Download Mechanisms of common and important adverse drug reactions

Mechanisms of common and
important adverse drug reactions
Jack W. Strandhoy, Ph.D.
Drug Safety
Pharmacovigilance
• Paracelsus: “All substances are
poisons…dose differentiates”
• Toxicology – adverse effects of chemicals,
incl drugs, on living organisms. ↑doses.
• Pharmacovigilance – concerns detection,
assessment, understanding, prevention of
adverse events with medicines in nl doses
• Adverse Drug Reactions – noxious and
unintended; at normal therapeutic doses
– Affect 2 million / yr in US; 100,000 deaths / yr
Idiosyncratic
Adverse Drug Reactions
(or Effects)
Mechanism-dependent
toxicities
Genetic
influences
Interactions:
drugs, foods
Mechanism-dependent
toxicities
• exaggerated effects
• ion disturbances
• cardiovascular problems
Mechanism-dependent toxicities
• An exaggeration of the expected
pharmacological effect
• Hyperkalemia – ACEI, ARB, K-sparing diuretics;
complicated by ↓renal fx, acidosis, diabetes …
• Cardiovascular risks –
– COX-2 inhibitors (rofecoxib) – ↑ stroke and MI
– Immediate release Ca blockers - ↓↓BP
• HTN, proteinuria – cediranib for cancer. VEGF-R
tyr kinase inhibitor. Titrate to dose
• Bleeding, coughing, GI ulcers, infection risk,
CNS effects …
Interactions
• drugs (Rx, OTC, herbal)
• foods (vitamins, suppl)
Interactions: drugs
Seldane
terfenidine
CYP3A4
(-)
Allegra
fexofenidine
erythromycin
Torsades de Pointes
- Ventricular tacharrythmia
- Prolonged QT
Interactions: drugs
• Interaction occurs esp. in patients with
altered KCNE2 gene for IK r potassium
channel that is important for repolarization
• ↑QT also by trimethoprim-sulfamethoxazole
Interactions: drugs
Tylenol Sinus Congestion & Pain Daytime
Tamoxifen
?
Tylenol Allergy Multi-Symptom
CYP2D6
chlorpheniramine
• also 2D6↓ antidepressants like fluoxetine
Interactions: foods
• Grapefruit juice – irreversibly inhibits
CYP3A4 on GI mucosa
– Consequence is ↑drug absorption
– Cyclosporine, some statins
• Ca+2, GI transit time may ↓ absorption of
some drugs
– Tetracyclines, ciprofloxacin
Genetic
Influences
•
•
•
•
metabolism
Disposition, PK
receptors
transporters
Effect, PD
HLA haplotypes
Env Health Perspect
Genetics in ADRs
metabolism: deficiency
• Clopidogrel (Plavix) - ↓platelet P2Y12
receptor binding of ADP
• Prodrug, activated by CYP2C19
• Loss of function = 2C19*2 allele
– Greater risk of thrombi, MI, stroke
• PPIs may also ↓2C19 (esp.omeprazole) but ↓
risk of GI bleeding (esp. pantoprazole)
– Ray et al., Ann Int Med (2010)
Genetics in ADRs
metabolism: surplus
• Azathioprine, 6-MP detoxified by
thiopurine S-methyltransferase (TPMT)
• Genetic ↓ TPMT → toxicity, pancytopenia
• Kits available for genotyping TPMT
• Dose adjustments in pts can be life-saving
Genetics in ADRs
metabolism, receptors
• Warfarin (Coumadin) – anticoagulant
antagonist of vit. K
• Wide variability in dosing, to effect
measured by INR
• Pharmacogenomic variability in CYP2C9
and VKORC1 [receptor]
Genetics in ADRs
transporters
• Pravastatin, simvastatin – myopathy risk ↑
with variant of organic anion transporter
polypeptide (OATP), SLC01B1
– More severe rhabdomyolysis may also be
linked but is very rare
• P-glycoprotein variant ↑digoxin
bioavailability; p-gp also site of drug
interactions
Genetics in ADRs
HLA haplotypes
• Carbamazepine (Tegretol) – used for seizures,
trigeminal neuralgia, etc.
– HLA B*1502 associated with propensity for severe
toxic epidermal necrolysis and Stevens-Johnson
syndrome
– Mechanism unknown
• Aspirin hypersensitivity – associated with HLAs
and altered AA metabolism to leucotrienes
– HLA DPB1*0301; HLA DB1*0609
Opportunities for teaching drug
safety in the curriculum
• Explaining ADRs and drug interactions illustrates
PK/PD mechanisms of drugs
• Vigilance in drug safety improves clinical
observational skills
• Predictive modeling of ADRs requires laboratory
skills and sagacity
• Population-based data supports EBM, regulatory
and cost-saving decisions
• Learners will better identify, predict, report,
model and prevent ADRs
Pre-clinical
Mechanisms
Education
Reporting
ADRs
Clinical
Observations