Toxicology

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Summary of Toxicology > Mdterm: October 27
Toxicology: Study of adverse effects of foreign chemicals
Toxicant: xenobiotic which produces toxicity
Xenobiotics can be drug or non-drug.
Toxicodynamics: Study of the mechanism of action, biochemical and physiological effects of toxicant
Toxicokinetics: Study of the influence of biotransformation, absorption, distribution and excretion on toxicant’s effects. 
Toxicokinetcs factors influencing toxicity: metabolism, absorption, distribution, excretion.
Toxicant related determinants of toxicity: potency & intrinsic activity; dose/target []; chemical form; physical state; route of exposure/adm.
Toxicology Divisions
> Mechanistic Basis
- Biochemical Toxicology: Consider events At Molecular /Biochemical level
- Behavioral Toxicology: Toxicant effects on animal/human behavior
- Carcinogenicity: Toxicant ability to induce malignancies
- Teratogenicity: Toxicant effect on development
> Measurement Based
- Analytical: Detection and /or quantification of toxicant
- Toxicity Testing: Use living systems to estimate toxicant effects
*Ames; Phase I/II Safety evaluation
> Mutagenesis: Toxicant effect on genetic material & transmission of influence to subsequent generations
> Organotoxicity: expression of toxicant adverse effect on whole organ
Toxicity Classification Basis
> Onset
- Acute: immediate; seconds-minutes *CN, H2S, sarin
- Sub acute: intermediate, days *acetaminophen
- Chronic: months-years *carcinogenesis
> Target Organ
- Neurotoxicant
- Hepatotoxicant
- Pulmonary toxicant
- Nephrotoxicant
> Application
- Clinical: antidotal therapy
- Forensic Toxicology: analytical
- Economic
- Environmental
- Veterinary
- Industrial/occupational
Environmental Toxicity
> influenced by: degradability/persistence; mobility through air/water/soil; bioaccumulation; biomagnification. 
Classes of Toxicant
> Agricultural xenobiotics
> Clinical/veterinary drugs
> Food additives
> Combustion products
> Naturally occurring
- Phytotoxins (plant origin): nicotine, cocaine
- Inorganic chemicals: cadmium, lead, arsenic
- Microbial toxins: botulinum toxin
- Mycotoxins: aflatoxins; ergot alkaloids.
Sensitization Reactions
- Preconditioning: initial exposure to xenobiotic
- Induced period
- Production of new protein
Xenobiotic Characteristics Predisposing to Sensitization
> Cross Sensitization
- Xenobiotics w/ similar structure
- Members of same chemical class
* Penicillin, barbiturates.
>> Carcinogenesis
>> Photosensitivity
>> Phototoxicity: drug/metabolite converted to toxicant due to light energy 
>> Photoallergy: light produces photochemical reaction between xenobiotic & cutaneous protein > photoantigen.
Adverse Drug Reaction Types
> Temporally Based: immediate ex.: anaphylaxis; delayed: after latent period ex.: carcinogenesis
 * Most likely ADR with: aspirin digoxin, anticoagulants, diuretics, antimicrobials, steroids, hypoglycemic.
> ADR type “A”: extension of effect seen w/ normal dose; predictable reaction based on known pharmacology of drug; dose dependency; relatively high incidence & low mortality.
> ADR type “B”: aberrant unexpected effects; low incidence & high mortality.
> Idiosyncratic ADR: genetic based abnormal reactivity to chemical:
- Hemolytic anemia: susceptible subject hemolysis of host RBC; normal subject hemolysis of transfused RBC. Lesion on susceptible RBC; GSH acts as RBC membrane reducing agent.
- Succinylcholine apnea causes: lack pseudocholinesterases; lower affinity for cholinesters
Mechanisms of Toxicity
Mechanism of toxicity occurs when perturbations induced by a toxicant exceed repair capacity, and occurs in four steps:
1) The toxicant is delivered to its target: the toxicant interact with target molecules and induces structural and/or functional alterations. The toxic effect depends on the concentration and persistence of the toxicant.
Factors that influences toxicant concentrations are:
a) Absorption: related to surface area of exposure, characteristics of the surface area and specially lipid solubility. > Presystemic elimination is an important factor to toxicity because may eliminate a fraction of toxicant thus reduce toxicity.
b) Distribution: toxicants exit the blood and reach their target(s). The mechanisms that facilitate its distribution are porosity of the capillary endothelium (It favors the accumulation of chemicals in the liver and kidneys), specialized transport across the plasma membrane (ion channels and membrane carries), and accumulation in cell organelles.
c) Excretion: the route and speed of excretion depends on the physicochemical properties of the toxicant. 
d) Reabsorption: there are mainly two ways of reabsorption, a) toxicants delivered into the renal tubules may diffuse back across the tubular into the peritubular capillaries, which increases the intratubular concentrations as well as the residence time of the chemical by slowing urine flow; and b) toxicants delivered to the GI tract by biliary, gastric, and intestinal excretion and secretion by salivary glands and exocrine pancreas may be reabsorbed by diffusion across the intestinal mucosa > is possible only is they are sufficiency lipophilic or are converted to more lipid-soluble forms.
Xenobiotic Immune ADR
Xenobiotic Allergic Reaction
> Rare reaction
> Mediated via T-cell and IgE (prior exposure/sensitization increase IgE; mast cell bound IgE target producing anaphylaxis). * Histamine: major autacoid due to bronchoconstriction/hypotension/GI toxicity.
> Skin most common manifestation
Hypersensitivity Classification:
- Type I: Immediate drug specific IgE ab
- Type II: Cytotoxic drug specific IgG/IgM ab
- Type III: Immune complex reaction. 
- Type IV: Delayed type hypersensitivity. a) Monocytes; b) Eosinophils; c) CD4/CD8+ T-Cells; d) neutrophils
- Drugs that can release histamine from mast cell by non IgE mediated mechanisms vancomycin, protamine, narcotic analgesics.
- Anaphylaxis: due release of histamine; epinephrine treatment; no mast cell bound IgE no ADR on xenobiotic binding; severe allergic Rx affecting multiple organs; asphyxia main cause of death; desensitization is possible.
- T-Cell Rx: most common; delayed hypersensitivity; contact dermatitis.
* Drugs that react with red blood cells: diclofenac, ibuprofen, levodopa, mefenamic acid, methyldopa, procainamide > bind protein on red cell membrane > when they bind the proteins, they form a macromolecule which isn’t recognize by the surveillance system> AB fight against this complex. Can occur in the liver, serum… able to interact with a large protein molecule
> Bioactivaiton yielding haptens: hepatic biotransformation forms haptens reacting with skin proteins. (Delayed type of Rx) Dermal reaction usually appear 7-10 days after exposure. Drugs: sulfonamides, carbamazepine, lidocaine, procainamide, diclofenac. 
EX: halothane: metabolized to triflouruacetyl chloride (TFAC) very reactive with liver proteins recognize as neoantigen immune response to neoantigen halothane hepatitis.
> Haptens & cell mediated reactions: react with CD4/TH1 cells/macrophages mediate lesions involving inflammatory effects 24-48 hours after exposure > skin, liver, kidney.
Haptens: small molecular compounds evoking immune response when attached to carrier proteins necessary protein+hapten exceed 3000 MW to elicit AB response
> Drugs reacting with serum proteins: 
- Penicillin (haptenic metabolites); B lactam ring of penicillin & binds to protein increases immunogenicity.
 - Cephalosporin: 
- Tetracycline
- Tolbutamide
Drug-induced “lupus-like” disease
Transient lupus-like symptoms
Transient anti-DNA AB production
Memory cells aren’t generated
Reversible upon ceasing drug exposure
* Drugs: chlorpromazine, isoniazid, procainamide, etanercept, adalimumab, hydralazine, methyldopa, quinidine, infliximab, minocycline.
Delayed Type Dermal Hypersensitivity (DTDH)
> Dermatitis can be caused by 2 mechanisms:
* Immunologic: photocontact dermatitis7-10 days after drug initiation, pruritic, vesicular lesions resemble sunburn, symptoms subside after drug cessation. EX of drugs: quinolones, sulfonamides, tetracycline, trimethoprim. Allergic contact dermatitis: second cell mediated type; paraphenylenediamine (hair dyes), formaldehyde, latex mfg, contaminants, neomycin.
* Non immunologic: irritant: acids, alkalis, solvents 
Xenobiotic Allergy Presence
> Alternative drug
> Unavailability of skin test results: 
a) Desensitization: changes patient immune response to drug; oral dose preferred; double dose 15-30 min intervals; gradually deplete drug specific IgE levels; non-permanent. 
b) Graded: less probability; 1 hr dosing intervals
* Tardive Drug Specific IgE (DSI): stop drug admin can increases DSI levels to yield severe allergic reaction.
* IgG & IgM mediated ADR: cease drug limits ADR; inflammation w large prolonged doses. 
* ACE-inhibitors: respiratory reactions: not w/ angiotensin receptor antagonists; non dose related; stop drug stop cough.
* Morbilliform rashes: CD4+ more than CD8+; appears 3-10 days after treatment starts; stops after ceasing drug.
* Bullous skin rashes: delayed onset.
* Contact Dermatitis: recruitment of nonspecific T cell; pruritic, vesicular inflammation; glucocorticoid often neded.
* Drug-induced photodermatitis/photosensitization: UV light; T-cell interaction; skin rash produced; NSAIDs, thiazides, tetracyclines.
* Drug reaction w/ eosinophilia and systemic symptoms (DRESS): bullous rash; hepatic, renal or pulmonary involvement; allopurinol, sulfamethoxazole, penicillin, NSAIDs.
* Aspirin exacerbation of respiratory disease symptoms (AERD): rhinoconjuntivitis, bronchospasm, urticarial, angioedema, pneumonitis, more common in females. Aspirin/NSAIDS inhibit Cox-1 Decr [PGE2]; Increased [Cysteinyl Leucotriene] synthesis; Increased Cell Leucotriene membrane receptors; Effect avoided by Cox 2 inhibitors. MANAGEMENT: avoid NSAID, surgery, aspirin desensitization.
* Pseudoallergy: non immune mediated: no specific AB or Tcell; drug irritates vascular endothelium/basophils/mast cell; no specific histamine release.
Antidotal Therapy
Principles of AT: minimize toxicant’s systemic absorption; antagonize effects of absorbed tocixant; enhance bioinactivation; inhibit bioactivation; promote elimination from body; supportive patient care.
Decrease Ascending Slope
- Emetics: IPECAC > mix of cephaeline & emetine alkaloids; stimulates CRTZ; abuse can cause cardiomyopathy, ventricular fibrillation. Contraindications in coma or convulsions. 
- Activated charcoal: interrupts toxicant’s enterohepatic circulation; promotes unabsorbed & secreted toxicant’s fecal elimination.
- Polythiol resin
- Cholestyramine
- Gastric lavage
- Chemical inactivation: change toxicant to less toxic product; ammonia, sodium bicarbonate.
- Dilution
- inhibit bioactivation: cimetidine > acetaminophen; methanol & ethylene glycol. 
* Promote absorbed toxicant elimination: increase bioinactivation (n-acetylcysteine > acetaminophen; sodium nitrite, sodium thiosulfate); increase excretion (chelation > EDTA, dimercaprol, deferoxamine; diuretics > furosemide, osmotic; ion trap > increase urine pH, urinanry acidification). 
* Elevated Threshold: receptor antagonism > opiates, Ach inhibitors; toxicant neutralization/target toxicity reversal > antidigitoxin immunotherapy, methylene blue. 
Hepatotoxicity
Hepatic functions: 
Nutrient homeostasis: glucose, glycogen, cholesterol, fatty acid metabolism. 
Protein synthesis: clotting factors, albumin, and lipid transport proteins. 
Biotransformation: xenobiotic, steroid hormones, bilirubin, ammonia (coma due excess)
Bile synthesis & secretion: intestinal lipid uptake, fatty diahrrea, malnutrition due to decrease fatty vitamin uptake, cholesterol uptake, bilirubin, drug disposition.
> Liver toxicant susceptibility: liver gets highest toxicant [ ] first; biotransformation capacity; liver secrets xenobiotic into bile leads to toxicity epithelial bile ducts cells; activation of Kupffer cells.
> Causes of Hepatic Toxicity: 
- Indirect extrahepatic: effect on circulation/respiration hypoxia
- Indirect intrahepatic: inhibition of VLDL synthesis; interference w/ biliary function.
- Direct hepatotoxicity: direct toxicant effect necrosis, apoptosis, neoplasia.
Types of Liver Injury
Hepatmegaly: hepatocyte enlargement due to fat, water, protein.
Fatty Liver (steatosisis): imbalance between TG synthesis & release; decreased plasma lipoprotein & lipids; ETOHNADHFA oxidation
Hepatocyte Death: apoptosis, necrosis.
Cholestasis: cholangiodestructive cholestasis bile duct damage, inflammatory cell infiltration, bilirubin serum level elevation. Canalicular cholestasis impaired secretion of solutes into bile; bilirubin serum accumulation.
Sinusoidal damage: progressive destriction of endothelial wall; liver engorgement w/ blood circulatory shock.
Cirrhosis: fibrosisi develops near central & portal blood vessels limit diffusion from sinusoids; non reversible result of chronic toxicant exposure; ETOH decrease lipid metabolism decreased lipoprotein synthesis fatty liver fibrosis decreased biotransformation ammonia accumulation decreased protein synthesis hemorrhage death.
Neoplasia: tumor derived from hepatocytes, bile ducts bile, and sinusoid epithelial cells dut to androgens or aflatoxin dietary.
Kupffer & Stelalte Cell Activation
> changed morphology of sinusoid resident macrophages after liver toxicant exposure.
> K cel activation secretion of cytotoxins, reactive oxygen & nitrogen species, effect can be attenuated w/ TNF AB.
> Antibiotics which decrease intestinal bacteria decrease K cell activation
> K cell inactivation/activation alters liver toxicant effects.
Hepatic Sensitization Responses
>immune mediated halothane toxicity: hepatotoxicity on repeat exposure, bioactivation to adduct adduct formation (hapten) antigen AB production.
Serum Enzyme Indicators of hepatotoxicity
* Cytotoxic: ornithine carbamyltransferase & sorbitol DH (specific); aspartate aminotransferase & lactate DH (nonspecific)
* Cholestatasis: alkaline phosphatase, 5’ nucleotides, gamma glutamyl transpeptidase.
Toxicant Bioactivation & Hepatotoxicity
> Toxicity related to reactive intermediate
> Treshold reactive [metabolite] required
> Endogenous protectants such as GSH 
> Glutathione transferases, epoxide hydrolases protect cell
> Selective inducers/inactivators of bioactivation alter toxicity
Acetaminophen
> Primary metabolism to glucuronide & sulfate conjugation
> P450 Mediated electrophillic quinoneimine conjugated w/GSH and excreted as mercapturate in urine
> High acetaminophen dose GSH depletion covalent binding of metabolite
> Necrosis
> Early treatment w/ SH cpds [N-Acetylcysteine] protects
> P450 Inhibition [metyrapone] protects
> P450 Induction potentiates toxicity
> Chronic ETOH use potentiates
> Acute ETOH potentiates
* Analgetic/ Antipyretic
- 4gm max adult daily dose
* With Aspirin Contraindication
- Peptic Ulcer Patients
- Where c/n tolerate bleeding time prolongation
Acetaminophen Toxicity
> Dose related hepatic/renal necrosis
> Elevated Plasma Aminotransferases
> Prolonged prothrombin times
> Elevated Plasma Bilirubin
> Can relate plasma [acetaminophen] at fist 24 hrs to potential hepatotoxicity
> Hypoglycemic coma
Acetylcysteina
AC L-cysteine + L glutamate + Y glutamyl/cysteine synthetase L-Y-glutamyl/cysteine + L-glycine reduced glutathione.
Acetylcysteina Antidote
> Rumack-Matthew Nomogram
- Estimates hepatotoxicity liklihood from time after ingestion and [acetaminophen serum]
- Whether to use acetylcysteine
- 4 gm/day max
Neurotoxicity
Antipsychotic drug classes
a) Conventional Typical (First Generational)
* Buterophenones (Haloperidol/Droperidol) Phenothiazines (chlorpromazine/Promethazine/Thioridazine
b) Atypical (Initial use preference) (Second Generational) minimal Extrapyramidal Effects Less D2 binding/ 
Adverse Effect ImportanceA) Patient distress due to quality of life
B) Influence adherence to prescribed agent
 * Influence on poor response on initiation or relapse during maintenance
C) Stigma of Abnormal Invouluntary movement or weight gain 
D) Morbidity eg., V. arrhythmias, Sudden death, orthostatic hypotension, weight gain cardiac ischemia.
Patient Factors Influencing Adverse Effect
>Age: Elderly
- More frequent, lower body mass, Increased receptor sensitivity
- Higher proportion of body fat to body water
- Decreased renal function
- Higher plasma drug conc. Than young
- Decreased regulation of temp/BP
- Multiple drug use drug Interactions
- E.g. elderly have more QTc prolongation &
- Orthostatic Hypotension, Tardive Dyskinesia,
> Gender
- Hyperprolactinemia & QTc prolongation
- Clozapine agranulocytosis & seizures more common in females
Receptor Affinity Differences among Atypical Antipsychotics
D2 Receptor Antagonism
Dissociation from D2 receptor
Antimuscarinic activity
5 HT2A antagonism
Alpha-1 blockade
* Risperidone
* Olanzapine
* Quetiapine
* Aripiprazole
* Above Orthostatic Hypotension
>> Acetylcholine Antagonism:
CNS & PNS (e.g. Clozapine, Olanzapine, Quetiapine)
Tachycardia
Sedation
Urinary Retention
Typical Effects of Atypical Antipsychotics
Hypotension
Muscarinic Antagonism
Sedation
QRS Widening
QTc Prolongation
Atypical Antipsychotics & Uses
Zolepine: Schizophrenia
Sertindole: Schizophrenia
Amisulpride: Schizophrenia
Quetiapine: Schizophrenia; Mania
Olanzepine: Schizophrenia; Mania; Prevent bipolar recurrence
Risperidone: Acute/chronic Psychoses; Mania
Clozapine: Schizophrenia w/ non responsive/intolerance to conventional antipsychotic drugs
Extrapyramidal Effects of Antipsychotics
Conventional agents (Haloperidol) :High EPS due to D2 blockade potency : Highest antiparkinson supplement needed
Long Term Treatment: Tardive Dyskinesia
Initial, High Frequency
Parkinsonism (c/b Treated w/ anticholinergics)
Akathisia (c/b treated w/ benzodiazepines;propranolol)
Acute dystonia (c/b treated w/ anticholinergics)
Extrapyramidal Adverse Effect (EPS)of Atypical Antipsychotic Agents
Throughout dose range low EPS frequency
Clozapine/quetiapine
At High Dose 
Amisulpride/risperidone dose related EPS
Tardive Dyskinesia (TD)
Involuntary Movements :Myoclonic Jerks,Tics, Chorea, Dystonia (5% first Yr, Increasing)
Older Pts more frequently 6X higher than younger Pts
Affective disorder Pts more frequent than Schizophrenia Pts
? Do initial EPS predict TD eventuality?
Hyperprolactinemia
Pituitary D2 Receptor Blockade decreases dopamine tonic inhibition of prolactin release
All conventional antipsychotic agents
Atypical agents
Aripiprazole: partial D2 agonist decr Prolactin level
Clozapine/Quetiapine d/n incr prolactin
Risperidone/amisulpride : c/ increase prolactin 
Hyperprolactinemia Symptoms
Gynecomastia
Galactorrhea
Oligomenorrhea
Amenorrhea
Decreased Libido (Reports of priapism w/clozapine/risperidone/olanzzapine/quetiapine)
Delayed Orgasm
Decreased Bone Mineral Density
Infertility
Acne & Hirsuitism (Females)
Weight Gain
Associated w/ Comparable Increases in Conventional & Atypical Agents (3-8 wks)
Stigma; hypertension; Type II Diabetes;Coronary Heart Disease;Respiratory difficultis; some cancers
Aripiprazole least (7%)Weight gain
Olanzapine/quetiapine/risperidone Most gain (18-25%)
Hyperglycemia& Hyperlipidemia
Both Conventional & Atypical agents
Atypical agents: Comparable to weight gain potential
Cardiovascular
EKG Abnormalities
Torsades de Pointes (TDP) /QTc Prolongation
QTc Prolongation
Thioridazine (30%)/Haloperidol Olanzapine (4%)
TDP Risk Factors 
Elderly/Bradycardia/Drug/ETOH abuse/Renal or hepatic impairment/Female/Pharmacokinetic factors
Myocarditis/Cardiomyopathy/Pericarditis reports
Antimuscarinic
Classical Antimuscarinic except Clozapine : incr salivation)Clozapine c/ Constipation as expected delay GI removal of overdose
Physostigmine to treat delerium
Precaution w/ BPH/ Narrow Angle Glaugoma
Blood Dyscrasias
Neutropenia due to atypical agents / clozapine (2X Asians compared w/ Caucasian)
Age Related Risk increase in elderly
Agranulocytosis : Severe neutropenic state
Withdrawal Reactions
Restlessness
Insomnia
N/V
Cease on readministration
Neuroleptic Malignant Syndrome(NMS)
Life Threatening
Muscle Rigidity: Increased Creatine phosphokinase
Autonomic Instability
Fever/Confusion
Diaphoresis
? Decr frequency due to increased atypical agent use?
NMS Treatment
Withdraw Causative Agent
Benzodiazepine vs agitation
Bromocriptine/Amantadine Dopamine Agonism
Dantrolene Case reports of efficacy (works in Malignant Hyperthermia by stabilizing ryanodine receptor on sarcoplasmic Reticulum)
Sedation (S)/Seizures (SS)
(S) Dose Related : Tolerance c/ develop
Antipsychotics Lower SS threshold
Pts w/ Alzheimers have lowered SS threshold
Greater S potential greater SS potential
Cerebrovascular (CBV) Reactions
CBV: Elderly more likely to get Transient Ischemic Attacks /Strokes
Serotonin Syndrome
Causses:
Increased doses of L-tryptophan will proportionally increase
5-hydroxytryptamine (5-HT or serotonin) formation. 
Amphetamines and other drugs increase
the release of stored serotonin. 
Inhibition of serotonin metabolism by monoamine oxidase (MAO) inhibitors will increase presynaptic 5-HT concentration. 
Impairment of 5-HT transport into the presynaptic
neuron by uptake blockers (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants) increases synaptic 5-HT concentration. 
Direct serotonin agonists can stimulate postsynaptic 5-HT
receptors. 
Lithium increases postsynaptic receptor responses.
Drugs Predisposing to Serotonin Syndrome
Triptans + Selective Serotonin(SSRI) Reuptake Inhibitors Selective Serotonin/NE (SSNRI) Inhibitors. Exemples: sumatriptan (imitrex)ç zolmitripan (zomig); frovatriptan (frova); rizatriptan (maxalt). SSRI Examples: citalopram (celexa); sertraline(Zoloft); fluoxetine (Prozac); paroxetine(paxil); escitalopram (lexapro). Selective Serotonin/NE Reuptake Inhibitor (SSNRI) Examples: duloxetine (Cymbalta); venlafaxine (Effexor).
MAOI
Meperidine
Detromethorphan
Serotonin Syndrome Toxidrome
Hallucinations
Agitation/Shivering/Tremor
Muscle Spasms (myoclonus)
Nausea/Vomiting/Diarrhea
Hyperthermia/Perspiration
Tachycardia
Ataxia/Hypomania
Rapid BP changes
Lethality **
Rhabdomyolysis **
Diagnosis: 1) Serotonergic plus at least 3 symptoms of above 2) R/O Cocaine, Lithium, MAO Inhibitor ovedrose/ ** Severe Toxicity
Serotonin Syndrome Treatment
Serotonin Antagonist : Cyprohepatadine
Benzodiazepine
IV Fluids
Withdraw drug cause 
Breathing support **
Muscle Paralysis**
** Life-Threatening situation
	
	NMS
	SS
	MH
	Trigger
	Idiosyn
	Dose Related
	Idiosyn
	Fever
	2+
	2+
	3+
	Dis
autonomia
	3+
	3+
	3+
	Motor Features
	Tremor
Rigidity
	Myoclonus Hyperreflex
	___
	
	NMS
	SS
	MH
	Causes
	L-DOPA Withdrawal
Antiemetics
Antipsychotics
	MAOI , SSRI, SSNRI
TCA, Tryptophan
	Volatile G.Anesthetics
Succinyl Choline
Rocuronium **
	Drug Antidotes
	Bromocriptine
Amantadine
Dantrolene
	Cyproheptadine
Methylsergide
	Dantrolene
Azumolene
Comparison of Three CNS Toxidromes