Clinical toxicology

Dep. of Biopharmaceutics and Clinical Pharmacy

Drug-induced poisoning: Relevance!
• Substances people purposefully take or use to relieve
their illness or produce symptoms of pleasure and cause
dissociation from reality (illicit psychotomimetics)
• The incidence of adverse reactions related drugs is
reported up to 30% of all hospitalized patients
• From 2 to 9% of all admissions to medical clinics are
due to adverse drug reactions
• Reasons:
 Children accidentally from unguarded containers
 Children given inappropriate doses
 Adults Tx with overdose accidentally or intentionally
 Drug-drug, drug-food & drug-ethanol interactions
Drug-induced poisoning: Relevance!

• Drug reactions have increased in number and severity

due to:
 Increased availability of potent prescription and
OTC drugs
 Increased number of variety of illicit drugs
• 85% due to the pharmacologic action of the drug!!!
• 15% due to immunologic mechanisms (as anaphylaxis)
NSAID’S INTOXICATION
 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

 Overview:
Definition: NSAIDs are a chemically diverse class of
drugs  (>70 NSAIDs in use) that have anti-
inflammatory, analgesic, and antipyretic, anti-
aggregant properties
KINETICS — Oral absorption of NSAIDs approaches 100 percent and peak serum levels
usually occur within one to two hours. Large toxic ingestions or concomitant food
consumption can delay peak levels up to three to four hours. NSAIDS are weak acids
that are extensively (up to 99 percent) protein bound, with a small volume of
distribution (0.1 to 0.2 L/kg). Diseases causing low protein levels or large NSAID
ingestions can decrease plasma protein binding, resulting in an increased volume of
distribution and greater penetration into body tissues, including the central nervous
system.
 NSAIDs

 Among the most frequently prescribed

drugs worldwide:
 70 million people/day  prescribed NSAIDs
 230 million people/day take OTC NSAIDs 
 USA:  80 billion aspirin tablets consumed/year  
   USES 
1. Anti-inflammation
2. Analgesic
3. Anti-pyretic
4. Treatment of gout, arthritis
5. Prophylaxis of heart disease (myocardial
infarction and stroke)
6. Prophylaxis of colorectal cancer
7. Prevention of development of Alzheimer
disease
 Background

Patients who ingest NSAIDs in overdose, manifest

only mild GI upset and CNS disturbances that are
usually self limiting
However, serious and fatal outcome may result after
overdose with oxyphenbutazone, phenylbutazone,
mefenamic acid, piroxicam, or diflunisal
….from acute renal failure, hepatic failure, respiratory
depression, coma, convulsion and cardiac arrest
 Mechanism of action
 Normal inflammatory response
• series of events that aid our survival in response to injury
 Mediated by a host of endogenous compounds
-histamine
-serotonin
-bradykinin
-prostaglandins
-leukotrienes

Mechanism of action & toxicity: inhibit cyclooxygenase, the

enzyme that mediates the initial step in PGs synthesis
Properties of Prostaglandins
 NSAID Mechanism
a) NSAIDs inhibit cyclooxygenase (COX)

b) Three types of cyclooxygenase:

- COX-1 is constitutively expressed
- COX-2 is induced at sites of inflammation by
inflammatory mediators
- COX-3 recently identified
 COX-2 Hypothesis (1990s)
Normal Tissue Inflammation Site
Arachidonic Acid
Cytokines
+ Growth factors

COX-1 COX-2
Constitutive Inducible

COX-2
NSAIDs
Inhibitors
Physiolgical Pathological
Prostaglandin Prostaglandin
Production Production

Normal Functions Inflammation, pain, fever

 Properties of Prostaglandins

Physiological Functions of PG:

• Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin,
histamine and substance P
• Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema,
erythema)
• Protection of the gastric mucosa: PGI2
• Maintenance of renal blood flow: PGE2
• Fever: PGE2
• Platelets: PGI2 inhibit platelet aggregation; TXA2 stimulates
platelet aggregation
• Uterus: PGD2 contracts uterus
 Side Effects of NSAIDs
• GI: N, V, abdominal pain, GI hemorrhage from local irritation
• Hematologic: hemorrhage resulted from impaired platelet
aggregation
• Renal: Na, K & water retention. Nephrotoxicity is due, in part,
to interference with the autoregulation of renal blood flow
• Cardiac: worsening of congestive heart failure due to water and
sodium retention
• Obstetric: delay in the onset of labor, prolonged labor,
increased risk of hemorrhage and may close ductus arteriosum
by inhibition of PG
• Neurologic: minor CNS disturbances….drowsiness, blurred
vision
• Hypersensitivity reactions
 Inhibition of the Cyclooxygenases
a. Competitive inhibition of the substrate
(arachidonic acid) binding site of COX. The inhibition
is reversible when the drug washes out.

COX-1
COX-1 COX-2
COX-2

From Nature Structural Biology, vol 3, number 11, 1996

 COX-2 Specific Inhibitors

• The newest generation of NSAIDs, (rofecoxib [Vioxx],

celecoxib [Celebrex], valdecoxib [Bextra]), selectively inhibits
the COX-2 isoform at therapeutic doses
• The likelihood of GI bleeding is less with these drugs than
with conventional NSAIDs
• There is limited information regarding overdoses of COX-2
inhibitors……hypertension, acute renal failure, respiratory
depression, and coma may occur in overdose
• Rofecoxib and valdecoxib have been removed from the market
because increased risk for CV events (including MI & stroke)
 NSAIDs Classification

NSAIDs are subdivided into six groups based on their

chemical structure
1. Salicylates
2. Pyrazolones: phenylbutazone
3. Indoleacetic acid (pyroles): diclofenac, indomethacin
4. Phenylpropionic acids: ibuprofen, ketoprofen,
naproxen
5. Anthranilic acids: mefenamic acid
6. Oxicam: piroxicam
 Inhibition of the Cyclooxygenases
b. Acetylation of a key serine within the active site. This
reaction is not reversible and is unique to aspirin.
 Pyrazolones

 Phenylbutazone; oxyphenbutazone: available for

veterinary use, may present in some herbal
preparation (withdrawn from the market)

 Aplastic anemia and agranulocytosis have been

associated with the use of phenylbutazone
 Indoleacetic acid (pyroles)

Indomethacin, diclofenac, etodolac, ketorolac,

sulindac:
Rapidly absorbed from GI, they undergoes hepatic
circulation
Clinical presentation: nausea, vomiting, abdominal
pain, tinnitus, drowsiness, confusion, restlessness
Self-limiting
 Indoleacetic acid (pyroles)

 Management:
1. Gastric lavage should be performed in cases of
serious overdose
2. Activated charcoal should be given and repeated
every 4 hrs
3. Supportive and symptomatic treatment
 Phenylpropionic acids

 Ibuprofen, fenoprofen, flurboprofen, ketoprofen,

naproxen
 In general, overdose with “propionic acids” do not
result in significant morbidity or mortality, although
death after overdoses of ibuprofen & fenoprofen have
occurred
 Ibuprofen: the most widely used and rapidly absorbed
from GI
 Neither the rate of absorption nor elimination seems
to be altered by overdose
 Ibuprofen

Therapeutic range: adult 400-2400 mg/day

children 20-50 mg/kg/day
Poisoning is usually manifested by mild GI symptoms:
N, V, abdominal pain, anorexia, GI hemorrhage (rare)
CNS depression
Nystagmus, tinnitus
Respiratory depression
Metabolic acidosis
Headache, seizures
Hypotension, bradycardia, hypothermia
 Ibuprofen

In the presence of normal renal function, patients

usually fully recover within 24hrs

Reports of severe and fatal outcomes following the

onset of acute renal or hepatic failure, hypotension

and coma
 Ibuprofen

Treatment…..GI decontamination
1. Ingestion less than 100mg/kg: dilute with water to
reduce gastric irritation
2.More than 100mg/kg:
 Gastric lavage
 After gastric emptying, activated charcoal and a saline
cathartics should be administered
 Ibuprofen

4. Hypotension: treated with i.v. fluids , if it persist

dopamine or NE may be required
5. Seizures: treated with diazepam
6. Bradycardia may respond to atropine
7. Metabolic acidosis (PH < 7.1) may require
administration of sodium bicarbonate
8. Ibuprofen weak acid….urine alkalinization? NO coz
short half-life and extensive protein binding
 Anthranilic acids

Mefenamic acid & maclofenamate

 Is well absorbed, more than 50% excreted
unchanged in urine, the reminder as conjugate
Clinical presentation:
1. May produce no symptoms
2. Muscle twitching either focal or generalized has
been reported
3. Seizures are common following overdose
4. Diarrhea, rash, elevated BUN and coma
 Anthranilic acids

Management:
 Tx with gastric lavage, and administration of
activated charcoal

 Observation for seizures development

 Oxicam

Piroxicam
It undergoes enterohepatic circulation, long half-life
(45h)
Clinical presentation:
Usually not develop severe symptoms
Can cause photosensitivity reaction (use sunscreen
when outside)
GI hemorrhage, dizziness, difficulty in breathing,
hematuria, proteinuria, renal and hepatic dysfunction
Management:
Gastric lavage, followed by repeated doses of AC
 N.B

Specific levels of NSAIDs are not usually readily

available and do not contribute to clinical
management
Antacids may be used for mild GI upset

There is no antidote….vitamin K may be used for

patients with elevated prothrombin time caused by
hypoprothrombinemia
Enhanced elimination? NSAIDs are highly protein-
bound and extensively metabolized……
 PGs and uterus

TOCOLYSIS
• COX inhibitors (selective or not)
• Beta-2 agonists
• CCB
• Oxytocin antagonist
• Nitric oxide donors
• Magnesium sulfate
• Fetal side effects — The primary fetal concerns with use of
indomethacin and other COX inhibitors (are constriction of the
ductus arteriosus.
• COX INHIBITORS — Prostaglandin E2 (PGE2) is a vasodilator that
promotes ductal patency. In the 1970s, two studies
demonstrated pharmacologic closure of patent ductus
arteriosus (PDA) within 24 hours with the administration of
indomethacin, an inhibitor of cyclooxygenase (COX), the pivotal
enzyme in the synthesis of PGE2 [6,7]. Currently, the two
cyclooxygenase inhibitors used to medically close PDAs are
indomethacin and ibuprofen.
• Dose — The dose of indomethacin for labor inhibition is a 50 to
100 mg loading dose (may be given per rectum), followed by 25
mg orally every four to six hours. Fetal blood concentrations are
50 percent of maternal values, but the half-life in the neonate is
substantially longer than that in the mother (15 versus 2.2
hours).