Module 4.2.1 (Pharmacology of Drugs for Multiple Sclerosis) Flashcards
What is MS?
MS is an inflammatorymediated demyelinating disease of the CNS
> Inflammatory lesions are characterised by high infiltration of
Immune cellular and soluble mediators: T & B cells Macrophages Microglia
A broad range of: Cytokines Chemokines Antibodies Complement Toxic substances
Demyelination is also associated with axonal injury, hence disruption of communication among neurons of the brain and spinal cord. It may follow a relapsing-remitting course or be progressive (gradual deterioration of neurologic function) with or without relapses.
Several disease-modifying therapies with different mechanisms of action are available for MS. These have immunosuppressive & immunomodulatory effects that target:
A) Lymphocyte number
B) Lymphocyte proliferation
C) Lymphocyte trafficking
D) Cyotkine production
A)
- Alemtuzumab
- Ocrelizumab
- Cladribine
B)
- Teriflunomide
C)
- Fingolimod
- Natalizumab
D)
- Interferon beta
- Glatiramer
Summary of drugs and the type of MS used for
What is included in the types of interferon? MOA?
- Interferon beta-1a
- Interferon beta-1b
- Peginterferon beta-1a
MOA
- Exact mechanism unknown - thought to act through immunoregulatory actions
- Interferon beta reduces cytokine release and enhances suppressor T cell activity, inhibits lymphocyte trafficking into CNS & also reduces the amount of interferon-gamma secreted by activated lymphocytes.
AE (CIR) and precautions of interferon
Common
- Injection site reactions
- Flu-like Sx
- Headache
- Interferon beta neutralising antibodies
> Incidence lower with peginterferon beta
Infrequent
- Hypertension, seizures
Rare
- Palpitations, HF, cardiomyopathy
- Thrombocytopenia
- Hepatotoxicity
Precautions
> Cardiac disease eg heart failure – may worsen
> Seizure disorder – may worsen or reoccur
What is the MOA of Alemtuzumab?
- Recombinant humanised monoclonal antibody
- Binds to CD52 surface protein on T and B lymphocytes, resulting in their depletion with subsequent repopulation
AE (CI) and precuations of Alemtuzumab
Common
- Infusion related reactions
- Autoimmune disorders
- Infection
- Lymphopenia
Infrequent
- Pneumonitis
Precautions
Infection –> CI in HIV infection
> for infusion related reactions –> consider paracetamol, corticosteroids and antihistamines
> continued monitoring of infections, FBC, TFT, U+E, PML and SeCR need to occur
> prescreening for cancer, HIV, TB, hepatitis B + C and pregnancy also need to occur
> baseline FBC, TFT, U+E, SeCr
MOA of dimethyl fumarate?
- Is a derivative of fumaric acid
- Thought to activate the nuclear factor (erythroid derived 2)-like 2 (Nrf2) transcriptional pathway
> Activation of this pathway results in antiinflammatory and antioxidant actions
- Taken orally bd
AE (CR) and precuations of dimethyl fumarate
Common
- Flushing
- GI SE eg N, V, D, abdominal pain
- Leucopenia
- Lymphopenia
Rare
- PML = viral disease of white matter of the brain
Precautions
- Infection
- Persistent severe lymphopenia
What is the MOA of fampridine?
potassium channel blocker
- Thought to increase conduction in demyelinated nerves by inhibiting potassium channels
What are the indications of fampridine?
Symptomatic improvement of walking in adults with MS (in those with walking disability
- If no response within 8 weeks - stop
> oral bd
AE (CR) of fampridine and precautions
Common
- UTI
- Insomnia
- Dizziness
- Headache
- Anxiety
Rare
- Seizure
Precuations
- Epilepsy, Hx of seizures = CI
MOA of fingolimod?
Is a sphingosine 1-phosphate receptor modulator
- Fingolimod traps naive memory T cells and effector memory T cells in lymph nodes
- Prevents cells from entering the bloodstream and therefore crossing the blood-brain barrier thus reducing inflammation and demyelination
> dose od
> eliminated by metabolism –> most of the metabolites are excreted in the urine (t1/2 = 6–9 days so it takes several weeks to reach steady state)
AE (CIR), precautions and drug interactions for fingolimod?
Common
- Bradycardia
- First-degree AV block
- Infection eg lower RTI, influenza
- Basal cell carcinoma
Infrequent
- Melanoma
- Second-degree AV block
Rare
- Opportunistic CNS infections including cryptococcal meningitis & PML
Precautions
- Cerebrovascular or cardiovascular disease – use not recommended
- Diabetes - ↑ risk of macular oedema
Drug Interactions
- CYP3A4 may metabolise fingolimod
- Combining it with CYP3A4 inhibitors eg clarithromycin may increase its conc & the risk for adverse effects
MOA of glatiramer?
Is a synthetic protein that mimics the structure of myelin basic protein
- Which is a component of the myelin covering nerve fibre.
> Blocks myelin damaging T cells by acting as a myelin decoy
> The proposed mechanism of action is induction of T-lymphocyte suppressor cells and interference with antigen presenting capabilities, essentially decreasing the autoimmune inflammatory processes
