Adverse drug reactions Flashcards

1
Q

Incidence of ADRs and burden of cost

A
  • ARDs cause substantial morbidity and mortality
  • Estimates of incidence vary with study methods, populations and ADR definitions
  • ARDs are the 4th to 6th leading cause of death amongst hospitalised patients
  • There is a very high percentage of serious, adverse drug reactions (6.7% are serious
  • ADRs are responsible for many hospital admissions (0.3% to 7%), and therefore cost a lot of money
  • 30-60% of these events are preventable
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2
Q

How are ADRs classified?

A

Onset, severity and type

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3
Q

What are the categories of onset of ADRs?

A

Acute: Within 1 hour

Sub-acute: 1 to 24 hours

Latent: more than 2 days

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4
Q

What are the categories of severity of ARDs?

A

Mild: requires no change in therapy

Moderate: requires a change in therapy, may require additional treatment, and possibly hospitalisation

Severe: disabling, life-threatening, or ones that cause damage to the foetus

  • Results in death/ may be life-threatening
  • Requires or prolongs hospitalisation
  • May cause disability and congenital anomalies
  • Requires intervention to prevent permanent injury to the person
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5
Q

What are the different types of ADR reactions?

A

Type A: Augmented pharmacological effect

Type B: Bizarre

Type C: Chronic

Type D: Delayed

Type E: End-of-treatment

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6
Q

What is a type A reaction?

Examples?

A
  • Most ADRs are type A effects
  • This reaction is often an extension of the pharmacologic effect of the drug that we already know about
  • It is therefore usually predictable and often dose dependent
  • E.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
  • These ADRs are understandable because we know that they are related to the pharmacology of the drug
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7
Q

………….

A

The green rectangle represents the area where we achieve therapeutic effects. Paracetamol can be given up to a certain dose with very few side effects. Once we go above this, toxicity increases to lethal levels. Digoxin toxicity gradually increases at any dose. There is no dose that you can give without causing some degree of toxicity.

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8
Q

What are type B reactions?

Examples?

A
  • Type B reactions tend to be more dramatic
  • They are idiosyncratic (particular to given individuals) or immunologic reactions
  • These reactions include allergy and “pseudo-allergy”
  • They are rare and unpredictable
  • E.g. chloramphenicol and aplastic anemia, ACE inhibitors and angioedema (pseudo-allergy)
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9
Q

What are type C reactions?

Examples?

A
  • Type C reactions are associated with long-term use of drugs
  • These reactions involve dose accumulation (total dose someone’s exposed to over a period of time)
  • There is a cumulative dose of these drugs
  • E.g. methotrexate (used in chemotherapy and as an immunosuppressant) and liver fibrosis
    Anti-malarial drugs and ocular toxicity (damage to the retina)
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10
Q

What are type D reactions?

Examples?

A
  • Type D reactions often have delayed effects (sometimes dose independent)
  • This is not strongly linked to dose, it may happen at very low doses
  • Carcinogenicity (e.g. immunosuppressants)
  • Teratogenicity (affects fetus/embryo e.g. thalidomide)
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11
Q

What are type E reactions?

Examples?

A

Withdrawal reactions: Opiates, benzodiazepines, corticosteroids

Rebound reactions: Clonidine, beta-blockers, corticosteroids

Adaptive reactions: Neuroleptics (major tranquillisers)

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12
Q

Example of a rebound reaction - clonidine withdrawal

A
  • Clonidine used to be used as an anti-hypertensive
  • It is an alpha 2 agonist, so it reduces the release of noradrenaline from sympathetic neurones
  • This reduction in sympathetic outflow leads to a drop in blood pressure
  • If you miss one or two doses of clonidine, it could lead to a substantial rise in blood pressure
  • This is because long-term use of clonidine causes long-term suppression of peripheral noradrenaline production, which, in turn, leads to a compensatory upregulation in adrenergic receptors on the post-synaptic neurone
  • This upregulation in receptors means that when the inhibition of NA release by clonidine is removed, NA starts being produced again and has more receptors to act on and can cause a much great effect
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13
Q

How are allergies classified?

A

Type I – immediate, anaphylactic (IgE): e.g. anaphylaxis with penicillin

Type II – cytotoxic antibody (IgG, IgM) e.g. methyldopa and hemolytic anemia

Type III – serum sickness (IgG, IgM) – antigen-antibody complex e.g. procainamide-induced lupus

Type IV – delayed hypersensitivity (T cell) e.g. contact dermatitis

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14
Q

What are pseudoallergies?

A

Pseudoallergies have nothing to do with the immune system, they are mediated pharmacologically

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15
Q

Pseudoallergy - example of aspirin/NSAIDs and bronchospasm

A
  • 5% of people who take these drugs get bronchospasm
  • The reason for this is because these drugs inhibit COX enzymes
  • Blocking COX results in a reduction in prostanoid/prostaglandin synthesis (bronchodilators)
  • Instead, the body makes more leukotrienes (pro-inflammatory, and bronchoconstrictors)
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16
Q

Pseudoallergy - example of ACE inhibitors and cough/angioedema

A
  • 10-20% of people taking ACE inhibitors suffer from a chronic, dry cough
  • This is to do with accumulation of inflammatory peptides (e.g. bradykinin) in the lung
  • Bradykinin triggers cough through sensory receptors in the lung
  • In less than 1% of people taking the drug, people may suffer from angioedema
  • Angioedema: has many of the same signs and symptoms of anaphylaxis, but much less severe
17
Q

What are common agents causing ADRs?

A
  • Antibiotics
  • Antineoplastic drugs
  • Anticoagulants
  • Cardiovascular drugs
  • Hypoglycemic drugs
  • Antihypertensive drugs
  • NSAID/Analgesics
  • CNS drugs

A lot of ADRs are probably a result of interactions of multiple drugs, and not necessarily the drugs themselves.

18
Q

How do we detect ADRs?

A

We have to investigate into whether what patient’s are complaining about are to do with the drugs, or to do with the actual disease for which they are being treated. This is quite difficult.

  • Subjective report e.g. patient complaint
  • Objective report: direct observation of events and abnormal findings
  • Physical examination
  • Laboratory test (e.g. LFTs and methotrexate)
  • Diagnostic procedure
19
Q

What is the yellow card scheme?

A
  • This is a public way of detecting adverse reactions, which was introduced in 1964 after thalidomide
  • Before 1964, there was no system of checking whether drugs that were marketed were effective or safe
  • This scheme is run by the Medicines and Healthcare Products Regulatory Agency and is voluntary
  • It can be used by doctors, dentists, nurses, coroners and pharmacists, and members of the public
  • It includes blood products, vaccines, contrast media
  • For established drugs, only report serious ADRs (fatal, life-threatening, hospital admission, disabling etc.)
  • For “black triangle” drugs (newly licensed, usually <2 years), report any suspected adverse reaction
20
Q

Why is determining the incidence of drug-drug interactions difficult?

A
  • The true incidence of this occurring is difficult to determine
  • There are no proper databases for finding this out, and many people take over-the-counter medicines
  • Data for drug-related hospital admissions do not separate out drug interactions, and focus on ADRs
  • The is lack of availability of comprehensive databases
  • There is difficulty in assessing OTC and herbal drug therapy use
  • There is difficulty in determining contribution of drug interaction in complicated patients
21
Q

What are the 3 types of drug interactions?

A

Pharmacodynamic interactions: related to the drug’s effects in the body.

Pharmacokinetic interactions: Related to the body’s effects on the drug

Pharmaceutical interactions: drugs interacting outside the body (mostly IV infusions)

22
Q

Pharmacodynamic drug interactions - the types and examples

A

Additive, synergistic, or antagonistic effects from co-administration of two or more drugs

Additive: if you put two drugs together, they produce an effect that is the sum of the drugs.
Overlapping toxicities - ethanol & benzodiazepines

Synergistic actions of antibiotics. Two drugs potentiate each others’ actions to get a greater effect than expected

Antagonistic effects: drugs that antagonise each others’ actions. Anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)

23
Q

Pharmacokinetic drug interaction types

A

Alteration in absorption

Protein binding effects

Changes in drug metabolism

Alteration in elimination

24
Q

Altered absorption of drugs caused by chelation - what is it and give an example

A
  • Irreversible binding of drugs in the GI tract
  • Tetracyclines and quinolone antibiotics can be involved in chelation
  • They may be given together with ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
  • They form a stable chelate – so you don’t absorb the mineral ion, but you also don’t absorb the drugs
25
Q

Protein Binding Interactions (PBIs) - what is it and example

A
  • Competition between drugs for protein or tissue binding sites
  • Increase in free (unbound) concentration due to displacement may -> enhanced pharmacological effect
  • Many interactions previously thought to be PBIs were found to be primarily metabolism interactions
  • PB interactions are not usually clinically significant, but a few are (mostly with warfarin)
  • Warfarin is very tightly bound to proteins, so even displacing a small amount can have drastic effects
26
Q

How are drugs excreted?

A
  • A drug may be excreted completely unchanged by the kidney
  • You may get a phase I reaction, after which the drug can be excreted in its changed form by the liver or the kidney
  • Or you can get a phase II reaction, meaning that the kidney will clear the drug after being changed
27
Q

What types of reactions occur in phase 1 and 2 metabolism?

A

Phase I Metabolism: Oxidation, Reduction, Hydrolysis.

Phase II Metabolism:: Conjugation, Glucuronidation, Sulphation, Acetylation.

28
Q

What is the purpose of phase 1 and 2 reactions?

A
  • Phase I and II reactions have the purpose to make the drug more polar – easier to excrete by kidneys
  • Drug metabolism interactions may be inhibited or enhanced by co-administration of other drugs
29
Q

CYP 450 system

A
  • The CYP 450 system has been the most extensively studied

- CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others

30
Q

Isozymes

A
  • Some drugs undergo metabolism by a single isozyme
  • Most drugs undergo metabolism by multiple isozymes
  • E.g. Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
  • If we inhibit metabolism via one pathway, we get metabolism redundancy
  • If co-administered with a CYP450 inhibitor, some isozymes “pick up slack” for inhibited isozyme
  • Being metabolised by more than one enzyme is useful because if one of the isozymes is inhibited, the other isozymes could increase their activity to compensate for the inhibited isozymes
31
Q

Proportion of Drugs Metabolised by CYP450 Isozymes

A
  • Over half of drug metabolism is done by 2D6 and 3A4
  • They are therefore the most important cytochrome enzymes
  • 2D6 shows a great degree of variability
32
Q

Give examples of CYP 450 inhibitors

A
  • Cimetidine
  • Erythromycin and related antibiotics
  • Ketoconazole etc.
  • Ciprofloxacin and related antibiotics
  • Ritonavir and other HIV drugs
  • Fluoxetine and other SSRIs
  • Grapefruit juice – inhibits cytochrome P450
33
Q

Give examples of CYP 450 inducers

A
  • Rifampicin (antibiotic)
  • Carbamazepine
  • Phenobarbitone
  • Phenytoin
  • St John’s Wort (hypericin is the compound that induces CYP450)
34
Q

Speed of inhibition vs induction and why

A

Inhibition is very rapid (can take minutes)

Induction takes hours/days (because we are waiting for new CYP450 to be synthesised)

35
Q

Where do drug elimination reactions normally occur?

Give examples of drug elimination interactions

A
  • Drug elimination interactions almost always take place in the renal tubule
  • E.g. probenecid and penicillin (good) – reduces elimination of penicillin – it makes it last longer
  • E.g. lithium and thiazides (bad) – thiazides reduce clearance of lithium, which can lead to toxicity
36
Q

Give examples of deliberate interactions that are prescribed

A

Levodopa and carbidopa (inhibitor of decarboxylase in peripheral tissues)

ACE inhibitors and thiazides (reduce BP by different mechanisms)

Penicillins and gentamicin (antibiotics)

Salbutamol and ipratropium (beta-2 antagonist and anti-cholinergic – used in asthma to bronchodilate