DMARDS Flashcards
(112 cards)
1
Q
What does DMARDS stand for?
A
Disease modifying anti-rheumatic drugs
2
Q
What are the aims of therapy of DMARDS?
A
They are immuno-suppressant drugs that according to NICE aim to influence the course of a disease (halt or reverse progression of an auto-immune disease)
3
Q
What are the three classifications of DMARDS within some examples?
A
Conventional DMARDs: this includes methotrexate, sulfasalazine, hydroxychlorquine
Biological DMARDs: Adalimumab and Rituximab
Synthetic/targeted DMARDs: Tofacitinib (JAK inhibitor) and Apremilast
4
Q
Who normally initiates the use of DMARDs?
A
Secondary care (consultant with additional training in a specialised area) although GPs may be involved in the monitoring of a patient once they are commenced on a DMARD regime.
5
Q
What conditions often have DMARDs prescribed?
A
Widely used in the treatment of Rheumatoid arthritis in addition to:
Ankylosing spondylitis
Connective tissue diseases
Psoriasis
Psoriatic arthritis
Vasculitis
Inflammatory bowel disease
6
Q
Briefly describe the mechanism of methotrexate.
A
Methotrexate is an inhibitor of dihydrofolate reductase - an enzyme crucial for the metabolism of folic acid required for the production of purine and thymidylate synthase crucial for nucleic acid synthesis. This mechanism correlates to Methotrexate’s cytotoxic activity indicated for neoplasia. However Methotrexate’s indication for auto-immune diseases is not related to this mechanism but instead is believed to link to being an adenosine uptake inhibitor resulting in adenosine accumulation.
7
Q
What are the three structural elements of folates which correlate with the structure of methotrexate?
A
A pteridine ring, p-aminobenzoic acid and glutamic acid
8
Q
Can methotrexate cross the blood brain barrier?
A
No as the drug has low lipid solubility
9
Q
Aside from methotrexate’s cytotoxic activity mechanism, describe the effects the drug has on T cells in the application of rheumatoid arthritis.
A
Methotrexate is known to reduce the production of pro-inflammatory cytokines crucially reducing the synthesis of IL-2 and the expression of the IL-2 receptor on CD4+ T cells or Th1 cells hence this reduces the activation of the T cells resulting in a further decreased activity of osteoclasts and fibroblasts which normally activate metalloproteinases which leads to the erosion of the bone and cartilage.
10
Q
How is methotrexate uptaken into cells and metabolised?
A
By the folate transport system and is metabolised to polyglutamate derivatives, which are retained in the cell for weeks or months even in the absence of extracellular drug.
11
Q
Is Ciclosporin orally bioavailable?
A
Despite not following Lipinski’s rules, Ciclosporin is orally bio-available due to having a balance of hydrophobicity and hydrophilicity which enables it to be able to cross the gut membrane.
12
Q
What is the main metabolism of Ciclosporin?
A
CYP 450
13
Q
Describe the structure of ciclosporin.
A
It is a cyclic peptide of 11 amino acid residues - some of the amino acids are not found in animals
14
Q
Describe the activity of ciclosporin.
A
Ciclosporin has immunosuppressent activity but it doesn’t have an effect on the acute inflammatory response.
It does not have cytotoxic activity like methotrexate.
15
Q
What are the four ways ciclosporin is an immuno-suppressant?
A
Inhibits IL-2 synthesis and the expression of IL-2 receptors which leads to decreased T cell proliferation
Reduced induction and clonal proliferation of cytotoxic T cells from CD8+ precursor T cells
Reduced function of the effector T cells responsible for cell-mediated responses (e.g. decreased delayed-type
hypersensitivity)
Some reduction of T cell-dependent B-cell responses
16
Q
When does the peak plasma concentration of ciclosporin occur?
A
Within 3-4 hours of administration
17
Q
What is the half life of ciclosporin?
A
24 hours
18
Q
Describe the distribution of ciclosporin in the body.
A
Ciclosporin accumulates in the tissue at a concentration 3-4 times greater than its accumulation in the plasma. Most of the drug remains in the lymphomyeloid tissue and fat deposits long after the administration of the drug has stopped.
19
Q
Describe the pharmacokinetics of Leflunomide.
A
-It is orally active and well absorbed from the GI tract.
-It has a long plasma half-life which increases its risk of cumulative toxicity
-The active metabolite undergoes enterohepatic circulation.
20
Q
Describe the mechanism of Leflunomide.
A
It has not yet being fully determined however it is believed that the drug regulates the autoimmune lymphocytes by interfering with its cell cycle progression. It inhibits the enzyme dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity.
21
Q
What are the indications of Ciclosporin A?
A
Irritable bowel disease
Immunosuppressive therapy in transplant patients
Psoriasis
Severe atopic dermatitis
Rheumatoid arthritis
22
Q
What are the formulations of Ciclosporin?
A
Oral capsules or IV
What formulation is prescribed is dependent upon the indication
23
Q
What are the initial administrative requirements for Ciclosporin?
A
The dose of Ciclosporin should be up titrated according to effective balanced against the patient tolerability to the drug (side effects and close monitoring).
24
Q
What are the most common side effects of Ciclosporin?
A
Headache
Tremor
Hypertension
Hiruitism
Renal impairment
25
What are the fairly common side effects associated with Ciclosporin?
GI disturbances
Fatigue
Convulsions
Muscle cramps
Myalgia
Leukopenia
Hepatic impairment
Hypertrichosis
26
What are the effects Ciclosporin has on U & Es?
Hyperglycaemia
Hyperlipidemia
Hyperkalemia
Hyperuricaemia
Hypomagnesia
27
When is it more likely a patient will experience side effects associated with Ciclosporin?
When the patient is taking a high dose of the drug for a long period of time
28
What type of cancers is Ciclosporin associated with?
Lymphoma and skin malignancies
Therefore it should be recommended to the patient to avoid/limit UV exposure such as sunlight
29
What are the contra-indications of Ciclosporin?
Renal impairment
Malignancy
Uncontrolled hypertension
Uncontrolled infection
(All due to potential side effects of the medication)
30
What infections may you want to screen for before initiating the patient on Ciclosporin therapy?
Latent or active TB
Hepatitis
Varicella Zooster
31
When should Ciclosporin be cautioned and why?
In the elderly - due to already reduced renal and hepatic function in this population, causing them to be increasingly susceptible to experiencing these side effects. Elderly patients tend to have a higher blood pressure also
Patients with gout- exacerbation due to side effect of hyperuricaemia
Hepatic impairment - will require a dose adjusted as the drug is CYP450 metabolised and excreted from the biliary
32
What are the toxic monitoring parameters for Ciclosporin?
Renal function
Hepatic function
Blood pressure
Lipids
Electrolytes - potassium and magnesium
Uric acid
33
In an non transplant patient how often should the toxic monitoring parameters of Ciclosporin be measured?
In non-transplant patients, occasional monitoring of ciclosporin blood levels is recommended.
This could be when Ciclosporin is co-administered with substances that may interfere with the pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g., lack of efficacy or increased drug intolerance such as renal dysfunction).
34
What classes of drugs does Ciclosporin interact with?
Ciclosporin relies on CYP450 for its metabolism and therefore plasma concentrations of Ciclosporin can be increased (by CYP450 inhibitors) or decreased (by CYP450 inducers) by drugs of that class.
35
What are some examples of drugs that are CYP 450 inhibitors?
Drugs that will increase the concentration of Ciclosporin:
Macrolides - Clarithromycin
Dilitazem
Verapamil
Lercandipine
Fluconazole, Itraconazole, Ketoconazole
Grapefruit juice
36
What are some examples of drugs that are CYP450 inducers?
Drugs that will decrease concentrations of Ciclosporin:
Rifampicin
Carbamazepine
Phenobarbital
Phenytoin
St Johns Wort
37
What is the risk of prescribing Ciclosporin with statins?
Should be avoided or dose reduction
This is due to Ciclosporin increasing the exposure of Statins as it is a CYP3A4 inhibitor. This increases the potential for adverse events such as myopathy and potentially rhabdomyosis
38
When should Statin therapy be with held?
Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis
39
What are some of the other drug interactions with Ciclosporin?
Drugs that also exhibit Nephrotoxic synergy
NSAIDs
Aminoglycides
Fibric acid derivatives
H2 antagonists
Methotrexate
Drugs that have similar side effects
Potassium sparing diuretics
40
If Ciclosporin is prescribed alongside a drug that has the potential to cause Nephrotoxicty what pharmaceutical care considerations should be made?
Increased renal function monitoring
Discontinue if renal function drops
41
Describe the difference in bioavailability between oral and IV Ciclosporin?
Oral dose is approximately 3x that of the IV dose
42
Are brands interchangeable of Ciclosporin?
In both transplant and non transplant patients, switching brands of Ciclosporin is not recommended unless done under supervision of prescriber.
43
Is dose monitoring required more intensely for transplant or non- transplant patients?
Transplant patients require more frequent monitoring especially when there is a dose alteration.
44
How should the oral solution of Ciclosporin be diluted?
With orange or apple juice
Not grapefruit juice
45
What advice should be given to patients receiving Ciclosporin therapy?
Twice daily preparation
Maintained on the same brand
There should be consistency within their administration- time of day and proximity to food as Ciclosporin exposure increases with a high fat meals
Should avoid live vaccines
46
What are the indications for Leflunomide?
Moderate to severely active Rheumatoid arthritis
Active psoriatic arthritis
47
What is the initial dosing regimen for Leflunomide?
100mg once daily for 3 days PO
Then decrease to 10-20mg once daily
48
When may a patient not receive a loading dose for Leflunomide?
If the patient is at risk of experiencing adverse effects
49
When would a patient begin to experience the therapeutic effect of Leflunomide?
After 4-6 weeks they may begin to experience the benefit however the full therapeutic effect may not be until 4-6 months.
50
State the common side effects associated with Leflunomide.
Hepatic impairment
Bone marrow suppression
Increased blood pressure
GI associated side effects
Alopecia
Skin reactions
51
What is a rare side effect associated with Leflunomide?
Respiratory problems - these may initially present as cough and dyspnoea.
This can lead to the discontinuation of treatment and require further investigation.
There have been reported cases of interstitial lung disease and pulmonary hypertension associated with Leflunomide.
52
When is the risk of developing hepatic impairment associated with Leflunomide the greatest?
When used in combination with other hepatotoxic drugs
During the first six months of treatment
53
What are some of the side effects associated with bone marrow suppression?
Leukopenia
Anaemia
Thrombocytopenia
Pancytopenia
54
When is the risk of developing bone marrow suppression associated with Leflunomide the greatest?
Those with already bone marrow suppression to an extent or
With pre-existing anaemia, leucopenia etc
55
If bone marrow suppression is detected from monitoring for Leflunomide what is the recommended treatment?
Discontinue Leflunomide
Perform washout procedure
56
What is the washout procedure for Leflunomide and why do you have to perform it?
Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is administered 4 times daily. Duration of a complete washout is usually 11 days
57
State the contra-indications of Leflunomide.
Hypersensitivity
Hepatic impairment
Severe immunodeficiency
Severe infection
Severe hypoproteinaemia
Moderate to severe renal impairment
Pregnancy and breastfeeding
58
Explain why patients with hepatoxicity as contra-indicated for use of Leflunomide?
The active metabolite of Leflunomide undergoes hepatic metabolism and then biliary excretion so if a patient already has underlying hepatic impairment there is a risk of accumulation of the drug.
59
Why are patients with severe immunodeficiency and severe infection unable to receive Leflunomide?
Patients already have bone marrow suppression therefore they will be at high risk of contracting infections in addition to opportunistic infections.
Those with already severe infections (such as latent TB) will be at risk of reactivation of the infection.
60
Why are patients who have severe hypoproteinuria contra-indicated for the use of Leflunomide?
The active metabolite of the drug is protein bound, therefore in low protein levels, there is a higher concentration of the drug.
61
Why are patients who have moderate to severe renal impairment contra-indicated for the use of Leflunomide?
There is no safety information in this class of patients
62
Why is Leflunomide contra-indicated in those who are pregnant and breastfeeding?
Has been shown to cause severe birth defects in pregnancy and the active metabolite is present in breast milk.
63
What contraception considerations must be made whilst a patient is on Leflunomide?
Women of childbearing potential have to use effective contraception during and up to 2 years after treatment (waiting period) or up to 11 days after treatment (washout period).
Both drugs used in the washout period (Colestyramine and Coal tar) reduce the absorption of oral contraceptives and therefore additional methods of contraceptives should be used during this period.
64
For both the waiting and washout period what plasma concentrations of Leflunomide is deemed safe to try for pregnancy?
Following the waiting period:
After two years the plasma concentration of Leflunomide must be measured and repeated again after an interval of 14 days. There must be two positive readings of the plasma concentration being below 0.02 mg/l for no risk to be determined.
Following the washout procedure:
There must be verification by 2 separate tests at an interval of at least 14 days of Leflunomide concentrations AND
There must be a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and fertilisation.
65
What are the initial monitoring requirements for Leflunomide?
Initial monitoring requirements before initiation:
FBC
LFT (ALT)
Renal
Blood pressure
Protein levels
Exclude pregnancy
Screen for underlying infection
66
What are the ongoing monitoring requirements for Leflunomide?
Monitor full blood count (including differential white cell count and platelet count) before treatment and every 2 weeks for 6 months then every 8 weeks.
Monitor liver function before treatment and every 2 weeks for first 6 months then every 8 weeks.
Monitor blood pressure periodically.
67
What is the recommended pharmaceutical intervention if the ALT levels increase by between 2-3 fold the upper limit of normal whilst on Leflunomide?
Dose reduction of 20mg to 10mg, monitoring parameters become weekly
68
What is the recommended pharmaceutical intervention if the ALT levels persist at 2 times the upper limit of normal or of more than 3-fold the upper limit of normal are present whilst on Leflunomide?
Discontinuation of Leflunomide and perform wash out procedure. Continue monitoring LFTs until they have reached baseline again.
69
When is use of Leflunomide cautioned?
Concomitant administration of hepatotoxic or haematotoxic drugs
History of TB
Patients with elements of bone marrow suppression
70
What is the half life of Leflunomide and when is it considered cleared from the body? What effects does this have on the pharmaceutical care considerations of the drug?
The half life of the active metabolite of Leflunomide is 1-4 weeks and as a drug is not considered cleared from the body until 5.5 half lives have occurred this would estimate that the drug is cleared from the body 5.5-22 weeks after the last administration.
Therefore it is recommended to maintain monitoring the parameters until they have resumed to baseline rather than after stopping the drug.
71
How does Colestryamine and Coal tar work to clear the body of Leflunomide?
Interrupts the hepato-enteric cycling or GI dialysis
72
What advice should be provided to a patient who is receiving Leflunomide therapy?
The drug can be taken with or without food
Avoid alcohol during its use
Avoid live vaccines
73
What are some of the indications of low dose Methotrexate?
Severe psoriasis
Crohn's disease
Moderate to severely active Rheumatoid arthritis
74
What are some key interventions that have been made following over dose of Methotrexate as a never event?
In order to prescribe Methotrexate, clinicians must have competence in that area
Comes in a single 2.5mg strength
Frequency of low dose Methotrexate should be once a week, the same day each week and the patient must be educated on this for auto-immune diseases
Patient carries an alert card
Warnings on the packaging
75
What are the different formulations of low dose Methotrexate?
Oral
Intramuscular
S/c
(Other formulations available for neoplastic disease)
76
What is the first line formulation choice for low dose Methotrexate?
Oral
77
What is the oral bioavailability of Methotrexate?
64-90%
78
What is the purpose of receiving a test dose of Methotrexate?
To rule out idiosyncratic adverse effects (these are reactions that cannot be predicted from the pharmacology of the drug for example anaphylaxis from penicillin)
79
How long does it take for a patient to begin to experience the therapeutic effects from Methotrexate?
Using the indication of Rheumatoid Arthritis:
The patient may begin to experience effects from Methotrexate 6 weeks after initiation however the full (maximum) therapeutic effect is not until 12 weeks.
80
Why is a dose escalation required for Methotrexate?
Ensure close monitoring due to potential for adverse effects
81
What is an example of a dose escalation for Methotrexate?
Initially 7.5mg with an increase of 2.5-5mg every 1-3 weeks
There should be an aim for the optimal dose to be reached within 4-6 weeks
82
What is the purpose of completing a baseline assessment before the initiation of Methotrexate?
To ensure the patient is not contra-indicated before starting the medication
To record the patient's baseline so then any changes in the patient's parameters can be detected and appropriate response is recorded.
83
What are some of the key parameters that need to be recorded before starting low dose Methotrexate?
FBC - including white blood cells, neutrophils, platelets and haemogloblin
LFT
Electrolytes and urea
Renal - including eGFR and creatinine
Chest X-ray
Exclude pregnancy
84
What are the approximate monitoring parameters for low dose Methotrexate and how frequently should they be monitored?
Although dependent upon the indication you would expect;
LFT, renal function and FBC - every 1-2 weeks until stable
Then every 2-3 months
85
When would you expect the monitoring of Methotrexate to increase?
Abnormalities detected in monitoring
Patient reports side effects suggestive of toxicity
86
What side effects would you counsel patients to look out for when starting Methotrexate?
Signs of bone marrow suppression / infection - sore throat, bruising, bleeding
Signs of hepatotoxicity- nausea and vomiting, abdominal discomfort, dark urine
Pulmonary toxicity- shortness of breath
87
State the key side effects associated with use of Methotrexate.
Bone marrow suppression
GI toxicity
Liver toxicity
Pulmonary toxicity
Skin reactions
88
When is the risk of developing adverse side effects with Methotrexate higher?
Patients with already underlying impairment (underlying infection, impaired renal function)
Patients receiving doses above 20mg
89
What are some of the GI associated side effects that can occur with Methotrexate therapy?
Mucositis
Stomatitis
GI bleeding (black and tarry stools)
Ulcers
90
What is the appropriate pharmaceutical action to take if diarrhoea or ulcerative stomatitis or haematemesis occurs?
Methotrexate should be discontinued due to the risk of perforation which would result in haemorrhagic enteritis and death.
Occurrence of haematemesis (blood in stools or black tarry stools) would result in the discontinuation of treatment also?
91
What are the different side effects associated with bone marrow suppression?
Leukopenia
Thrombocytopenia
Anaemia
Pancytopenia
Risk of infection
Increased risk of bruising and bleeding
92
What monitoring parameter would be suggestive of hepatotoxicity and how often does it occur?
An increase in ALT
There is a temporary increase in ALT of 2-3 times the upper fold limit in comparison to the baseline. This is said to occur in 13-20% of patients.
93
Would you consider reducing or stopping the dose of Methotrexate in a patient that expresses an increase in ALT?
Most likely not, instead increase the frequency of the monitoring parameters.
If there was a persistent increase in ALT would then be suggestive of severe hepatotoxicity and/or decrease in serum albumin. Then consider reducing or discontinuing treatment.
94
What are some of the ways to reduce the potential of hepatotoxicity?
Limited alcohol - preferably avoid
Avoid concurrent use of additional hepatotoxic medications
95
What are some additional risk factors for hepatoxicity?
Excessive prior alcohol consumption
Persistent elevation of liver enzymes
History of liver disease
Family history of hereditary liver disorders
Diabetes mellitus
Obesity
Previous contact with hepatotoxic drugs or chemicals
Prolonged methotrexate treatment
96
Do liver function tests always indicate hepatoxicity?
No, histological changes, fibrosis and cirrhosis are not always shown by an increase in ALT for example. Therefore liver biopsies and other investigations may have to be made.
An example of this is there is an increased risk of hepatoxicity specifically cirrhosis associated with insulin dependent diabetes where there is no increase in transaminase enzyme.
97
What are some of the symptoms associated with pulmonary toxicity?
Shortness of breath
Thoracic pain
Dry cough
Fever
98
State the key contra-indications of Methotrexate use?
Active infection
Severe renal impairment
Hepatic impairment
Bone marrow suppression
Immunodeficiency
Pregnancy or breast feeding
99
Why is Methotrexate contra-indicated for use in individuals with renal impairment?
The kidneys are responsible for elimination of the drug, if there is impaired function there would be an increase in drug concentrations increasing the potential of adverse reactions.
100
What pharmaceutical interventions should be made based upon the creatinine clearance?
An increase in serum creatinine levels should result in a dose reduction.
Use of Methotrexate is contra-indicated when creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given. If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m2 not be given.
101
When there is a possibility of renal impairment monitoring of renal function should occur more frequently when taking Methotrexate, what patient groups may therefore have more intensive monitoring?
Elderly (reduced hydration status, increases risk of toxicity)
Concurrent use of drugs that affect the elimination of Methotrexate
Those that cause kidney damage (NSAIDS) or potentially lead to impairment of haematopoiesis
102
Which drug interaction involving Methotrexate and another should be avoided in renal impairment?
Methotrexate and PPIs
103
When is use of Methotrexate cautioned?
Surgery
Renal impairment
Diarrhoea
Ascites
Peptic ulcer
Elderly
104
When does nausea, vomiting and diarrhoea usually occur with Methotrexate therapy?
At the beginning and is self limiting.
If there is no improvement within a couple of weeks then the dose of folic acid should be increased. Introduce anti-emetics.
Switch to IV or s/c if there is still no improvement.
105
Why is folic acid prescribed alongside Methotrexate?
Minimise GI associated side effects and hepatoxicity
106
What is the initial dosing regimen of folic acid?
Folic acid 5mg once a week
Not to be taken on the same day as the Methotrexate
This can be increased to taking folic acid 5mg, 6 days a week still not the same day as the Methotrexate.
107
Why is Methotrexate cautioned in patients with Diarrhoea?
Has the potential to cause renal impairment alongside dehydration and is therefore cautioned.
108
Why is Methotrexate cautioned in the elderly?
Due to naturally reduced folate
Naturally reduced renal function
109
What is the crucial advice that should be provided regarding infections, vaccines and Methotrexate?
A patient should not receive live vaccines whilst taking Methotrexate
It is advised for a patient to receive the inactive pneumococcal and annual influenza vaccines during treatment to prevent infection.
A patient should be screened for infections before starting treatment such as latent TB due to potential for reactivation once taking Methotrexate and receive appropriate chemoprophylaxis
If an infection occurs, treatment should be paused.
110
What are some of the key drug interactions associated with use of Methotrexate?
Drugs also causing hepatotoxicity, haemotoxicity or nephrotoxicity
Anti-folates such as Co-trimoxazole and Trimethoprim
NSAIDs - okay but under close prescribing
Live vaccines
Ciclosporin - increase risk of toxicity
111
What happens if you miss a dose of Methotrexate?
It is okay to take within the next 2 days
If the dose of Methotrexate is missed longer than 2 days then it should be a missed dose and resume to taking as normal when the next scheduled dose is.
112
What are the key counselling points of Methotrexate?
Encourage patients to carry their Methotrexate alert card with them and healthcare professionals record in their monitoring booklet
NSAID OTC use is not allowed, only when under the supervision of a healthcare professional
Occasional use of alcohol only
Make patients aware of the common side effects
Remind the patient Methotrexate is not a painkiller and takes multiple weeks to feel an effect
Discuss the dosing regimen of the drug and establish a day it is going to be taken (once weekly dosing)
Encourage patients to check their own medication
Explain why patients need regular blood tests
Make patients aware of common side effects and which signs they should contact their prescriber about
What to do if they take too much Methotrexate
