L08 - Drugs Used in the Management of Arthritis Flashcards
• Identify the rationale behind the selection and the regimen of steroidal anti-inflammatory drugs in the management of joint disorders • Describe the risk for chronic usage of anti-inflammatory steroids • Describe the different categories of DMARDs • Explain the pharmacological differences between nonbiological and biological DMARDs • Recognize the benefits and the risks associated with the use of non-biological and biological DMARDs
Name a non-opioid analgesic used to treat arthritis?
Paracetamol (Acetaminophen)
List 2 advantages and 2 disadvantages of using Paracetamol for arthritis?
Advantages:
• Analgesic effect: preferred drug against mild to moderate pain
• Therapeutically safe - RARE skin rash and minor allergic reactions
Disadvantages:
• Liver and/or kidney damage - only at toxic dosage
• Lack of anti-inflammatory effect - limited to osteoarthritis
What can increase the risk of liver and/or kidney damage under high dose paracetamol consumption?
Risk increased with cytochrome enzyme induction (e.g. heavy alcohol consumption)
or GSH depletion (e.g. fasting or malnutrition)
What can decrease the risk of liver and/or kidney damage under high dose paracetamol consumption?
risk reduced by treatment with N-acetylcysteine (Mucolytic)
What are the 2 classes of NSAIDs?
Non-steroidal anti-inflammatory drugs (NSAIDs)
- traditional NSAIDs (tNSAIDs)
- selective cyclooxygenase-2 inhibitors
What 2 classes of drugs can be used to treat inflammation caused by arthritis?
NSAIDs
Steroids
Why do Glucocorticoids take time to achieve therapeutic effects?
MoA: bind to intracellular cytoplasmic receptors
> > induce / repress gene transcription in nucleus
> > affect level of mRNA, proteins
Long process, full effect comes after several hours, weeks
What are the effects of NSAIDs?
- Anti-inflammatory
- Analgesic effect
- Antipyretic effect
Explain the overall MoA of NSAIDs?
Inhibit the activity of cyclooxygenase»_space; decrease production of prostanoids
Explain how NSAIDs have anti-inflammatory effect?
Decrease production of prostanoids
> > decrease vasodilation and vascular permeability
> > Decrease edema and swelling and redness
Explain how NSAIDs have analgesic effect?
Decrease production of prostanoids
> > Decrease sensitization of pain nerve endings
decrease low to moderate pain from integumental structures
Explain how NSAIDs have antipyretic effect?
Decrease production of prostanoids
Decrease set-point of hypothalamic thermoregulatory center
> > relieve fever
What are the 2 ways that Glucocorticoids can impact synthesis of eicosanoids?
Affect synthesis of eicosanoids/ arachidonic metabolites by:
a) Increase expression of lipocortin (annexin-1) to INHIBIT phospholipase A2»_space; less cell membrane phospholipids converted to arachidonic acid to make leukotrienes
b) Decrease expression of cyclooxygenase 1 and 2»_space; LESS CONVERSION of arachidonic acid to prostaglandins and Thromboxane respectively
How does glucocorticoid impact inflammatory response by cytokines?
Decrease pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1))
- Decrease vasodilation and vascular permeability
- Decrease expression of adhesion molecules between WBC and endothelial cells
- Inhibit function of macrophages and APCs
- Inhibit production of prostaglandins, leukotrienes and platelet-activating factor
Name 6 synthetic glucocorticoids and group them into functional groups.
1) Hydrocortisone and Prednisolone = short to medium acting
2) Cortisone and Prednisone = Inactive pro-drug
3) Betamethasone and Dexamethasone (long- acting) ( less commonly used for oral therapy to avoid adverse effects)
Advantages of Hydrocortisone, Prednisolone?
- Oral intake, convenient
- Short acting, avoids long-lasting adverse effects
Which glucocorticoids cannot be given to patients with severe liver failure and why?
Cortisone and Prednisone:
- inactive (Pro-drug) converted by 11β-HSD1 in the liver to biologically active forms (hydrocortisone and prednisolone)
- Severe hepatic failure = impaired 11β-HSD1 activity
Where are glucocorticoid and Mineralocorticoid made naturally in body?
Adrenal Cortex
What stimulates the production of Glucocorticoids and Mineralocorticoids in the body?
Hypothalamus»_space; Corticotrophin- Releasing Factor (CRF)»_space; Corticotrophs @ Anterior Pituitary»_space; Adrenocorticotrophic Hormone (ACTH)»_space; Adrenal Cortex
How is Glucocorticoid production regulated in the body?
Production by Adrenal Cortex»_space; Glucocorticoid level increases»_space; NEGATIVE FEEDBACK ONTO HYPOTHALAMUS»_space; cease release of CRF …etc
Compare the mode of action of glucocorticoids on cells at low level and high level in body?
Low level = Permissive effect: permit the actions of other hormones in its presence (occur primarily in the resting state)
High level = Direct action in cells in response to threat
What is the metabolic effect of Glucocorticoids at low dose?
Increase adrenergic- receptor-mediated lipolysis in fat cells (e.g. under increased NE/E levels)
> > fat lysis to glycerol for gluconeogenesis in liver
Overall normal physiological Metabolic effect of Glucocorticoids?
Maintenance of adequate glucose supply to the brain and heart (glucose-dependent tissues)
What is the metabolic effect of Glucocorticoids at HIGH dose?
1) Increase activity of PEP carboxykinase and G6P to increase gluconeogenesis in liver
2) Translocate glucose transporters internally to decrease glucose uptake in muscles
3) Increase protein breakdown to use amino acid for gluconeogenesis
Explain why high dose glucocorticoid treatment can cause fat redistribution?
High dose glucocorticoids increases Blood Glucose levels massively
Cause increase in insulin and Lipogenesis
Cause fat deposition to trunk, back of neck, face …etc
Explain effect of chronic high dose glucocorticoid intake on fat redistribution?
Chronic intake = decrease fat cell responsiveness = fail to breakdown fat
Cause further fat accumulation and redistribution
Compare Electrolyte and water balance effects between low and high dose glucocorticoid intake?
Low = Maintain glomerular filtration rate, facilitate water excretion by the kidney (permissive effects on tubular function)
High = Decrease calcium absorption in GIT, Increase Calcium excretion by kidney = BONE LOSS (attempt to compensate for low plasma Ca)
Vascular and Neuronal effects of glucocorticoid intake?
Vascular = Enhance vascular reactivity to other vasoactive substances = Hypertension
Neuronal = mood elevation, euphoria, insomnia, restlessness, increase motor activity
List the 7 adverse effects of glucocorticoid intake?
- Immunosuppression = Infection and peptic ulcer (H. pylori)
- Impaired inflammatory response = impaired wound healing
- Impaired carbohydrate metabolism = hyperglycemia → diabetes mellitus
- Impaired protein metabolism = muscle
wasting, weakness - Impaired lipase activity, insulin secretion = redistribution of fat to trunk
- Impaired calcium metabolism = osteoporosis
- Abnormal CNS effects = insomnia, euphoria, depression
Why is chronic glucocorticoid use not recommended for children?
Growth inhibition
Only give short term, not oral preparation
What pre-existing conditions are contraindicated against use of glucocorticoids?
infectious illnesses, peptic ulcer, heart disease, diabetes, psychoses, osteoporosis, hepatic dysfunction
Glucocorticoids can be quickly withdrawn after chronic admin. True or False?
False
Immediately withdrawal Cause Adrenal insufficiency (Body cannot make glucocorticoids for normal processes)
What are the consequences of adrenal insufficiency?
- disturbances in fluid and electrolyte balance
- hypoglycaemia
- impaired responses to the stress of illness or trauma → circulatory shock and even death
How to stop glucocorticoid treatment after long term admin?
Graded reduction of glucocorticoid therapy
- 2-12 months for recovery of adrenal function
- another 6-9 months for recovery of corticosteroids level
- close monitoring due to individual differences
What are the 3 considerations when admin. glucocorticoids?
1) Duration of action = preferably medium-acting for large doses
2) Route of admin = preferably topical preparation, local therapy to reduce systemic effects
3) Dosage regimen= lowest possible dosage to reduce side effect + Alternate day therapy for normal adrenal function
DMARDs can be given to cure Rheumatoid arthritis over chronic admin. True or False?
False
Only Modify disease activity and retard progress of bone and cartilage damage, not cure RA
Explain the mechanism of glucocorticoid intake causing adrenal insufficiency?
Due to negative feedback, when glucocorticoids are given as drugs, their plasma level is enough to suppress the hypothalamic-anterior pituitary-adrenal cortex (HPA) axis
> > body cannot synthesize glucocorticoids
What drugs are given to treat Rheumatoid arthritis?
Disease-modifying anti-rheumatic drugs (DMARDs)
Function of DMARDs?
Modify disease activity: retard the progress of bone and cartilage damage
achieve clinical remission, prevent irreversible damage to joints
Why are DMARDs used in conjunction with anti-inflammatory drugs at the beginning of therapy?
Act Slowly - 2 weeks to 6 months
Which is more toxic: DMARDs or NSAIDs? Why?
DMARDs
Affects more basic inflammatory mechanisms (immune response) than do glucocorticoids / NSAIDs
What are some toxic effects of DMARDs?
- Hematologic toxicity / bone marrow suppression
- Gastrointestinal disturbances, mucosal ulcers
What types of drugs should be given against pain from arthritis?
Acetaminophen + NSAIDs
What types of drugs should be given against inflammation from arthritis?
Glucocorticoids, NSAIDs
What types of drugs should be given against joint damage from arthritis?
DMARDs, glucocorticoids
List 4 groups of Conventional Synthetic DMARDs (csDMARDs)?
1) Cytotoxic agents
2) Sulfasalazine
3) Antimalarial drugs
4) Immunosuppressants
What is Sulfasalazine used for?
Treating Ulcerative Colitis, Rheumatoid Arthritis and Crohn’s disease
List 4 cytotoxic agent csDMARDs?
methotrexate most important
leflunomide, cyclophosphamide, azathioprine
List 2 Antimalarial csDMARDs?
chloroquine, hydroxychloroquine
List 2 Immunosuppressant csDMARDs.
cyclosporine
mycophenolate mofetil
MoA of Methotrexate? (4)
Folic Acid Analog (Antifolate), Cytotoxic Agent
Polyglutamated in cells, block active site of dihydrofolate reductase*** > decrease FH4 production»_space; Decrease methylation processes
- Inhibit AICAR, nuclear factor kappa B (NFκB)»_space;
suppress neutrophils, macrophages, dendritic cells and lymphocytes at low dose - inhibit proliferation and stimulate apoptosis of immune-inflammatory cells
- inhibit proinflammatory cytokines
Adverse effects of Methotrexate? What drugs reduce adverse effects of Methotrextae?
1) GI disturbances, mucosal ulcers
2) Hypersensitivity reaction > Methotrexate lung fibrosis*
3) Hematotoxicity, Nephrotoxicity*
4) Dose - related hepatotoxicity
Concomitant use of leucovorin or folate
What is the ONLY DMARD that can be given to pregnant women?
Hydroxychloroquine
Antimalarial agent ^
What is the triple therapy of csDMARDs?
Methotrexate + Sulfasalazine + Hydroxychloroquine
List 5 groups of Biological DMARDs?
- Tumour necrosis factor (TNF)-a blocking agents
- T-cell co-stimulation modulator
- B-cell cytotoxic agent
- Interleukin-1 receptor antagonist
- Interleukin-6 receptor antagonist
Give 5 examples of Tumour necrosis factor (TNF)-a blocking agents?
etanercept**,
infliximab, adalimumab, golimumab, certolizumab
Give example of T-cell co-stimulation modulator?
Abatacept
Give example of B-cell cytotoxic agent?
rituximab
Give example of IL-1 and IL-6 receptor antagonists?
IL-1»_space; Anikinra
IL-6»_space; tocilizumab, sarilumab
MoA of Abatacept?
Abatacept = T-cell co-stimulation modulator*
contains the endogenous ligand CTLA-4
> > binds to CD80 and CD86 of antigen-presenting cell
inhibit CD28 - CD80/86 complex formation
prevent activation of T-cells
Administration and preparation of Abatacept?
intravenous infusion over 30 minutes (once every 2 weeks x 3, followed by monthly infusions)
Adverse effects of Abatacept?
Injection site irritation / allergy/ hypersensitivity reaction
Modest increase in risk for infection
What is the Rheumatoid arthritis regimen for latent TB positive patients?
start anti-TB drugs 1 month before biological DMARDs and JAK inhibitors
What combo of bDMARDs are not recommended?
Do not combine:
T- cell co-stimulation modulator (Abatacept)/ B cell cytotoxic agent (rituximab)/ IL-1 receptor antagonist (anakinra)
+
TNF- a blocking agent (etanercept)
TNF - a blocking agents must not be given with any other bDMARDs, only give alone or with IL-6 receptor antagonist
Why are certain combos of bDMARDs not recommended?
Massive decrease in pro-inflammatory cytokines = cannot vasodilate or express adhesion molecules = Huge increase in risk of infection
List 4 general adverse effects of bDAMRDs?
- Increase risk of infection
- GI disturbances
- Bone marrow suppression + hematologic toxicity
- Allergy/ Hypersensitivity reaction/ Injection site irritation
3 Precautions before administering bDMARDs?
Must screen for latent TB
NO live vaccines when on bDMARDs
Must not combo TNF-a blocking agent with other bDMARDs
No bDMARDs are allowed for pregnant woman
Name one group of tsDMARDs and give 2 examples of these drugs?
Targeted Synthetic DMARDs (tsDMARDs)
Janus-Activated Kinase Inhibitors
Tofacitinib: more specific for JAK1, 3
Baricitinib: more specific for JAK1, 2
MoA of JAK inhibitors?
binds to ATP binding site of the catalytic domain of JAK
> inhibit Janus-activated kinase (JAK)
> DECREASE SIGNALLING BY IL-6, IFN*****
> cytokines cannot activate immune cells to produce further pro-inflammatory signals = decrease joint damage
When is JAK inhibitor chosen for treating RA?
Indicated for patients with inadequate responses to one or more DMARDs
orally bioavailable
Precautions of JAK inhibitors?
1) INFECTION RISK, particularly for herpes virus
2) SKIN CANCER RISK
3) Increase plasma level of liver enzymes, lipoproteins
4) GI perforation
5) BONE MARROW TOXICITY:
Potential risk of anemia, leukopenia, neutropenia, lymphopenia and thrombocytopenia (many hematopoietic growth factors affected through JAK pathway)
