Download Clinical toxicology

yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Medication wikipedia, lookup

Neuropharmacology wikipedia, lookup

Metalloprotease inhibitor wikipedia, lookup

Prescription costs wikipedia, lookup

Pharmacogenomics wikipedia, lookup

Discovery and development of direct thrombin inhibitors wikipedia, lookup

Bad Pharma wikipedia, lookup

Discovery and development of direct Xa inhibitors wikipedia, lookup

Drug interaction wikipedia, lookup

Discovery and development of neuraminidase inhibitors wikipedia, lookup

Neuropsychopharmacology wikipedia, lookup

Discovery and development of integrase inhibitors wikipedia, lookup

Discovery and development of ACE inhibitors wikipedia, lookup

Psychopharmacology wikipedia, lookup

Bilastine wikipedia, lookup

Discovery and development of proton pump inhibitors wikipedia, lookup

Discovery and development of cyclooxygenase 2 inhibitors wikipedia, lookup

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
 Increased number of variety of illicit drugs
85% due to the pharmacologic action of the drug!!!
15% due to immunologic mechanisms (as anaphylaxis)
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Definition: NSAIDs are a chemically diverse class of
drugs (>70 NSAIDs in use) that have antiinflammatory, analgesic, and antipyretic, antiaggregant 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
 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
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
 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
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
Growth factors
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: blood dyscrasias and 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
• 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.
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,
4. Phenylpropionic acids: ibuprofen, ketoprofen,
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.
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,
 Rapidly absorbed from GI, they undergoes hepatic
 Clinical presentation: nausea, vomiting, abdominal
pain, tinnitus, drowsiness, confusion, restlessness
 Self-limiting
Indoleacetic acid (pyroles)
Gastric lavage should be performed in cases of
serious overdose
Activated charcoal should be given and repeated
every 4 hrs
Supportive and symptomatic treatment
Phenylpropionic acids
Ibuprofen, fenoprofen, flurboprofen, ketoprofen,
In general, overdose with “propionic acids” do not
result in significant morbidity or mortality, although
death after overdoses of ibuprofen & fenoprofen have
Ibuprofen: the most widely used and rapidly absorbed
from GI
Neither the rate of absorption nor elimination seems
to be altered by overdose
 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
 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
Treatment…..GI decontamination
Ingestion less than 100mg/kg: dilute with water to
reduce gastric irritation
More than 100mg/kg:
Gastric lavage
After gastric emptying, activated charcoal and a saline
cathartics should be administered
Hypotension: treated with i.v. fluids , if it persist
dopamine or NE may be required
Seizures: treated with diazepam
Bradycardia may respond to atropine
Metabolic acidosis (PH < 7.1) may require
administration of sodium bicarbonate
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
 Tx with gastric lavage, and administration of
activated charcoal
Observation for seizures development
 It undergoes enterohepatic circulation, long half-life
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
 Gastric lavage, followed by repeated doses of AC
 Specific levels of NSAIDs are not usually readily
available and
 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
 Enhanced elimination? NSAIDs are highly protein-
bound and extensively metabolized……
PGs and uterus
COX inhibitors (selective or not)
Beta-2 agonists
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