO HYPOKALAEMIA AND FLUID OVERLOAD. -HEMODIALYSIS THIS MAY BE INDICATED FOR SEVERE SALICYLATE, PHENOBARBITONE, LITHIUM, ISOPROPANOL, METH-ANOL OR ETHYLENE GLYCOL POISONING. -HEMOPERFUSION THIS IS LARGELY AN UNPROVEN FORM OF THERAPY ALTHOUGH IT IS OFTEN RECOMMENDED FOR SEVERE THEOPHYLLINE OVERDOSAGE (PARTICULARLY IF SEVERE AND ASSOCIATED WITH VOMITING), METHOTREXATE POISONING (PARTICULARLY IN ASSOCIATION WITH RENAL FAILURE), DISOPYRAMIDE AND CAMPHOR OVERDOSAGE. CHARCOAL FILTERS ARE COMMONLY USED, ALTHOUGH POLYSTYRENE RESINS (E.G. AMBERLITE XAD-4) HAVE BEEN DEVELOPED WHICH HAVE A HIGH AFFINITY FOR LIPID- SOLUBLE COMPOUNDS.  4. ANTIDOTAL THERAPY ANTIDOTES MAY PLAY AN IMPORTANT ROLE IN THE TREATMENT OF POISONING. WHILE GOOD SUPPORTIVE CARE AND ELIMINATION TECHNIQUES MAY, IN MANY CASES, RESTORE A POISONED PATIENT TO GOOD HEALTH AND STABILIZE HIS OR HER BODY FUNCTIONS, THE APPROPRIATE USE OF ANTIDOTES AND OTHER AGENTS MAY GREATLY ENHANCE ELIMINATION AND COUNTERACT THE TOXIC ACTIONS OF THE POISON. IN CERTAIN CIRCUMSTANCES THEY MAY SIGNIFICANTLY REDUCE THE MEDICAL RESOURCES OTHERWISE NEEDED TO TREAT A PATIENT, SHORTEN THE PERIOD OF THERAPY, AND, IN SOME CASES, SAVE A PATIENT FROM DEATH. THUS, ANTIDOTES MAY SOMETIMES REDUCE THE OVERALL BURDEN ON THE HEALTH SERVICE OF MANAGING CASES OF POISONING. IN AREAS REMOTE FROM GOOD HOSPITAL SERVICES, AND PARTICULARLY IN DEVELOPING COUNTRIES THAT LACK ADEQUATE FACILITIES FOR SUPPORTIVE CARE, ANTIDOTES MAY BE EVEN MORE ESSENTIAL IN THE TREATMENT OF POISONING ANTIDOTES HAVE BEEN CLASSIFIED AS THOSE NEEDED: *IMMEDIATELY (WITHIN 30 MINUTES) *WITHIN 2 HOURS *WITHIN 6 HOURS  ANTIDOTES NEEDED IMMEDIATELY MUST BE STOCKED AT ALL HOSPITALS, AS WELL AS IN HEALTH CENTERS OR DOCTORS' SURGERIES IF THE NEAREST HOSPITAL IS SOME DISTANCE AWAY. IT MAY ALSO BE NECESSARY TO HAVE CERTAIN ANTIDOTES AVAILABLE AT PLACES OF WORK FOR USE UNDER MEDICAL SUPERVISION (E.G. IN FACTORIES USING CYANIDE). ANTIDOTES NEEDED WITHIN 2 HOURS CAN BE STOCKED AT CERTAIN MAIN HOSPITALS; PATIENTS CAN BE TAKEN TO THESE HOSPITALS FOR TREATMENT OR THE ANTIDOTES CAN BE TRANSPORTED - WITHIN THE TIME LIMIT - TO THE HEALTH FACILITIES AT WHICH TREATMENT IS PROVIDED. ANTIDOTES NEEDED WITHIN 6 HOURS MAY BE STOCKED AT CENTRAL REGIONAL DEPOTS, PROVIDED THAT THERE ARE ADEQUATE FACILITIES FOR TRANSPORTING THEM WITHIN THE TIME LIMIT. FOR ALL CATEGORIES OF ANTIDOTES, THERE IS THE FURTHER OPTION OF KEEPING A SMALL AMOUNT, SUFFICIENT TO START TREATMENT, IN STOCK LOCALLY, FURTHER SUPPLIES BEING OBTAINED FROM A CENTRAL SOURCE AS REQUIRED.  IN DECIDING WHERE ANTIDOTES SHOULD BE STOCKED, A NUMBER OF FACTORS SHOULD BE TAKEN INTO CONSIDERATION, NOTABLY THE FOLLOWING: *THE SIZE OF THE COUNTRY AND THE AREA TO BE COVERED BY A DEPOT; *THE DENSITY OF THE POPULATION; *THE INCIDENCE OF POISONINGS THAT REQUIRE SPECIAL THERAPEUTIC MEASURES AND/OR ANTIDOTES; *THE SOCIAL AND ECONOMIC ACTIVITIES OF THE REGION THAT MAY BE ASSOCIATED WITH A HIGH RISK OF POISONING; *THE DISTANCES OF HOSPITALS AND HEALTH CENTERS FROM THE DEPOT; *COMMUNICATIONS (ROAD, AIR SERVICES, ETC.) BETWEEN THE DEPOT AND THE HOSPITALS OR HEALTH CENTERS; *THE COST OF ANTIDOTES AND OF THE WASTAGE CAUSED BY EXPIRY OF EFFECTIVENESS COMPARED WITH THE COST OF TRANSPORT IN CASE OF EMERGENCY.  BETTER KNOWLEDGE OF THE MECHANISM OF ACTION OF TOXIC SUBSTANCES WOULD ENABLE MORE SPECIFIC ANTIDOTES TO BE DEVELOPED. APPROPRIATE RESEARCH ON ANTIDOTES IS ALSO ESSENTIAL AND SHOULD INCLUDE KINETIC, TOXICOLOGICAL, AND PHARMACODYNAMIC STUDIES IN BOTH ANIMALS AND HUMANS. THE PHARMACEUTICAL INDUSTRY COULD EXPLORE WAYS AND MEANS OF ENSURING THE MANUFACTURE AND DISTRIBUTION OF ANTIDOTES, INCLUDING FORMULATIONS FOR HUMAN AND VETERINARY USE WHICH WOULD NOT NORMALLY BE MADE AVAILABLE IF COMMERCIAL CRITERIA ALONE PREVAILED.  EFFECTS OF POISONS ON TARGET ORGAN SYSTEM: THE CARDIOVASCULAR SYSTEM THE EFFECTS OF POISONING AND OVERDOSE ON THE CARDIOVASCULAR SYSTEM ARE DISTURBANCES IN: (A) CONDUCTIVITY (CHRONOTROPY) –RHYTHM AND RATE; (B) CONTRACTILITY (INOTROPY); AND (C) VASCULAR TONE. THE PATTERN OF THE PULSE, BLOOD PRESSURE, CARDIAC CONDUCTION AND TYPE OF DYSRHYTHMIAS MAY HELP IDENTIFY THE TOXIC AGENT. HOWEVER, HYPOXIA, SHOCK, HYPOTHERMIA, AND OTHER SUPERIMPOSED COMPLICATIONS MAY DISTORT THE TYPICAL PATTERN. THE HEART AND VASCULATURE ARE AFFECTED DIRECTLY OR INDIRECTLY, BY ALTERED AUTONOMIC FUNCTION. DIRECT MEMBRANE DEPRESSION DELAYS IMPULSE CONDUCTION AND IS REFERRED TO AS THE QUINIDINE-LIKE ACTION. THE SYMPATHETIC RESPONSE INCREASES THE AUTOMATICITY, CONDUCTION VELOCITY, AND CONTRACTILITY OF THE HEART, AND LENGTHENS THE REFRACTORY PERIOD AND PRODUCES CONSTRICTION OF MOST VASCULAR BEDS. THE PARASYMPATHETIC RESPONSE DELAYS CONDUCTION VELOCITY THROUGH THE AV NODE (VAGOTONIC BLOCK) AND THE VENTRICULAR TISSUE, DIMINISHES CONTRACTILITY, SHORTENS THE REFRACTORY PERIOD, AND GENERALLY PRODUCES VASODILATION. THERE ARE TWO TYPES OF PARASYMPATHETIC RECEPTORS: THE NICOTINIC RECEPTORS, WHICH MAY PRODUCE TACHYCARDIA AND HYPERTENSION, AND THE MUSCARINIC RECEPTORS, WHICH PRODUCE BRADYCARDIA AND HYPOTENSION.  1. BRADYCARDIA MAY BE PRODUCED BY EXCESS CHOLINERGIC ACTIVITY, INTERFERENCE WITH RELEASE OR DEPLETION OF THE CATECHOLAMINES, DAMAGE TO THE MYOCARDIUM, OR INCREASED INTRACRANIAL PRESSURE. 2. TACHYCARDIA MAY BE DUE TO EXCESS ANTICHOLINERGIC ACTIVITY, STIMULATION OF CATECHOLAMINE RELEASE, INADEQUATE VENOUS RETURN DUE TO VASODILATION, HYPOXIA, AND DIRECT INJURY TO THE MYOCARDIUM, OR INCREASED METABOLISM. 3. DYSRHYTHMIAS ARE CAUSED BY SPONTANEOUS DEPOLARIZATION (AUTOMATICITY), ABNORMAL IMPULSE CONDUCTION (REENTRY), AND “TRIGGERED” RESPONSES. THEY MAY BE CAUSED BY: (A) DIRECT OR INDIRECT SYMPATHOMIMETIC EFFECTS; (B) ANTICHOLINERGIC EFFECTS; (C) CNS-RELATED REGULATION OF PERIPHERAL AUTONOMIC ACTIVITY; (D) DIRECT EFFECTS ON THE MYOCARDIAL MEMBRANE; (E) MYOCARDIAL ISCHEMIA; OR (F) SECONDARY TO HYPOTENSION, HYPOXIA, OR DISTURBANCES IN ACID-BASE AND ELECTROLYTE BALANCE. CORRECTION OF HYPOXIA AND METABOLIC DERANGEMENTS (ELECTROLYTE IMBALANCES, HYPOGLYCEMIA, AND ACID-BASE DISTURBANCES) WILL SPONTANEOUSLY RECTIFY MANY DYSRHYTHMIAS.  4. VASCULAR TONE. TRANSIENT HYPERTENSION MAY BE PRODUCED BY SUBSTANCES ACTING INDIRECTLY TO INCREASE THE RELEASE OF NE FROM STORAGE GRANULES OR BY DECREASING THE REUPTAKE OF NOREPINEPHRINE. SUBSTANCES ALSO ACT DIRECTLY TO DECREASE THE DEGRADATION OF NE OR TO INTERACT WITH THE ALPHA RECEPTORS. THE VASCULAR TONE MAY BE REDUCED BY AGENTS THAT PRODUCE MYOCARDIAL DEPRESSION AND A DECREASE IN CARDIAC OUTPUT OR BY DYSRHYTHMIAS THAT INTERFERE WITH CARDIAC FILLING. VASCULAR TONE MAY BE ALSO INFLUENCED BY AGENTS AFFECTING THE ANS OR PERIPHERAL EFFECTOR SITES. THE CAUSE MAY BE HYPOXIA, VOLUME DEPLETION, AND ANAPHYLAXIS. A. HYPERTENSION WITH TACHYCARDIA IS OFTEN NOTED FROM ANTICHOLINERGIC AGENTS, CNS STIMULANTS, NICOTINE, SYMPATHOMIMETICS (PPA), THALLIUM, THYROID, AND IN WITHDRAWAL FROM ANTIHYPERTENSIVE AGENTS, ETHANOL AND SEDATIVE-HYPNOTICS. B. HYPERTENSION WITH BRADYCARDIA HAS BEEN REPORTED FROM INTOXICATIONS WITH AGENTS THAT INCREASE THE INTRACRANIAL PRESSURE, SUCH AS HYPERVITAMINOSIS A, NALIDIXIC ACID, TETRACYCLINE, CHRONIC LEAD POISONING WITH ENCEPHALOPATHY AND CORTICOSTEROIDS. C. HYPERTENSION MAY INITIALLY BE ASSOCIATED WITH REFLEX BRADYCARDIA FROM AGENTS SUCH AS PPA AND PHENYLEPHRINE  THE RESPIRATORY SYSTEM: THE EFFECTS OF OVERDOSE AND POISONING ON THE RESPIRATORY SYSTEM INCLUDE: A. DEPRESSION OR STIMULATION OF THE CNS B. OBSTRUCTION OF THE UPPER AND LOWER AIRWAYS BY A FOREIGN BODY, ASPIRATION, OR BRONCHOSPASM C. LUNG PARENCHYMA INVOLVEMENT BY ASPIRATION AND/OR CHEMICAL PNEUMONITIS, FIBROSIS, INTERSTITIAL DISEASE, ATELECTASIS, AND PULMONARY EDEMA D. PLEURAL DISEASE WITH LONG TERM EXPOSURE TO TOXIC INHALATIONS E. CHEST WALL DISTURBANCES WITH SUBSTANCES THAT PRODUCE PARALYSIS OF DIAPHRAGM AND INTERCOSTAL MUSCLES F. GASES AND VAPORS THAT MAY DISPLACE OXYGEN AND PRODUCE IRRITATION OF THE AIRWAYS, PARENCHYMAL INVOLVEMENT, AND SYSTEMIC TOXICITY BY INTERFERING WITH THE TRANSPORT AND UTILIZATION OF OXYGEN BY THE TISSUES.  DYSPNEA: ACUTE DYSPNEA IS APPARENT AS INCREASED WORK OF BREATHING. IT MAY BE ASSOCIATED WITH OBSTRUCTION OF THE AIRWAY PASSAGES, INVOLVEMENT OF THE PULMONARY PARENCHYMA THAT INTERFERES WITH OXYGEN EXCHANGE, AND ASPHYXIANT GASES. OXYGEN DEMAND MAY BE INCREASED BEYOND THE AVAILABLE SUPPLY BECAUSE OF METABOLIC STIMULATION. METABOLIC ACIDOSIS PRODUCES DYSPNEA BY COMPENSATORY HYPERVENTILATION. TACHYPNEA WITHOUT RESPIRATORY DISTRESS (“QUIET TACHYPNEA”) IS USUALLY FROM NONPULMONARY CAUSES SUCH AS FEVER OR AN EFFORT TO MAINTAIN A NORMAL PH BY RESPIRATORY COMPENSATION. KUSSMAUL BREATHING, WHEN THE PH IS BELOW 7.25 FROM METABOLIC CAUSES, IS AN EXAMPLE, ALTHOUGH SOMETIMES DYSPNEA MAY BE PRESENT. THE SITUATIONS THAT PRODUCE TACHYPNEA WITH RESPIRATORY DISTRESS ARE ASPIRATION PNEUMONITIS; INHALED GASES OR INGESTED SUBSTANCES THAT INTERFERE WITH OXYGEN TRANSPORT AND/OR TISSUE UTILIZATION OF OXYGEN; IRRITANT FUMES; CNS STIMULANT INTOXICATIONS SUCH AS FROM SALICYLATES, COCAINE, AMPHETAMINES, AND PPA; AND WITHDRAWAL STATES. TACHYPNEA AND INEFFECTIVE SHALLOW RESPIRATIONS (DECREASED TIDAL VOLUME) CAN COEXIST, PRODUCING ALVEOLAR HYPOVENTILATION. SLOW AND SHALLOW RESPIRATIONS INCLUDE BRADYPNEA AND APNEA. INHALATIONS OF HIGH CONCENTRATIONS OF AMMONIA, ACID FUMES, CARBON MONOXIDE, CHLORINE, CYANIDE, HYDROGEN SULFIDE, NITROGEN SULFIDE, AND SULFUR DIOXIDE MAY RESULT IN SUDDEN APNEA. “NOT ALL THAT WHEEZES IS ASTHMA.” PULMONARY EDEMA, BOTH CARDIAC AND NONCARDIAC, MAY DEVELOP FROM INTOXICATIONS. NONCARDIAC PULMONARY EDEMA DOES NOT HAVE THE SIGNS OF CONGESTIVE HEART FAILURE.  THE NERVOUS SYSTEM ALTERED MENTAL STATE. TO ALTER THE MENTAL STATE, THERE MUST BE CORTICAL OR ASCENDING RETICULAR ACTIVATING (ARAS) DYSFUNCTION. IT IS USEFUL TO CATEGORIZE THESE MANIFESTATIONS INTO THOSE INDUCED BY: CNS DEPRESSANTS, CNS STIMULANTS, HALLUCINOGENS, ANTICHOLINERGIC AGENTS, AND CHOLINERGIC AGENTS. SUCH A CLASSIFICATION ALLOWS THE CLINICIAN TO CONVEY TO THE TOXICOLOGIC ANALYST THE TYPE OF NEUROLOGIC MANIFESTATIONS PRESENT AND TO DIRECT THE ANALYSIS TOWARD THE MOST LIKELY SUBSTANCES ON THE BASIS OF THE CLINICAL EVALUATION. -THE HALLMARKS OF CNS DEPRESSANTS ARE CNS DEPRESSION AND LETHARGY. MOST SERIOUS INTOXICATIONS EVENTUALLY WILL PRODUCE COMA IF LEFT UNTREATED. MAJOR MANIFESTATIONS INCLUDE, BRADYCARDIA, BRDAYPNEA AND SHALLOW RESPIRATIONS, HYPOTENSION, HYPOTHERMIA, FLACCID COMA, MIOSIS MAINLY WITH OPIOIDS, HYPOACTIVE BOWEL SOUNDS, FROZEN ADDICT SYNDROME. -THE HALLMARKS OF CNS STIMULANTS ARE CONVULSIONS AND HYPERACTIVITY. MANIFESTATIONS INCLUDE: TACHYCARDIA, TACHYPNEA AND DYSRHYTHMIAS, HYPERTENSION, CONVULSIONS, SPASTIC COMA, TOXIC PSYCHOSIS, MYDRIASIS (REACTIVE), AGITATION AND RESTLESSNESS, MOIST SKIN. -HALLUCINATIONS IS THE MAJOR MANIFESTATION OF HALLUCINOGENS. OTHER MANIFESTATIONS INCLUDE: TACHYCARDIA AND DYSRHYTHMIAS, TACHYPNEA, HYPERTENSION, DISORIENTATION, PANIC REACTION, TOXIC PSYCHOSIS, MOIST SKIN, VARIABLE BOWEL SOUNDS, MYDRIASIS (REACTIVE), HYPERTHERMIA, FLASHBACKS IT MUST BE ASSUMED THAT ALL PATIENTS WITH AN ALTERED CONSCIOUSNESS LEVEL HAVE AN ASSOCIATED HEAD AND NECK INJURY UNTIL THESE POSSIBILITIES ARE EXCLUDED. THE GENERAL MEDICAL/SURGICAL CAUSES OF ALTERED MENTAL STATUS AND COMA MAY BE RECALLED BY SEVERAL MNEMONICS, USING THE VOWELS AEIOU FOR METABOLIC DISORDERS AND TIPS FOR OTHER CAUSES.  METABOLIC DISORDERS A-ALCOHOL E-ENDOCRINE, ELECTROLYTE DISTURBANCES, EPILEPSY I- INTOXICATION, INSULIN, INTUSSUSCEPTIONS IN CHILDREN O-OXYGEN DEPRIVATION, OPIOIDS U-UREMIA AND METABOLIC DISORDERS, HEPATIC DISORDERS, HYPERTENSION OTHER CAUSES T-TRAUMA, TUMOR I- INFECTION P-PSYCHOLOGIC S-SHOCK, SEIZURES, STROKES (CARDIOVASCULAR)  TERMINOLOGIES ASSOCIATED WITH CNS Coma – A state of deep unconsciousness where a person is unresponsive to external stimuli due to severe brain injury, illness, or toxins. Delirium – A sudden, severe confusion and rapid changes in brain function that cause hallucinations, disorientation, and agitation. Often temporary and caused by infections, medications, or metabolic imbalances. Dementia – A progressive decline in cognitive function affecting memory, thinking, and reasoning abilities, commonly caused by diseases like Alzheimer’s or vascular dementia. Convulsions – Sudden, uncontrolled muscle contractions caused by abnormal electrical activity in the brain, often seen in epilepsy or severe fever. Syncope – Temporary loss of consciousness (fainting) due to a sudden drop in blood pressure, lack of oxygen, or reduced blood flow to the brain. Aseptic chemically-induced meningitis – Inflammation of the protective membranes around the brain and spinal cord (meninges) caused by non-infectious agents like medications, vaccines, or chemicals rather than bacteria or viruses. Paralysis – The complete loss of muscle function in a part of the body due to nerve damage, stroke, or spinal cord injury. Paresis – Partial loss of muscle strength or mild paralysis, often due to nerve or brain damage. Neuromuscular disease – A group of disorders that affect the muscles and nerves controlling them, leading to weakness, cramps, spasms, and movement difficulties (e.g., muscular dystrophy, myasthenia gravis). Ataxia – Lack of muscle coordination affecting voluntary movements, often due to neurological conditions like stroke, multiple sclerosis, or cerebellar damage. Movement disorders – Neurological conditions affecting the ability to control movement, including: Trismus – Involuntary jaw muscle spasm, making it difficult to open the mouth (lockjaw). Risus sardonicus – A forced, unnatural grin due to sustained facial muscle spasms, often seen in tetanus. Choreoathetoid movements – Involuntary, jerky, twisting, or writhing movements, common in conditions like Huntington’s disease. Parkinsonism – A syndrome with symptoms similar to Parkinson’s disease, including tremors, slow movement, and muscle stiffness. Confusion – A mental state where a person has difficulty thinking clearly, remembering things, or making decisions, often due to illness, injury, or intoxication. Acute organic brain syndrome – A sudden decline in brain function due to physical conditions affecting the brain, such as infections, drugs, or metabolic disorders. Behavioral disturbances – Changes in mood or actions, including: Euphoria – An intense feeling of happiness or excitement, sometimes due to drugs or brain injury. Anxiety and panic – Feelings of fear, nervousness, or extreme worry. Mania – A state of excessive excitement, energy, or impulsive behavior, seen in bipolar disorder. Paranoia – An irrational mistrust or suspicion of others, common in psychiatric conditions like schizophrenia. Headache – Pain or discomfort in the head or neck, caused by stress, tension, infections, migraines, or other medical conditions.  THE LIVER THE RESPONSE OF THE LIVER TO CHEMICAL EXPOSURE DEPENDS ON THE INTENSITY OF THE INSULTS, THE CELL POPULATION AFFECTED, AND THE DURATION OF THE CHEMICAL EXPOSURE (ACUTE VS. CHRONIC). MILDER STRESSES MAY JUST CAUSE REVERSIBLE CELLULAR DYSFUNCTION, E.G., TEMPORARY CHOLESTASIS AFTER EXPOSURE TO ESTROGENS. HOWEVER, ACUTE POISONING WITH ACETAMINOPHEN OR CARBON TETRACHLORIDE TRIGGERS PARENCHYMAL CELL NECROSIS. EXPOSURE TO ETHANOL INDUCES STEATOSIS, WHICH MAY ENHANCE THE SUSCEPTIBILITY TO SUBSEQUENT INFLAMMATORY INSULTS.  TYPES OF HEPATOBILIARY INJURY / REPRESENTATIVE TOXINS: 1. FATTY LIVER : AMIODARONE, CCL4, ETHANOL, TAMOXIFEN, VALPROIC ACID 2. HEPATOCYTE DEATH: ACETAMINOPHEN, ALLYL ALCOHOL, COPPER, ETHANOL 3. IMMUNE-MEDIATED RESPONSE: DICLOFENAC, ETHANOL, HALOTHANE 4. CANNALICULAR CHOLESTASIS: CHLORPROMAZINE, CYCLOSPORINE A, ESTROGENS, MN, PHALLOIDIN 5. BILE DUCT DAMAGE: ISOTHIOCYANATE, AMOXICILLIN, METHYLENE DIANILINE, SPORIDESMIN 6. SINUSOIDAL DISORDERS: ANABOLIC STEROIDS, CYCLOPHOSPHAMIDE, MICROCYSTIN, PYRROLIZIDINE ALKALOIDS 7. FIBROSIS AND CIRRHOSIS: CCL4, ETHANOL, THIOACETAMIDE, VITAMIN A, VINYL CHLORIDE 8. TUMORS: AFLATOXIN, ANDROGENS, ARSENIC, VINYL CHLORIDE  THE KIDNEY: ONE OF THE MOST COMMON MANIFESTATIONS OF NEPHROTOXIC DAMAGE IS ACUTE RENAL FAILURE—AN ABRUPT DECLINE IN KIDNEY FUNCTION SECONDARY TO AN INJURY THAT LEADS TO A FUNCTIONAL OR STRUCTURAL CHANGE IN THE KIDNEY. PROGRESSIVE DETERIORATION OF RENAL FUNCTION MAY OCCUR WITH LONG-TERM EXPOSURE TO A VARIETY OF CHEMICALS (E.G., ANALGESICS, LITHIUM, AND CYCLOSPORINE). IT IS GENERALLY BELIEVED THAT PROGRESSION TO END-STAGE RENAL FAILURE IS NOT SIMPLY A FUNCTION OF THE PRIMARY RENAL INSULT PER SE BUT RATHER IS RELATED TO SECONDARY PATHOPHYSIOLOGIC PROCESSES TRIGGERED BY THE INITIAL INJURY.  THE BLOOD: HEMATOTOXICOLOGY IS THE STUDY OF ADVERSE EFFECTS OF DRUGS, NONTHERAPEUTIC CHEMICALS AND OTHER AGENTS IN OUR ENVIRONMENT ON BLOOD AND BLOOD-FORMING TISSUES. HEMATOTOXICITY MAY BE REGARDED AS PRIMARY, WHERE ONE OR MORE BLOOD COMPONENTS ARE DIRECTLY AFFECTED, OR SECONDARY, WHERE THE TOXIC EFFECT IS A CONSEQUENCE OF OTHER TISSUE INJURY OR SYSTEMIC DISTURBANCES. PRIMARY TOXICITY IS REGARDED AS AMONG THE MORE COMMON SERIOUS EFFECTS OF XENOBIOTICS, PARTICULARLY DRUGS. THE CONSEQUENCES OF DIRECT OR INDIRECT DAMAGE TO BLOOD CELLS AND THEIR PRECURSORS ARE PREDICTABLE AND POTENTIALLY LIFE-THREATENING. THEY INCLUDE HYPOXIA, HEMORRHAGE, AND INFECTION. THESE EFFECTS MAY BE SUBCLINICAL AND SLOWLY PROGRESSIVE OR ACUTE AND FULMINANT, WITH DRAMATIC CLINICAL PRESENTATIONS. HEMATOTOXICITY IS USUALLY ASSESSED IN THE CONTEXT OF RISK VERSUS BENEFIT. IT MAY BE USED TO DEFINE DOSAGE IN TREATMENT MODALITIES IN WHICH THESE EFFECTS ARE LIMITING, SUCH AS THOSE EMPLOYING CERTAIN ANTICANCER, ANTIVIRAL, AND ANTITHROMBOTIC AGENTS.  IRON DEFICIENCY ANEMIA – DIETARY DEFICIENCY OR INCREASED BLOOD LOSS SIDEROBLASTIC ANEMIA – DEFECTS IN THE SYNTHESIS OF PORPHYRIN RING OF HEME WITH ITS CHARACTERISTIC ACCUMULATION OF IRON IN BONE MARROW ERYTHROBLASTS MEGALOBLASTIC ANEMIA – DEFICIENCY OF FOLATE OR VITAMIN B12 APLASTIC ANEMIA – LIFE-THREATENING DISORDER CHARACTERIZED BY PERIPHERAL BLOOD PANCYTOPENIA, RETICULOCYTOPENIA, AND BONE MARROW HYPOPLASIA. METHEMOGLOBINEMIA – INCREASED LEVELS OF METHEMOGLOBIN MICROANGIOPATHIC HEMOLYTIC ANEMIA – THE PRESENCE OF SCHISTOCYTES (FRAGMENTED RBCS) IN THE PERIPHERAL BLOOD  THE IMMUNE SYSTEM: IMMUNOTOXICOLOGY CAN BE MOST SIMPLY DEFINED AS THE STUDY OF ADVERSE EFFECTS ON THE IMMUNE SYSTEM RESULTING FROM OCCUPATIONAL, INADVERTENT, OR THERAPEUTIC EXPOSURE TO DRUGS, ENVIRONMENTAL CHEMICALS, AND, IN SOME INSTANCES, BIOLOGICAL MATERIALS. HYPERSENSITIVITY CAN BE CLASSIFIED AS: TYPE 1: IMMEDIATE TYPE; TYPE 2: ANTIBODY DEPENDENT CELLULAR TOXICITY (HUMORAL) TYPE 3: IMMUNE COMPLEX DISEASE (HUMORAL) TYPE 4: DELAYED HYPERSENSITIVITY (CELL-MEDIATED)  THE OCULAR SYSTEM THE VISUAL APPARATUS AND ITS MUSCLES ARE ONE OF THE MOST IMPORTANT TOOLS IN THE DIAGNOSIS OF TOXICOLOGIC PROBLEMS BECAUSE THEY REFLECT THE CNS AND ANS RESPONSES FROM DISTANT ORGANS. PUPILLARY SIZE AND THE RESPONSE TO LIGHT IS DEPENDENT ON THE BALANCE BETWEEN SYMPATHETIC DILATION AND PARASYMPATHETIC CONSTRICTION. TESTING FOR POTENTIAL TOXIC EFFECTS OF COMPOUNDS ON THE EYE AND VISUAL SYSTEM CAN BE DIVIDED INTO TESTS OF OCULAR TOXICITY AND TESTS OF VISUAL FUNCTION. 1. MYDRIASIS (DILATION OF THE PUPIL) 2. MIOSIS (CONSTRICTION OF THE PUPIL) 3. NYSTAGMUS (REPETITIVE, INVOLUNTARY, TO-AND-FRO OSCILLATION OF THE EYES). 4. OPHTHALMOPLEGIA (PARALYSIS OR WEAKNESS OF THE EYE MUSCLE) 5. PAPILLEDEMA (OPTIC DISC SWELLING) 6. PTOSIS (DROOPING EYELID) 7. DISTURBANCES OF COLOR VISION 8. BLINDNESS 9. CATARACTS (CLOUDY PATCHES IN THE LENS)  SERIOUS EYE DAMAGE IS THE PRODUCTION OF TISSUE DAMAGE IN THE EYE, OR SERIOUS PHYSICAL DECAY OF VISION FOLLOWING APPLICATION OF A TEST SUBSTANCE TO THE ANTERIOR SURFACE OF THE EYE, WHICH IS NOT FULLY REVERSIBLE WITHIN 2 DAYS OF APPLICATION. EYE IRRITATION IS THE PRODUCTION OF CHANGES IN THE EYE FOLLOWING THE APPLICATION OF TEST SUBSTANCE TO THE ANTERIOR SURFACE OF THE EYE, WHICH ARE FULLY REVERSIBLE WITHIN 21 DAYS OF APPLICATION  TOXIC RESPONSES OF THE SKIN THE ABILITY OF THE SKIN TO METABOLIZE CHEMICALS THAT DIFFUSE THROUGH IT CONTRIBUTES TO ITS BARRIER FUNCTION. THIS INFLUENCES THE POTENTIAL BIOLOGICAL ACTIVITY OF XENOBIOTICS AND TOPICALLY APPLIED DRUGS, LEADING TO THEIR DEGRADATION OR THEIR ACTIVATION AS SKIN SENSITIZERS OR CARCINOGENS. SKIN CORROSION IS THE PRODUCTION OF IRREVERSIBLE DAMAGE TO THE SKIN; NAMELY, VISIBLE NECROSIS THROUGH THE EPIDERMIS AND INTO THE DERMIS, FOLLOWING APPLICATION OF A TEST SUBSTANCE FOR UP TO 4 HOURS. CORROSIVE REACTIONS ARE TYPIFIED BY ULCERS, BLEEDING, BLOODY SCABS, AND BY THE END OF OBSERVATION AT 14 DAYS, BY DISCOLORATION DUE TO BLANCHING OF THE SKIN, COMPLETE AREAS OF ALOPECIA, AND SCARS. HISTOPATHOLOGY SHOULD BE CONSIDERED TO EVALUATE QUESTIONABLE LESIONS.  1. CONTACT DERMATITIS (IRRITANT DERMATITIS, CHEMICAL BURNS, ALLERGIC CONTACT DERMATITIS) 2. GRANULOMATOUS DISEASE 3. PHOTOSENSITIVITY (PHOTOTOXICITY, PHOTOALLERGY) 4. ACNE (CHLORACNE) 5. PIGMENTARY DISTURBANCES - HYPERPIGMENTATION:ANTHRACENES, HYDROQUINONES,METALS, PSORALENS, UV LIGHT, AMIODARONE, CHLOROQUINES, TETRACYCLINES - HYPOPIGMENTATION:BHT, HYDROQUINONES, PHENOLIC COMPONDS 6. URTICARIA 7. TOXIC EPIDERMAL NECROLYSIS 8. SKIN CANCER  ALLERGIC CONTACT DERMATITIS: TOPICAL ANTIBIOTICS, ANTISEPTICS; PRESERVATIVES, COSMETICS; PLAT RESINS, LEATHER PRODUCTS, INDUSTRIAL SOLVENTS, CLEANING PRODUCTS AND PAINTS; JEWELRIES AND METALS CHEMICAL BURN: INORGANIC ACIDS OR BASES, AMMONIA, LIQUIDS OR CONCENTRATED VAPORS OF HALIDES, OXIDES, PHENOLS, PHOSPHORUS, ORGANIC SOLVENTS PHOTOALLAERGY: TOPICAL SALICYLIC ACID DERIVATIVES; HEXACHLOROPHENE, CAMPHOR, MENTHOL, PHENOL AS ADDITIVES, WOOD AND LEATHER OILS PHOTOTOXICITY: FUROCOUMARINS (PSORALEN DERIVATIVES), PAH, TETRACYCLINES, SULFONAMIDES, EOSIN DYES