SPR L12 ADRs and Drug Interactions Flashcards
Learning Outcomes
for general perusal
- Describe the different ways in which drugs can interact with each other
- List the factors that increase the risk of drug interactions
- Describe the common adverse drug effects and how to manage them
- Discuss how you would go about reporting a suspected adverse drug effect in the UK
Outline of the lecture
- Highlight common culprits
- Discuss Type A and Type B adverse drug reactions (ADRs) and how they differ
- Elements that can influence the probability of an ADR occurring
- How to manage an ADR
- Look at common drug interactions and how to minimise these
Adverse drug reactions: Epidemiology
- ADRs account for what percentage of hospital admissions and inpatients?
- Cause of death in what percentage of patients?
- What harm do they cause?
- Account for 5% of hospital admissions, occur in 10% of hospital inpatients
- 0.1% of medical and 0.01% of surgical patients
- Adversely affect quality of life, May mimic disease leading to unnecessary investigations or treatment, Cause patients to lose confidence
Intensive hospital monitoring of adverse reactions to drugs
Monitoring patients in the medical, surgical and dermatology wards of the Belfast City Hospital from admission to discharge.. A total of 506 patients were surveyed February to August 2001.
- What percentage of patients experienced ADRs in hospital?
- What were the commonest calsses of drugs causing ADRs?
- What were the drugs most commonly involved with severe ADRs?
- 16.6% of patients experienced ADRs in hospital (most were mild/moderate only).
- antibiotics, analgesics and anticoagulants.
- hypoglycaemic agents (insulin) and NSAIDS.
Nature of ADRs
Outline the nature of ADRS
- Nausea and vomiting
- Excessive sedation
- Rash
- Bleeding
- Renal failure / electrolyte abnormalities
- Abnormal liver enzymes
Drugs commonly causing ADRs
Give examples of the following drugs that especially cause ADRS
- Antibiotics
- Anticoagulants
- Analgesics
- Antihypertensives
nAntibiotics especially:
nFlucloxacillin / Co-amoxiclav
nClarithromycin
nCeftazidime
- Warfarin / LMWHeparin
- Morphine / Tramadol / Co-codamol 30/500, Ibuprofen other NSAIDs
- ACE inhibitors / ARBs, Diuretics Alpha blockers
Classificiation of ADRs
Type A (Augmented / accentuated)
Type B (bizarre)
Type C (Chronic)
Type D (Delayed)
Type E (End-of-Use)
Type F (Failure)
Classification of ADR
What do the following mean?
- Type A
- Type B
- Type C
- Type D
- Type E
- Type F
- Augmented / accentuated
- bizarre
- Chronic
- Delayed
- End-of-Use
- Failure
Type A - Augmented
Give the main characteristics of these reactions
- Dose-dependent
- Predictable from pharmacology of the drug
- Host independent
- Common
- Usually mild
- Low morbidity and mortality
- Reproducible in animal studies
- E.g. Bleeding/bruising on warfarin or aspirin
Reduce dose or withhold
Type A - Augmented
Mechanisms of Type A ADRs
- Outline the pharmacokinetic mechanism
- Outline the pharacodynamic mechanisms
- Pharamceutical mechanisms?
- renal excretion, hepatic metabolism, extremes of age, genetic variations
- genetic variations, extremes of age
- excipients (an inactive substance that serves as the vehicle or medium for a drug or other active substance), bioequivalence (is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.)
Cytochrome P450
Give the substrates (1) and inhibitors (2) for each of these enzymes
- CYP1A2
- CYP2D6
- CYP3A4
- CYP1A2
- Clozapine, R-warfarin, Ciprofloxacin, Theophylline
- Cimetidine, Erythromycin
- CYP2D6
- Amitriptyline Phenytoin S-warfarin
- Amiodarone Cimetidine Fluconazole
- CYP3A4
- Carbamazepine Cyclosporin Erythromycin
Lignocaine Terfenidine Verapamil
2. Cimetidine Clarithromycin Erythromycin Grapefruit juice Ketoconazole
Type A - Augmented
Outline this
- Poor metabolizers
- Extensive metabolisers
- CYP2D6
- CYP2C19
- acetylation “fast”/”slow”
- methylation
- non-hepatic metabolism (pseudocholinesterase)
Type B (Bizzarre)
- Give an examples
- Give an overview of the characterisitics of this type of ADR
- What can be done?
- E.g. Anaphylaxis to penicillin
2.
- Dose independent
- Unpredictable
- Host dependent
- Uncommon
- Can be severe
- High morbidity and mortality
- No animal models
- E.g. Anaphylaxis to penicillin
- withhold and avoid in future / put in notes
Allergic reactions
(Hypersensitivity reactions)
What are the following types of hypersensitivity reactions?
- Type I
- Type II
- Type III
- Type IV
- immediate: IgE => mast cell release => anaphylaxis
- antibody-mediated cytotoxic: drug induced haemolysis
- immune complex: fever, rash, arthropathy, glomerular damage
- delayed/cell mediated: drug acts as hapten, rash common
(Haptens are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. (In general, only large molecules, infectious agents, or insoluble foreign matter can elicit an immune response in the body.)
A typical drug induced rash
This rash is one of the most common drug-induced skin reactions seen in clinical practice. Patients may be asymptomatic or report itching, burning, or pain. The most common cutaneous manifestation is palpable purpura that are typically round and 1-3 mm. They may coalesce to form plaques (shown) or ulcerate and are most commonly found on the legs. The drugs most commonly responsible are antibiotics, particularly beta-lactams; NSAIDs; and diuretics. Leukocytoclastic vasculitis, also known as hypersensitivity vasculitis or hypersensitivity angiitis, is a small-vessel vasculitis that manifests in the skin, joints, gastrointestinal tract, or kidneys. Removal of the offending drug will typically cause lesions to disappear in up to 2 weeks. Elevation of dependent areas or the use of compressive stockings may be helpful.
Rare but Severe skin reaction:
Stevens-Johnson syndrome
What is this?
Drug reactions can mimic a wide range of dermatoses with morphologies that include morbilliform, urticarial, papulosquamous, pustular, and bullous lesions. The overall incidence of adverse cutaneous reactions to drugs is estimated to be 0.1%-2.2%. However, semisynthetic penicillins and trimethoprim/sulfamethoxazole may have an incidence as high as 3%-5%. Patients with HIV may also be at increased risk. For all patients with a suspected drug reaction, a detailed history of all medications, including over-the-counter and herbal remedies, taken over the last several months must be obtained. The diagnosis for cutaneous drug reactions is typically made based on a careful history and the appearance of the skin findings. The image shown is of an individual with Stevens-Johnson syndrome, a severe drug-induced bullous reaction that can lead to significant morbidity or mortality.
Photosensitivity reaction
What are the three mechanisms?
The pathogenesis underlying drug-related dyspigmentation can also be categorized into 3 mechanisms, which are
- drug or drug metabolite deposition in the dermis and epidermis
- enhanced melanin production with or without an increase in the number of active melanocytes
- drug-induced postinflammatory changes to skin.
Antimalarials, chemotherapeutic agents, heavy metals, miscellaneous medications (eg, amiodarone, zidovudine, minocycline, clofazimine, psoralens), and psychotropic drugs are among the most commonly implicated medications in acquired dyschromia.
Drug-induced photosensitivity
What are the most common causes?
- Antimalarials
- chemotherapeutic agents
- psychotropic drugs
- heavy metals
- miscellaneous medications (eg, amiodarone, zidovudine, minocycline, psoralens)
Identifying Adverse Drug Reactions
What can be used to identify ADRs?
- Timing of administration
- Previous evidence in literature
- Absence of alternative explanation
- Effects of re-challange
Reporting ADRs
- How can these be reported?
- What will this involve?
- What should be done with new drugs?
- Report to Committee on Safety of Medicines (MHRA) by Yellow Card scheme
- Established drugs report “all serious suspected reactions”, i.e., fatal, life-threatening, disabling, or which prolong hospital stay “even if the effect is well recognised.”
- report all suspected reactions, i.e., any adverse or unexpected event however minor which could conceivably be attributed to the drug.
Enzyme Inhibitors
What are the Substrates and Inhibitors (1) for each of the following CYP450 Isoenzymes?
- 1A2
- 2C9
- 2D6
- 3A4
- 3A4
- Theophylline
- Ciprofloxacin
- S - Warfarin
- Amiodarone
- Oxycodone
- Fluoxetine
- Verapamil
- -azoles
- Erythromycin
- Erythromycin
An enzyme inhibitor is a molecule that binds to an enzymeand decreases its activity. Since blocking an enzyme’s activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors.
Drug Interactions
mechanisms of drug interactions - Pharmacodynamic interactions
How can these bring about drug interactions?
-
Receptor interactions
- agonists, antagonists and partial agonists
-
Physiological interactions
- potentiation, summation, antagonism
Outline the potential for disaster in drug interactions
How are prescribing skills regulated?
National Prescribing Skills Assessment
