Hypersensitivity Flashcards
Which drugs are commonest causes of hypersensitivity reactions
Antibiotics
Antiepileptic
Factors that influence hypersensitivity
State of immune activation of the subject
Dose
Frequency
Route of exposure (epicutaneous more sensitised than oral)
Duration of exposure
Sex (frequent reactions in females)
Immunogenicity predisposition
Causes of type 2 hypersensitivity reaction
Beta lactams
Rifampicin
Sulfa antibiotics
Causes of type 2 hypersensitivity reaction
Beta lactams
Rifampicin
Sulfa antibiotics
Causes of type 3 hypersensitivity reaction
Beta lactams
Sulfa antibiotics
Minocycline
Pathogenesis of drug induced hypersensitivity
Drugs (or chemicals) are too small (<1000D) to induce an immune response on their own
Immunogenic only after coupling with a carrier protein to form a hapten-protein complex
Hapten (drug) must bind irreversibly to proteins
Hapten-protein complex processed by APCs
Needs prior exposure
Nevertheless, small compounds such as drugs or metal ions were found to be able to trigger an immune response.
They may stimulate the innate immune system by covalently binding to cellular proteins and thereby transmit a danger signal, which results in stimulation of cells of the innate immune system, such as upregulation of CD40. Exceptionally, they may happen to bind to TLR7 and TLR8 directly and thus stimulate dendritic cells. This was shown for imiquimod.
b) They may stimulate the specific immune system. By forming hapten-carrier complexes, they form neoantigenic structures. This hapten-protein complex is processed and presented as hapten-modified peptide to T cells, which can react with it.1Y4,11 Modified proteins can also be immunogenic for B cells and thus elicit a humoral immune response. This hapten modification can occur with soluble proteins, cell-bound proteins, or with the major histocompatibility complex (MHC) peptide complexes themselves, leading to distinct immune responses (Fig. 1)
Drugs (or chemicals) interact directly (noncovalently) with immune receptors
Most cases this is the HLA molecule or also T cell receptor
Direct activation of T-cells without the presence of a peptide
Most data from TCR transfectants demonstrate the critical necessity of the TCR more than the HLA molecule for activation.
Also extensive data from T-cell clonotypes.
Cross-reactivity amongst memory T-cells explanation for timing of skin reactions in certain drugs. Also increased incidence in infections/auto-immune environment
Polyclonal CD8 T-cell expansion may increase the numbers of small populations of drug specific TCRs (almost all ab).
e.g. EBV and ampicillin reactivity vice versa with DRESS and latter symptoms through reactivated HHV.
Drugs nonconvalently occupy sites within the peptide-binding groove of MHC proteins
Occupation leads to alteration of the specificities of MHC-peptide binding
Self-peptides then activate T-cells inappropriately
Clinical manifestations of Drug induced ANI
Rash
Joint pain
Eosinophilia
Eosinophiliuria
Treatment of drug related ANI
Cessation of drug
If no improvement:
Renal biopsy
High dose prednisone eg 500mg methyl prednisone then 1mg/kg of prednisone and taper over 1month
Managemt if tremor
Propanolon
Primidone
Gabapentin
Topiramate
Alprazolam
Nimodipine, clonazepam, mirtazapine, levetiracetam, zonisamide
Adverse effects of drugs used to treat tremors
Propanolon: Hypotension, Brady and fatigue
Contraindicated in asthma.
Primidone: Sleepiness, tiredness
Gabapentin: drowsiness, fatigue and unsteadiness
Topiramate: drowsiness, LOW, tingling
Alprazolam: drowsiness, fatigue
Drugs that can cause a tremor
▶ Alcohol**
▶ Neuroleptics*
▶ β–Agonists and sympathomimetics
▶ Lithium
▶ Valproate*
▶ Tamoxifen
▶ Ciclosporin
▶ Amiodarone
▶ Mexilitine
▶ Vincristine
▶ Adriablastine
Most of these drugs cause postural tremor. These also cause *rest tremor and **intention tremor.
Treatment of dystonic tremors
Anticholinergics
Botulinum toxin injection
Investigations for patients with dystonia
FBC and film for acanthocytes
Plasma caeruloplasmin (if low, Wilson’s-copper deficiency)
24 hour urine copper
Genetic testing DYT1 (young onset)
MR Brain scan
Slit lamp exam for Kayser Fleisher rings
Therapeutic trial of levodopa
Which movement disorder improved dramatically with alcohol
Myoclonus dystonia
Types of dystonia
Primary:
Dopa responsive dystonia
Myoclonus dystonia
DYT1 associated dystonia
Secondary:
Parkinsonism
Perinatal injury
Wilson disease
Pantothenate kinase ass/ neurodegeneration
Neuroferritinopathy
Structural pathologies
Diagnosis for Wilson’s
Diagnosis depends on demonstrating a low plasma caeruloplasmin (10–20% will be nor- mal), an increased 24 h urinary copper or Keyser– Fleisher rings. If the diagnosis remains uncertain, copper level in liver biopsy can be measured.
Treatment for Wilson’s
Diagnosis depends on demonstrating a low plasma caeruloplasmin (10–20% will be nor- mal), an increased 24 h urinary copper or Keyser– Fleisher rings. If the diagnosis remains uncertain, copper level in liver biopsy can be measured.
Causes of chorea
- Drug induced: levodopa and dopamine agonists, dopamine
antagonists, and less commonly agents such as lithium, oral contraceptives and corticosteroids. - Genetic: Huntington’s, rarer neurogenetic conditions include neuroacanthocytosis and dentatorubropallidoluy- sian atrophy.
- Immune mediated: Sydenham chorea, hiv
- Metabolic: hyperthyroidism, poly- cythaemia rubra vera and in non-ketotic hyperg- lycaemia. It can also occur in liver failure, referred to as acquired hepatolenticular degeneration.
- Structural: stroke, tumour, demyelination
Treatment of chorea
Chorea and ballismus are often improved by dopamine antagonists; haloperidol has been used
for years and newer agents such as risperidone can also be used. Tetrabenazine is effective but can be associated with drowsiness and depression.
Types of myoclonus
Myoclonus in epilepsy
Symptomatic myoclonus
Drug related myoclonus
Essential myoclonus
Spinal myoclonus
What worsened myoclonus seizures
Carbamezapine
Phenytoin
Gabapentin
Tiagabine
Treatment of myoclonus seizures
Sodium valproate
Others: lamotrigine, clonazepam, levetiracetam
Causes of drug related myoclonus
Most antipsychotics: lithium,
Most antidepressants
Some antiepileptic drugs
Symptomatic treatment for myoclonus
Sodium valproate
Benzos: clonazepam, levetiracetam
Ethosuzamide
Zonasemide
Conditions to consider in an acutely ill patient with prominent hyperkinetic movement disorder—chorea, myoclonus or dystonia
▶ Drug induced movement disorders (perhaps given as an antiemetic or for confusion)
▶ Autoimmune encephalopathies:
▶ Agonists and sympathomimetics
– Hashimoto’s
– Anti-NMDA receptor encephalitis
▶ Encephalitis lethargica
▶ Metabolic encephalopathies especially
– Renal failure
– Liver failure
– Thyroid disease
– Hyperglycaemia
▶ Creutzfeldt–Jakob disease
Treatment of tics
▶ α-agonists: clonidine (low dose 50–500 μg/ day) or guanfacine
▶ dopamine antagonists: risperidone, aripipra- zole, haloperidol. No comparative studies are available; use minimum effective dose.
▶ Others—botulinum toxin, clonazepam, tetrabenazine
Treatment of restless leg
▶ some improve following a course of iron replacement
▶ dopamine agonists (only non-ergot agents such as pramipexole or ropinerole) or levo- dopa improve symptoms but may cause ‘augmentation’—an increase in symptoms as the dose is increased. They also carry a small risk of dopamine induced dyscontrol syndrome. The dose of agonists needs to be kept as low as possible and titrated against clinical effect
▶ other drugs with more limited evidence include antiepileptics, most notably gabapen- tin and pregabalin, and benzodiazapines such as clonazepam or zolpidem.
Features/Sx of Parkinsonism
Bradykinesia
Rigidity
Posture instability
Remor
Depression and anxiety
Loss of smell
Constipation
Treatment of Parkinsonism
Give levodopa (as it’s caused by deficiency)
