Lecture 8: Adverse effects Flashcards
1
Q
Adverse drug reaction (ADR) classifications
A
- Type A (explainable)
- Type B (unexplainable)
- Type C (chronic effects)
- Type D (delayed effects)
2
Q
Type A ADR
A
- ~ 80 % ADR’s
- An exaggerated, but otherwise expected pharmacological effect of a drug
- Predictable and dose dependent
Examples:
- Toxicity of overdose (eg, hepatic failure with high dose acetaminophen)
- Side effects (eg, sedation with antihistamines)
- Secondary effects (eg, development of diarrhea with antibiotic therapy)
- Drug interactions (eg, theophylline toxicity in the presence of erythromycin therapy)
3
Q
Type B ADR
A
- Idiosyncratic effects (ie. not expected from the known pharmacological action of a drug)
- Dose independent and unpredictable
Examples:
- Intolerance (eg, tinnitus with use of aspirin)
- Hypersensitivity (eg, anaphylaxis with penicillin admin.)
- Pseudoallergic (eg, radio contrast dye reaction)
- Idiosyncratic (eg, development of anemia with use
of oxidant drugs in presence of G6PD deficiency)
4
Q
Type C ADR
A
- Associated with long-term therapy
- Well known and can be anticipated
Examples:
- Benzodiazepine dependence
- Analgesic nephropathy
5
Q
Type D ADR
A
- Carcinogenic and teratogenic effects
- Delayed in onset and very rare
6
Q
Mechanisms of drug toxicity
A
- ‘On-target’ adverse effects
- ‘Off-target’ adverse effects
- Production of toxic metabolites
- Production of harmful immune responses
- Idiosyncratic responses
7
Q
On Target Effect: A
A
- Increase in effective drug concentration at receptor increased biological response
- Deliberate or accidental dosing error
- Alterations in the PK of the drug (eg, liver / kidney disease)
- Alterations in the PD of the drug-receptor interaction (eg, increase in receptor number)
Examples:
- Insulin -> hypoglycemic coma
- Anticoagulants (eg, heparin) -> intracerebralbleeding
- Anxiolytics (eg, diazepam) -> sedation
8
Q
On Target Effects: B
A
- Activation of the intended receptor but in a non-target tissue
- Drug or metabolite can interact with correct receptor but in ‘wrong’ tissue
- Many receptors are expressed in multiple cell types / tissues, Ex. diphenhydramine
9
Q
Off Target Effects
A
Drug interacts with unintended targets
- Examples:
- Terfenadine (an antihistamine), also inhibits a cardiac potassium channel (hERG).
- Unintended inhibition of hERG led to fatal cardiac arrhythmias in some patients.
- Thalidomide
Unintended activation of different receptor subtypes • Many receptors have many different subtypes (eg, P2Y receptors > 8 known)
- Example:
- Beta1-adrenergic receptors are expressed in heart (increase HR & myocardial contractility)
- Beta2-adrenergic receptors are expressed primarily in airway / vasculature smooth muscle cells (causing relaxation & dilation)
- Beta-receptor antagonists (-blockers) are often targeted to the 1-receptor to treat angina or HF
- However, some Beta-blockers are not entirely selective for 1-R and thus contraindicated in asthmatics
10
Q
Harmful immune responses
A
Drugs are xenobiotics that can be recognized by the immune system as foreign substances
- Two principal immune mechanisms:
- Hypersensitivity (allergic) responses
- eg, penicillin allergy (wheal and flare), latex, poison ivy allergies (contact dermatitis)
- Autoimmune reactions
- eg, methyldopa (alpha2-agonist) can cause hemolytic anemia byeliciting autoimmune reaction against Rh antigens
11
Q
PK Interactions
A
- Competitive or irreversible inhibition of a specific enzyme can lead to an increase in drug concentration due to decreased metabolism
- Examples of inhibitors: cimetidine, ciprofloxacin, ketoconazole, clarithromycin, quinidine and grapefruit juice
- Induction of a specific enzyme can cause a decrease in drug concentration due to increased metabolism
- Examples of inducers: rifampin, phenobarbital, dexamethasone, carbamazepine and tobacco
12
Q
PD Interactions
A
- Sildenafil (erectile dysfunction) + nitroglycerin (angina):
- Sildenafil inhibits PDE5 -> prolongs action of cGMP
- Nitroglycerin stimulates GC -> increase cGMP.
- Coadmin = large increase in cGMP (can cause severe hypotension).
- Warfarin (antithrombotic) + heparin (antithrombotic):
- Coadministration of warfarin & heparin can result in supratherapeutic levels of anticoagulation
- Resulting in bleeding
13
Q
Drug-Herb interactions
A
- Ginkgo biloba: Inhibits platelet aggregation. Used simultaneously with NSAIDs (which also inhibit platelet aggregation) may increase risk of bleeding
- St John’s wort
- In combination with selective serotonin reuptake inhibitors, St John’s wort may cause a mild serotonergic syndrome
- consequence of excess serotonin on the CNS and/or peripheral nervous system.
- incr HR, shivering, sweating, dilated pupils, myoclonus (intermittent tremor or twitching), as well as overresponsive reflexes. However, many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin
14
Q
FDA Teratogens: Category A
A
Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities
15
Q
FDA teratogens: Category B
A
Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women.
OR
Animal studies have shown an adverse effect, but adequate and well- controlled studies in pregnant women have failed to demonstrate a risk to the fetus
