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Year 2 - LCRS - Pharmacology > Adverse Drug Reactions (20.02.2020) > Flashcards

Adverse Drug Reactions (20.02.2020) Flashcards

1
Q

Epidemiology of adverse drug reaction

A
  • substantial morbidity and mortality
  • estimates of incidence vary with study methods, population, and ADR definition
  • 4th to 6th leading cause of death among hospitalized patients*
  • 6.7% incidence of serious ADRs*
  • 0.3% to 7% of all hospital admissions
  • annual costs in the billions (?$120 billion in US)
  • 30% to 60% are preventable

UK prevelaance 6.5%

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2
Q

What criteria can you use to classify ADRs?

A

Onset
Severity
Type

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3
Q

Onset of event - classification of ADRs

A

Acute
- Within 1 hour

Sub-acute
- 1 to 24 hours

Latent
- > 2 days

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4
Q

SEVERITY - classification of ADRs

A

Mild
- requires no change in therapy

Moderate
- requires change in therapy, additional treatment, hospitalisation

Severe
- disabling or life-threatening

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5
Q

Severe ADRs

A
  • Results in death
  • Life-threatening
  • Requires or prolongs hospitalisation
  • Causes disability
  • Causes congenital anomalies
  • Requires intervention to prevent permanent injury
    • > you might have to stop the drug, give an antidote..
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6
Q

Type A ADR

A
  • extension of pharmacologic effect
  • usually predictable and dose dependent
  • responsible for at least two-thirds of ADRs
  • > 66% of ADRs
  • e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer
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7
Q

Different type A ADRs (examples)

A
  • digoxin: very linear dose dependance
  • paracetamol: not a problem at a lower dose when you get above a certain dose you get a sharp increase of toxicity and you may get liver damage.
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8
Q

Type B ADRs

A
  • idiosyncratic (you don’t really know why) or immunologic reactions
  • includes allergy and “pseudoallergy”
  • rare (even very rare) and unpredictable
  • e.g., chloramphenicol and aplastic anemia (=total BM failure, people tend not to survive it; other ABs available so people don’t use it), ACE inhibitors and angioedema (swelling of lips, tongue, breathlessness, rarely HF)

=> Many serious ADRs are totally unexpected eg Herceptin
and cardiac toxicity

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9
Q

Type C ADRs

A
  • associated with long-term use
  • involves dose accumulation (how much of the drug has accumulated over time?)
  • e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
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10
Q

Type D reactions

A
  • delayed effects (sometimes dose independent)
  • carcinogenicity (e.g. immunosuppressants)
  • teratogenicity (e.g. thalidomide)
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11
Q

Type E reactions

A

Withdrawal reactions
-> Opiates, benzodiazepines (fitting), corticosteroids (patients collapse if you stop suddenly)

Rebound reactions
-> Clonidine, beta-blockers, corticosteroids (when you stop the drug and then the situation is worse than when you started)

“Adaptive” reactions
-> Neuroleptics (major tranquillisers) ????

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12
Q

Clonidine withdrawl

A
  • after treatment the BP goes up again, higher than it was before treatment
  • can cause stroke, death..
  • pharmacological explanation of why it happens
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13
Q

ABCDE classification of ADRs

A 
A     Augmented pharmacological effect
B	Bizarre
C	Chronic
D	Delayed
E	End-of-treatment
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14
Q

Types of allergic reactions

A

Type I - immediate, anaphylactic (IgE)
e.g., anaphylaxis with penicillins
=> this is the most important one in this context because you have to be able to recognise it and treat it right away

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

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

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

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15
Q

Examples of peudoallergies

A

Aspirin/NSAIDs – bronchospasm

ACE inhibitors – cough in a large number of patients/angioedema

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16
Q

What are pseudoallergies?

A
  • similar presentation to a true allergy, though due to different causes.
  • Aspirin/NSAIDs – bronchospasm
  • ACE inhibitors – cough in a large number of patients/ angioedema (milde, non-immunological version of anaphylaxis, tongue and mouth swelling etc.)
17
Q

List some common drugs that cause ADRs

A 
Antibiotics
Antineoplastics*
Anticoagulants
Cardiovascular drugs*
Hypoglycemics
Antihypertensives
NSAID/Analgesics*
CNS drugs*

*account for two-thirds of fatal ADRs
=> many people take these drugs, the total numbers are very large even thought the incidence is not very large.

18
Q

Frequency of drug reactions in multipharmacy

A

the more medications, the more adverse reactions

19
Q

How are ADRs detected?

A

Subjective report
- patient complaint

Objective report:

  • direct observation of event
  • abnormal findings
    - physical examination
    - laboratory test
    - diagnostic procedure

There is a statistical problem: rare events will probably not be detected before the drug is marketed because you need a large number of participants for this.

20
Q

The yellow card scheme

A
  • introduced in 1964 after thalidomide
  • run by the Medicines and Healthcare Products Regulatory Agency (MHRA)
  • entirely voluntary
  • can be used by doctors, dentists, nurses, coroners and
    pharmacists, and members of the public
  • includes blood products, vaccines, contrast media
  • for established drugs only report SERIOUS adverse reactions(fatal, life-threatening, needing hospital admission, disabling)
  • for “black triangle “ drugs (newly licensed, usually <2 years) - there might not be a full picture for the adverse reactions of the drug.
  • > report any suspected adverse reaction
21
Q

What happens when an ADR is suspected?

A 
ADR SUSPECTED
->
ADR CONFIRMED (HIGH PROBABILITY)
->
FREQUENCY ESTIMATED
->
PRESCRIBERS INFORMED (by MHRA) - if it is dangerous and life threatening it might be withdrawn
22
Q

Incidence of drug-drug interactions

A
  • True incidence difficult to determine (because there are so many possible interactions and so many people)
  • Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs
  • Lack of availability of comprehensive databases
  • Difficulty in assessing OTC and herbal drug therapy use
  • Difficulty in determining contribution of drug interaction in complicated patients
  • Sometimes principal cause of ADRs with specific drugs eg statins
23
Q

What are the types of drug interactions?

A

Pharmacodynamic
Pharmacokinetic
Pharmaceutical

24
Q

Pharmacodynamic drug interactions

A
  • Related to the drug’s effects in the body
  • Receptor site occupancy

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

  • Synergistic actions of antibiotics
  • Overlapping toxicities - ethanol & benzodiazepines
  • Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
25
Q

Pharmacokinetic drug interactions

A

Related to the body’s effects on the drug
Absorption, distribution, metabolism, elimination

  • Alteration in absorption
  • Protein binding effects (e.g. albumin)
  • Changes in drug metabolism
  • Alteration in elimination
26
Q

Pharmaceutical drug interactions

A

drugs interacting outside the body (mostly IV infusions)

27
Q

Alterations in absorption (example)

A

Chelation

  • Irreversible binding of drugs in the GI tract
  • Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
28
Q

Protein Binding interactions

A
  • Competition between drugs for protein or tissue binding sites (binding to albumin)
  • Increase in free (unbound) concentration may lead to enhanced pharmacological effect
  • Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions
  • PB interactions are not usually clinically significant but a few are (mostly with warfarin)
29
Q

Drug Metabolism and Elimination

A

a) Excretedunchangedby kidney
b) Ph1 metabolism in liver or kidney (mainly oxidation)
c) Ph2 metabolism -> kidney (usually made. water soluble)

30
Q

Ph1 metabolism reactions

A

Mainly: oxidation

less frequent: reduction and hydrolysis

31
Q

Ph2 metabolism reactions

A

Mainly conjugation

also:
Glucuronidation
Sulphation
Acetylation

ionised compound added that is easily excreted

32
Q

???????

A

Drug metabolism inhibited or enhanced by coadministration of other drugs
CYP 450 system has been the most extensively studied
CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others
Phase 2 metabolic interactions (glucuronidation, etc.) occur, research in this area is increasing

33
Q

CYP 450 Substrates and drug interactions

A

Metabolism by a single isozyme (predominantly)

  • Few examples of clinically used drugs
  • Examples of drugs used primarily in research on drug interactions

Metabolism by multiple isozymes
- Most drugs metabolized by more than one isozyme
Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
- If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme

34
Q

Name some CYP inhibitors

A

The “usual suspects”

  • Cimetidine
  • Erythromycin and related antibiotics
  • Ketoconazole etc
  • Ciprofloxacin and related antibiotics
  • Ritonavir and other HIV drugs (often involved in drug interactions)
  • Fluoxetine and other SSRIs
  • Grapefruit juice (there is a natural compound in grapefruit that is a CYP450 inhibitor)
35
Q

Name some CYP inducers

A

The “usual suspects”

  • Rifampicin
  • Carbamazepine
  • (Phenobarbitone)
  • (Phenytoin)
  • St John’s wort (hypericin) -> antidepressant, similar to SSRIs

There might be some more in plants

36
Q

What is the difference in how fast the action is in (CYP) inhibitors and inducers?

A

Inhibition is very rapid

Induction takes hours/days

37
Q

Drug elimination interactions

A

Almost always in renal tubule

- probenecid and penicillin (good)
- lithium and thiazides (bad) -> given together you have increased excretion of sodium at the expense of lithium so you have high levels of lithium
38
Q

Deliberaate drug interactions

A
  • levodopa + carbidopa (BBB)
  • ACE inhibitors + thiazides (stronger BP reducing effect together, the ACE will stop the natural renin increase from thiazides)
  • penicillins + gentamicin
  • salbutamol + ipratropium
39
Q

Summary

A
  • much of therapeutics is about avoiding or detecting ADRs
  • most are avoidable
  • drug interactions are an important added
    risk for ADRs
  • more drugs = more trouble

Year 2 - LCRS - Pharmacology (34 decks)

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