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Pharmacology CP > Adverse Drug Reactions > Flashcards

Adverse Drug Reactions Flashcards

1
Q

What is an adverse drug reaction?

A
  • Noxious or unintended reaction to a drug
  • Administered in standard dose and by proper route for a purpose of prophylaxis, diagnosis or treatment of a specific disease
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2
Q

What are drug-related cases underlying ADR and drug hypersensitivity?

A
  • Chemical structure

- Toxic metabolites

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3
Q

What are patient-related cases underlying ADR and drug hypersensitivity?

A
  • Polymorphisms in gene-coding enzymes
  • Metabolic deficiency
  • Predisposing HLA-allele- HLA-B*5701 and abacavir hypersensitivity
  • Aberrant immune activation
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4
Q

What is type A?

A
  • Augmented
  • Dose-related, predictable, known pharmacological actions of drug
  • Adjusted dose can reduce ADR
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5
Q

Give an example of type A ADR?

A
  • Warfarin blocks vitamin K metabolism
  • Blood thinning
  • Primary action of blood causes excessive bleeding
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6
Q

What are the mechanisms of type A reactions?

A
  • Exaggerated therapeutic response at target site (e.g. bleeding with warfarin)
  • Desired pharmacological effect at another site (e.g. headache with GTN)
  • Additional (secondary) pharmacological action (e.g. prolongation if QT interval- many drugs)
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7
Q

Describe how a desired pharmacological effect can occur at another site with GTN as an example (type A)

A
  • GTN- glyceryl trinitrate- treatment of angina, acute MI and severe HT
  • GTN-nitro-vasodilator-prodrug needs to be denitrated to produce NO
  • Immediate headaches connected to vasodilation
  • Migraines (calcinotic gene related peptide glutamate/ change in ion channel function)
  • Drug-drug interaction- GTN used with vasodilators in ED can cause severe hypotension, circulatory collapse and death
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8
Q

Describe how secondary pharmacological action can occur using prolonged QT interval as an example (type A)

A
  • Occurs at drug combination
  • Torsade de pointes
  • QT interval represents depolarisation and repolarisation of ventricles
  • Prolongation of QT increases person’s risk of developing abnormal heart rhythm- ventricular tachycardia- tornado de pointes
  • May lead to death
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9
Q

What is the QT interval?

A
  • Measure of time between start of the Q wave and end of T wave in heart’s electrical cycle
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10
Q

What factors predispose to type A pharmacological ADRs?

A
  • Dose
  • Pharmaceutical variation in drug formulation
  • PK and pharmacodynamic abnormalities
  • Drug-drug interactions
  • Likelihood of developing adverse interaction also increases with number of drugs prescribed
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11
Q

What is Type C?

A
  • Chemical
  • Could be inefficiency of enzymes or overdose
  • Sometimes- chemically reactive metabolites detoxified by cell defence mechanisms- imbalance between bioactivation/ bioinactivation may result after overdoses
  • Leads to formation of large amounts of chemically-reactive metabolites- overwhelm cellular detoxification capacity
  • Leads to cell damage
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12
Q

Give two examples of Type C ADR

A
  • Paracetamol –> hepatotoxic quinone imine

- Azathiprine–> myelotoxic 6-mercaptopurine

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13
Q

Describe phase 1 of drug metabolism

A
  • Native drug- CYP450–> reactive intermediate

- Reactive intermediate –> direct toxicity

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14
Q

Describe phase 2 of drug metabolism

A

Removal of detoxication between reactive intermediate and inner metabolite

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15
Q

What happens to paracetamol in overdose?

A
  • Saturation of phase 2 pathways results in a greater proportion of drug undergoing bioactivation
  • Leads to glutathione depletion- allows toxic metabolite to bind to proteins
  • Resulting in hepatocellular damage
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16
Q

How is paracetemol metabolised?

A
  • 10% phase 1: paracetamol–> CYP450 –> quinone-imine
  • In healthy person- 90% glutathione pathway
  • Removal of glutathione pathway
  • Quinone-imine–> hepatotoxicity
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17
Q

Describe the metabolism of Isoniazid

A
  • If N-acetyl trans
  • Isoniazid–> impaired acetylation –> neuropathy
  • Isoniazid induced peripheral neuropathy in people deficient in enzyme N-acetyl transferase
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18
Q

Describe the metabolism azathiprine

A
  • Chemotherapy drug- now rarely used in chemotherapy, but more for immunosuppression in organ transplantation and auto-immune disease
  • Active metabolite, 6-mercaptopurine, is myelotoxic and must be further detoxified by thiopurine methyl transferase
  • Azathioprine–> 6-mercaptopurine –> myelotoxicity
19
Q

What is type B?

A
  • (Bizarre) Not dose-related, unpredictable
  • Idiosyncratic
  • Immune-based drug hypersensitivity
20
Q

What is type D?

A
  • Delayed
  • E.g. carcinogenesis or teratogenesis (thalidomide)
    Rare
21
Q

What type E?

A
  • End of dose
  • Effects following cessation of drug, e.g. first after benzodiazepines
    Rare
22
Q

Describe ADR-Type B

A
  • Toxic epidermal necrolysis

- Can affect single and multiple organ systems, but skin is most commonly involved

23
Q

How can a drug activate the immune system?

A
  • Native drug binds protein and creates haptens

- Recognised by the immune system

24
Q

Describe drugs as an antigen

A
  • Interaction between MHC molecule with T-cell
  • Impossible for penicillin to be presented
  • β-lactams are haptens
  • Needs to form covalent complex with proteins- haptenize
25
Q

Describe the structure of β-lactams and give examples

A
  • Penicillins, cephalosporins, carbapenems, monobactams, β-lactamase inhibitors
  • Haptens- penicilloyl moiety spontaneously forms complexes with serum proteins
  • -Carbamazepine metabolite forms complexes with proteins
  • Sensitised-haptenated protein becomes an allergen
26
Q

Describe the types of hypersensitivty

A
  • Type 1- IgE dependent
  • Type 4- T-cell dependent
  • Haptenated protein recognised by IgE molecule
  • Penicillin- muscle relaxant
27
Q

What happens in the early phase of hypersensitivity?

A
  • Histamine, prostaglandins
  • Itching and swelling
  • Haptenated protein can cross-link FCER on Mast cell
28
Q

Describe early phase hypersensitive reaction

A
  • Seconds-min after haptenated protein exposed
  • Mediated by histamine
  • Histamine- vasodilation- redness
  • Skin lesion- wheal-and-flare
  • Persistent reaction- oedema and urticaria
  • Certain mast cell products can influence structural cell biology
29
Q

What cells might make cell derived products influence?

A
  • Vascular endothelial cells
  • Epithelial cells
  • Fibroblasts
  • Smooth muscle cells
  • Nerve cells- itching
30
Q

Describe the late phase of hypersensitivity reaction

A
  • Mast cells with FCER cross-linked by an allergen recruit neutrophils, eosinophils and Th2 T cells
31
Q

Describe type 1 hypersensitive reactions

A
  • Urticaria (angioedema), asthma, anaphylaxis
  • β-lactams- penicillins and cephalosporins
  • Drugs in anaesthetics
    • Muscle relaxants (70% of peri-operative anaphylaxis)
    • Suxamethonium, vecuronium
32
Q

Describe type 4 hypersensitivity reactions

A
  • 1-3 day delay in sensitised or 7-14 days after continuous exposure
  • Skin-main
  • 2-3% on in patients
  • Mediated by T-lymphocytes
  • Multiple symptoms, rare for each single drug
  • DTH reactions in skin observed after systemic administration- 7-10 days after initial- associated with fever
33
Q

How are CD4 T helper cells and CD8 cytotoxic T cells primed?

A
  • Depends on innate immune system activating capacity of substances co-exposed with antigen
  • Co-signals for cell differentiation and status of cells/cytokines in microenvironment CD4 naive T cell- differentiates to
  • Th1, 2, 9, 17 or 22 type memory and effector cells
34
Q

What is the ability of T cell subsets to promote inflam responses based on?

A
  • Based on respective cytokine profiles,
  • response to chemokine
  • interaction with other cells, subsets can promote different types of inflammatory responses
35
Q

How can a drug be presented to a T cell?

A
  • Happen-Like drugs (penicillins) can covalently bind to soluble/ cell-attached proteins
  • Pro-haptens (sulphometoxazole) require metabolism to become haptens
  • Haptens can bind to MHC complex and change repertoire of peptides presented by MHC
36
Q

What is the pharmacological interaction concept?

A
  • Drug can bind directly to T cell receptor
37
Q

How do CD4 T cell and CD8 T cells present differently in delayed type hypersensitivity?

A
  • CD4- Maculopapular or eczematous drug eruptions- MHC-1 restricted drug presentation
  • CD8- more severe skin symptoms (e.g. bullous skin disease)
38
Q

What are eczematous delayed hypersensitivity reactions caused by?

A
  • Th1
  • Tc1
    (contact allergic DHR)
39
Q

What are drug induced exanthems delayed hypersensitive reactions caused by?

A
  • Th2

- Tc2

40
Q

What are drug reactions with eosinophilia and systemic systems (DRESS) caused by?

A
  • Th2

- Tc2

41
Q

What delayed hypersensitive reactions does CD8+ T cell cause?

A
  • Eythema multiforme
  • Stevens-Jonson syndroms (SJS)
  • Toxic epidermal Necrolysis (TEN)
42
Q

What causes Acute generalised exanthematous pustulosis (AGEP)?

A
  • IL8-T cells

- Neutrophils

43
Q

What do Type 4a correspond to and involve?

A
  • Corresponds to Th1 reactions with high IFN/TNF secretion

- Involves monocyte/ macrophage activation

Pharmacology CP (11 decks)

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