Toxicology Flashcards
Dose vs Concentration
Concentration: can refer to the strength of e.g a dosing solution or content in a foodstuff
AND the resulting amount of the drug/metabolite in biological matrices* after dosing *= plasma, serum, urine
Dose and concentration are not interchangeable
Concentration (mg/ml) x volume (mL) = dose (mg)
Dose (mg) / Volume distribution (L) = concentration (mg/L)
Adverse Drug Reactions (ADR): General info
Pre-approval:
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.
Post-approval:
A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.
Side effect:
It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse effect or adverse reaction
ADR vs Adverse event
“Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment”
Category A-D harm severity
No harm
Category E
Temporary harm to the patient and required intervention
Category F
Temporary harm to the patient and required initial or prolonged hospitalisation
Category G
Permanent patient harm
Category H
Intervention required to sustain life
Category I
Patient death
Factors causing adverse drug reactions
Related to pharmacology?
Apoptosis or necrosis?
Species
Route
Reversible
Cumulative
Organ-specificity
Gender
Metabolic activation
Macromolecular target
Genetic predisposition
Chemical modification
Concentration
Time-course
ADR Mechanistic Classification: Broad
Type 1 or Type A: Predictable, concentration-dependent based on the known pharmacology of the drug
Type 2 or Type B: Not predictable, no clear concentration-dependency and not due to the known pharmacology of the drug
ADR Mechanistic Classification: Specific
Type A (Augmented): Predicted from known pharmacology of drug, usually drug-dependent and alleviated by dose reduction. E.g hypotension with anti-hypertensives or haemorrhage with anticoagulants
Type B (Bizarre): Not predicted from basic pharmacology, with no simple concentration-response relationship. Dependent or host?
Type C (Chemical): These are reactions whose biological characteristics can be be predicted, or clearly rationalized in terms of the chemical structure of the drug, or its metabolite.
Type D (Delayed): Occur after many years of treatment e.g secondary tumours with chemotherapeutic agents
Type E (End of treatment): Due to withdrawal of treatment, especially when the drug is withdrawn suddenly. e.g seizures on stopping phenytoin
Serious vs Severe
Severe is often used to describe the intensity of a specific event. (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache)
Serious is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. Results in death or is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect
Chemical vs Pharmacological toxicity
Is the ADR related to the pharmacology of the drug? If YES, then it is likely to be associated with all the drugs that work in this way (a class effect), problematic for drug development (hard to dissociate risk & benefit), need to get balance of pharmacological effects through e.g target concentration intervention
If NO, then it may be something to do with the particular structure of the drug, or its metabolite, may require tweaking of the molecules to retain pharmacophore and remove the toxicophore
Importance of metabolism in adverse drug reactions
Drug metabolism is important in drug clearance, generally terminates pharmacological activity, alterations in drug metabolism influence clearance and thus influence pharmacological effectiveness
Changes can be due to, dose, intrinsic patient factors, extrinsic factors such as other drugs or environment
Most drugs are designed to be chemically non-reactive , metabolism may lead to the formation of a chemically-reactive species that bind to, and inhibits the biological function of, a macromolecule.
Type 1 NSAIDS: Analgesic-Associated Nephropathy
Patients often present with hypertension, GI ulceration, urinary tract infection, headaches, depression & cardiovascular disease
Involves necrosis within loop of Henle and medullary capillaries spreading throughout papilla, may be secondary to acute interstitial nephritis. Requires continuous analgesic abuse over many years
Type 1 NSAIDS: Chronic Aspirin use
NSAID-induced gastro-duodenal ulceration and bleeding reported in ~15-30% of chronic users
Aspirin GI toxicity - long thought to be due to chronic COX inhibition (ie related to pharmacology of the drugs), needs to be oral
Rather aspirin may be induce lesions by interacting with phosphotidyl choline and reduce the ability of gastric mucosa to protect herself from e.g HCI
Inhibition of COX important because some prostaglandins (PGE2 & PGI2) are cytoprotective and so initial results in overt damage
Type 1 NSAIDS: Aspirin & Reye’s Syndrome
Reye’s syndrome is a very rare but serious condition that causes inflammation and swelling of the brain and fatty degeneration of the liver. It occurs almost exclusively in children, symptoms start with vomiting and varying degrees of neurologic impairment, including fluctuating personality changes and deterioration in consciousness
Generalized disturbance in mitochondrial metabolism, eventually resulting in metabolic failure in the liver and other tissues, death occurs in about 30-40% of cases from brainstem dysfunction
Type 1 NSAIDS: Acute Renal Toxicity general
Characterised by marked decrease in urine (<400 mL/day in adults), weight gain, increased BUN, increased serum creatine. Readily reversed when drugs withdrawn
Elderly more likely to take NSAIDS AND have renal impairment
Type 1 NSAIDS: Acute Renal Toxicity detailed
COX present throughout the vasculature;
PGI2 & PGE2 cause vasodilation of afferent renal arterole and increase GFR
PGE2 decreased reabsorption in Na
PGI2 renin release (RAAS) so increased aldosterone secretion, increased reabsorption of Na & K secretion
Risk factors for NSAID-induced acute kidney injury
Type 2: Penicillins and Allergy
- 3-10% of patients report allergic reactions to penicillin and its analogues
- Allergic (hypersensitivity) reactions include:
- Skin eruptions (ranging from maculopapular to exfoliative dermatitis)
- Urticaria (nettle rash/itchy skin)
- Reactions resembling serum sickness, including chills, fever, oedema and muscle pains
- Anaphylaxis which may be fatal
