SPECIFIC

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