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DRUGS/TOXINS
TERMINOLOGY
TOXICOLOGY
Study of the adverse effects of chemicals or
physical agents on living organisms
TOXICOLOGIST
A person/scientist that determines the
harmful effects of agents; biochemical,
cellular and molecular mechanisms
responsible for the effects
TOXINS
Poisonous substance produced within living
cells organisms
Ex: botulinum toxin and mushroom toxin
POISONS
Substance that cause disturbances in
organisms, usually by chemical reaction or
other activity on the molecular scale, when an
organism absorbs a sufficient quantity
Ex: pesticides
TOXICANTS
Substances that produce adverse biological
effects made by humans or introduced into the
environments by human activity
May be chemical or physical in nature
TOXIC AGENTS
SYSTEMIC EFFECTS
Affects the entire body or many organs of the
body
ORGAN-SPECIFIC EFFECTS
Substance that does not affect the entire body
Attacks a particular organ or body system
ACUTE TOXICOLOGY
Adverse effects of a substance that result
either from a single exposure or from multiple
exposures in a short space of time
CHRONIC TOXICITY
Adverse health effects from repeated exposures
of ten at lower levels, to a substance over a
longer time period
Months to years
CARCINOGENECITY
Any substance or agent that tents to produce
a cancer
DEVELOPMENTAL TOXICITY
Any structural or functional alteration,
reversible or irreversible which interferes with
homeostasis, normal growth, differentiation,
development or behavior
Embryolethality: failure to conceive, abortion
or stillbirth
Embryotoxicity: growth retardation or delayed
growth of systems
Teratogenicity: irreversible condition that
leave permanent birth defects
GENETIC TOXICITY
Result from damage to DNA and altered
genetic expression
Gene mutation: change in DNA sequence
with in a gene
Chromosome aberration: change in the
chromosome structure
aneuploidy?/polyploidy: increase or decrease
in number of chromosomes
PREGNANCY RISK
FACTORS
CATEGORY A
Controlled studies show no risk
Adequate, well controlled studies in pregnant
women have failed to demonstrate a risk to the
fetus in any trimester of pregnancy
CATEGORY B
No evidence risk in humans
Adequate, well controlled studies in pregnant
women have not shown increased risk of fetal
abnormalities despite adverse findings in
animals
PREGNANCY RISK
FACTORS
CATEGORY C:
Risk cannot be rule-out
Adequate, well-controlled human studies are
lacking and animal studies have shown a risk
to the fetus or are lacking as well
There is a chance of fetal harm if the drug is
administered during pregnancy, but the
potential benefit may outweigh the potential
risk
CATEGORY D
Positive evidence of risk
Studies in humans or investigation or post-
marketing data have demonstrated fetal risk
Nonetheless, potential benefits from the use
of the drug may outweigh the potential risk
CATEGORY X
Contraindicated in pregnancy
Studies in animals or humans or
investigational or post-marketing reports
have demonstrated positive evidence of fetal
abnormalities or risk that clearly outweighs
any possible benefits for the patients
ANALGESICS
• ACETAMINOPHEN
• NSAIDS
• SALICYLATES
ACETAMINOPHEN
Other name: Paracetamol
Analogue of phenacetin and acetanilid
MOA: inhibits prostaglandin synthesis
Advantage over salicylates:
Relative lack of sensitization
Absence of gastrointestinal irritation
Lack of effect on coagulation
Not associated with Reye’s syndrome
ACETAMINOPHEN:
PHARMACOKINETICS
ABSORPTION
Rapid and complete
Depends of gastric emptying
Peak therapeutic concentration occurs within 1
hours
DISTRIBUTION
Plasma protein binding: 25% to 50%
Volume of distribution: 0.75 to 1.0L/kg
ELIMINATION
Liver biotransforms 90% of acetaminophen by
conversion to sulfate or glucoronide
ACETAMINOPHEN:
CLINICAL PRESENTATION
Phase 1: (0.5-24 hours after ingestion)
Asymptomatic or may present with anorexia,
nausea or vomiting and malaise
Phase 2: (18-72 hours after ingestion)
Right upper quadrant pain/tenderness,
anorexia, nausea and vomiting
Tachycardia and hypotension
Can present with oliguria
ACETAMINOPHEN
Phase 3 (72-96h after ingestion)
Hepatic phase
Continued nausea and vomiting, abdominal
pain and tender hepatic edge
Hepatic necrosis and dysfunction associated
with jaundice, coagulopathy, and hepatic
encephalopathy
Acute renal failure may develops
Death may occur from multi-organ failure
Phase 4 (4days to 3weeks after ingestion)
Recovery phase
Patients who survive critical illness in phase 3
have complete resolution of symptoms and
resolution of organ failure
ACETAMINOPHEN:
CLINICAL PRESENTATION
CARDIOVASCULAR EFFECTS
Fatty degeneration of myocytes, focal myocardial
muscles necrosis, left ventricular dilation sub-
endocardial necrosis
dysrhythmias
PANCREATIC EFFECTS
Doses of acetaminophen as low as 9.75 grams is
associated with pancreatitis
HYPERSENSITIVITY EFFECTS
Rare
Bullae, eczema, urticaria, and exfoliative
dermatits
CHRONIC EFFECTS
Chronic excessive use by adults who seek
pain relief and fever control may lead to a
toxic hepatitis
ALCOHOLIC PATIENTS
More susceptible to the hepatic effects of an
overdose of acetaminophen
Glutathione storage depletion
ACETAMINOPHEN
TOXIC DOSE/DEATH
Adult: single dose of 150 to 250mg/kg
Children younger than 10 years old appear to
be more resistant than adult
PREGNACY/LACTATION
Pregnancy risk factor: category B
Can cross placenta
LABORATORY
Analytic methods: measured by immunoassay
ACETAMINOPHEN:
TREATMENT
GUT DECOMTAMINATION
Activated charcoal and emesis: given within the
first several hours of ingestion
ELIMINATION ENHANCEMENT
Exchange transfusion
Used in neonates following acetaminophen
ingestion by the mother shortly before birth
Hemofiltration
Treatment of associated hepatic encephalopathy
Hemodialysis
Treatment of renal failure
ACETAMINOPHEN:
TREATMENT
SUPPORTIVE MEASURES
Baseline blood test: CBC, liver function test,
glucose, electrolytes, and creatinine
Prothrombin time (give Vitamin K or FFP for
elevated protime)
Serum amylase/lipase
Maintain normal hydration and electrolyte
balance
Regular lactulose and enemas for elimination
of nitrogenous substances and endotoxins from
the bowel in encephalopathic patients
Cerebral edema: treated with mannitol and
fluid restriction
ACETAMINOPHEN:
TREATMENT
ANTIDOTES
N-ACETYLCYSTEINE (Oral form)
Helps replenish diminished glutathione stores
METHIONINE
Acts as a glutathione precursor
Protects against acetaminophen-induced
hepatic and renal toxicity if administered 8-10
hours of overdose
ACETAMINOPHEN:
TREATMENT
CIMETIDINE
Reduces acetaminophen-induced liver toxicity
in animal models
4-METHYLPYRAZOLE
Animal studies suggest inhibition of
acetaminophen-induced hepatotoxicity when
administered within 4 hours of ingestion
Inhibition of the main cytochrome P450
enzyme involved in acetaminophen activation
in humans
Clinical studies are required to validate this
observation
SALICYLATES
Acetylsalicylic acid/aspirin
Bismuth subsalicylate
Methyl salicylate
MOA: inhibits prostaglandin synthesis;
prevent the formation of thromboxane
Aspirin
Weak acid (pKA of 3)
50% to 80% protein bound
SALICYLATE TOXICITY:
CLINICAL PRESENTATION
METABOLIC EFFECTS
Respiratory alkalosis or mixed with metabolic
acidosis
Hyperglycemia more common than
hypoglycemia
HEMATOLOGIC EFFECTS
Thrombocytopenia
Decreased platelet adhesiveness
Decreased factor VII
Hypoprothrombinemia
CARDIOVASCULAR EFFECTS
May induce cardiac depression and asystole
SALICYLATE TOXICITY:
CLINICAL PRESENTATION
GASTROINTESTINAL EFFECTS
Benign gastric erosions
60% duodenal erosions
Nausea, vomiting and epigastric pain
Hematemesis
Hepatotoxicity when the level exceeds
20mg/dL
OTOLOGIC EFFECTS
Hearing loss and tinnitus (reversible)
SALICYLATE TOXICITY:
CLINICAL PRESENTATION
NEUROLOGIC EFFECTS
Tinnitus and lethargy (mild)
Irritable and disoriented
Asterixis, hallucination, seizures, or coma
(serious)
PULMONARY EFFECTS
Noncadiogenic pulmonary edema
Precipitate bronchial asthma
Acute airway obstruction secondary to
angioedema
RENAL EFFECTS
Renal papillary necrosis and cortical intsterstitial
nephritis
SALICYLATES: CLINICAL
PRESENTATION
REYE’S SYNDROME
Rare, biphasic illness
Characterized by encephalopathy and fatty
infiltration of viscera
Occurs in children under 16 years old
May occur in adult (rare)
PSEUDOSEPSIS SYNDROME
Chronic salicylate intoxication
Resembles occult sepsis including
Fever
Leukocytosis and leftward shift in the
differential count
Hypotension
Reduced systemic vascular resistance
Multi-organ system failure
Respiratory distress syndrome
Acute renal failure
SALICYLATES
DRUG INTERACTIONS
Caffeine, phenylbuatzone, indomethacin, and
alcohol
Increase ulcerogenic effect of aspirin
Food, chelation with iron
Potentiates penicillins and sulfonamides
Displaces OHAS
Antagonizes uricosoric effect of probenecid,
sulfinpyrazone, phenylbuazone
Decrease the effect of spironolactone
PREGNANCY AND LACTATION
Cross placenta
Possible teratogenic effect and an increase in
stillbirth
Fetal death may occur
Delay the onset of labor, increasing
postmaturity, increase the duration of
spontaneous labor
Late gestation: abnormalities inhemostasis,
acid-base balance, tachypnea, and glucose
metabolism
Daily small doses: reduce incidence of
pregnancy-induced hypertension and
preeclamsia
LABORATORY
Analytic method
Trinder method (ferric Choride Test)
Positive result: Urine will turn violet or purple
Plenistix
Positive: brownish purple color
Gas chromatography and HPLC
Blood levels
TOXIC LEVEL: over 25mg/dL
SALICYLATE TOXICITY:
TREATMENT
GUT DECONTAMINATION
Gastric lavage
Activated charcoal (in significant overdose)
ELIMINATION ENHANCEMENT
CHARCOAL HEMOPERFUSION
Produce better salicylate clearance
Does not correct fluid and electrolyte
imbalance
HEMODIALYSISIndication:
Presence of cardiac or renal failure
Intractable acidosis
Severe fluid imbalance
Seizures (assoc. with poor prognosis)
SUPPORTIVE MEASURES
Fluid replacement for adequate hydration
Relative vit. K deficiency: give 2.5 to 5mg vit. K
daily
Hyperthermia: use cooling blanket, ice in the
axilla and groin
Laboratory test: CBC, BUN, creatinine,
electrolytes, glucose, ABG, urinalysis, protime,
calcium and liver function tests.
O2 supplementation
PPIs, antacids, misoprostol, H2 blockers and
sucralfate
URINARY ALKALINIZATION
Increase urinary salicylate excretion
Increase urine pH to 7.5
Mild toxicity: 1 mEq/kg sodium bicarbonate
added to a liter of 5% dextrose
Moderate to severe toxicity: 50 t0
100meQ/kg NaHCO3 over 1 to 2 hours
Closely monitor blood and urinary pH
METABOLIC SUPPORT
Closely monitor electrolytes
Monitor blood glucose
Signs of hypocalcemia and development of
pulmonary edema with hydration must be
monitored
REYE’S SYNDROME
Manangement is directed toward
encephalophathy
Lower the ICP
Admit at the ICU
Elevate the head
Give Mannitol
NONSTEROIDAL
ANTIINFLAMMATORY DRUG
MOA: inhibits prostaglandin synthesis
Rapid absorption
95% protein bound
Small volume of distribution
Mostly conjugated with glucuronic acid
Kidney excretes only 1% to 5%
NSAIDS: CLINICAL
PRESENTATION
GASTROINTESTINAL EFFECTS
Gastric erosion, strictures, erosions,
perforations, blood loss, diarrhea, villous
atrophy
Risk factors for serious GIB:
age> 60y.o
History of peptic ulcer
Cigarette and alcohol use
High dose and prolonged use of NSAID
Concomitant use of steroids
Serious concomitant disease
NEUROLOGIC EFFECTS
Disorientation, hallucination, LOC
Convulsions, coma, and brainstem signs
(Mefenamic and Phenylbutazone)
RESPIRATORY EFFECTS
Eosinophilic pneumonia (cough, fever,
dyspnea, malaise, pleuritic chest pain,
pleural effusion)
CARDIOVASCULAR EFFECTS
Atrial fibrillation (Ibuprofen)
RENAL EFFECTS
Risk factors:
Age > 60 year old
Vascular disease
Renal or functional depletion
Preexisting renal insufficiency
SLE
Three distinct forms of NSAID nephrotoxicity
Acute renal insufficiency
Acute tubular necrosis
Papillary necrosis
HEPATIC EFFECTS
Risk factors:
Advanced age
Renal insufficiency
Multiple drug use
Alcohol use
Higher NSAID drug dose
HEMATOLOGIC EFFECTS
Increase bleeding time
Aplastic anemia: Phenlbutazone and piroxicam
NSAIDs
TOXIC DOSE/DEATH
Death is very rare
2 grams in phenylbutazone
Blood level of 518mg/ml (ibuprofen)
DRUG INTERACTION
Salicylates may exacerbate gastropathy
Increased bleeding when used together with
warfarin
PREGNANCY AND LACTATION
Ibuprofen: Category B or D if used in the third
trimester
Indomethacin: Category B
LABORATORY
HPLC
NSAIDS: TREATMENT
GUT DECONTAMINATION
Asymptomatic: Give activated charcoal
Gastric lavage with tracheal protection
followed by instillation of activated charcoal
Do not give Ipecac for Mefenamic and
Phenlbutazone overdose
SUPPORTIVE MEASURES
For severe cases: admit at the ICU for
monitoring
Give diazepam for seizures
Check the CBC, electrolytes, crea, liver
function, ABG, protime
Watch out for gastrointestinal bleeding