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MSK Pharmacology Flashcards

1
Q

DMARD Therapy

A

Disease Modifying Antirheumatic Drugs (DMARD) are a group of medications
that are used to suppress the body’s overactive immune and/or inflammatory
systems. When use in diseases like Rheumatoid Arthritis and other autoimmune
disease, DMARD Therapy can help to:
● Decreases pain and inflammation
● Reduce or prevent joint damage
● Preserve the structure and function of joints

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2
Q

DMARD Therapy Types include:

A

● Synthetic / Traditional DMARDs
○ Nonspecific targeting (Systemic)
● Biologic and small molecule DMARDs
○ Genetically engineered drugs that block cytokines
○ Specific targeting

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3
Q

Methotrexate (MTX) - Folate Analogue MOA

A

○ MTX is a folate analogue that enters cells via a
reduced folate carrier (RFC). Once inside the cell
MTX:
■ Inhibits dihydrofolic acid reductase
■ Inhibits purine and thymidylic acid synthesis;
which interferes with DNA synthesis, repair,
and cellular replication
○ These processes result in antiinflammatory and
antiproliferative (immunosuppressive) effects

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4
Q

Methotrexate (MTX) indications

A

○ Rheumatoid Arthritis, Rheumatoid Arthritis - Related Conditions (Felty’s Syndrome, Large
Granular Lymphocyte Syndrome), Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Systemic
Lupus Erythematosus, Vasculitis, Inflammatory Myopathies
■ PEARL: MTX works better on peripheral joints and not axial. It can help with skin
issues, but typically is used to help with joints.
○ Other Rheumatic Diseases: Systemic Sclerosis, Corticosteroid-Resistant Multisystem
Sarcoidosis, Inflammatory Ocular Disease, Multicentric Reticulohistiocytosis

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5
Q

Methotrexate (MTX) side effects

A

○ Increased liver enzymes, Drowsiness, fatigue, malaise, alopecia (≤10%), diarrhea
(≤11%), nausea and vomiting (3-10%), skin rash (≤3%), stomatitis (2-10%),
anemia (macrocytic), URI
■ Folic acid, minimum 1 mg daily, is given with MTX to help alleviate side
effects (e.g. nausea, mouth sores)
■ Leucovorin (rescue therapy) can also be given to help with side effects

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6
Q

Methotrexate (MTX) and pregnancy

A

○ Category X (Contraindicated), reliable birth control must be in place

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7
Q

Hydroxychloroquine (Plaquenil) - Antimalarial MOA

A

○ Postulated immunomodulatory and
anti-inflammatory properties via increased pH of
cytoplasmic vesicles. Antimalarials also have
inhibitory effects on pro-inflammatory cytokines.
■ The precise MOA in rheumatic diseases is
unknown.

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8
Q

Hydroxychloroquine (Plaquenil) Indications

A

○ Rheumatoid arthritis, Systemic Lupus Erythematosus, Discoid Lupus, Sjogren’s

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9
Q

Hydroxychloroquine (Plaquenil) PEARL

A

Plaquenil can help with rashes and peripheral arthritis (mild to
moderate) - more severe arthritis may require MTX or Imuran

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10
Q

Hydroxychloroquine (Plaquenil) and Pregnancy

A

○ Category C, may be helpful preventing neonatal lupus

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11
Q

Hydroxychloroquine (Plaquenil) Side effects

A

○ Retinal toxicity (greatest concern), agranulocytosis (less common),
hepatic failure (rare), hepatic insufficiency (rare)

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12
Q

Sulfasalazine - 5-Aminosalicylic Acid Derivative MOA

A

○ Although Sulfasalazine has been
shown to possess multiple
anti-inflammatory and
immunomodulatory properties, the
exact MOA in rheumatic disease is
unknown

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13
Q

Sulfasalazine Indications

A

○ Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Reactive
Arthritis, Inflammatory Bowel-Related Arthritis, Juvenile Inflammatory Arthritis

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14
Q

Sulfasalazine PEARL

A

Sulfasalazine can help with peripheral arthritis, and also axial arthritis to a degree

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15
Q

_____ can be used in moderate to severe Rheumatoid Arthritis where
biologics cannot be given, or insufficient insurance coverage, and can be
similarly effective as the addition of MTX + Biologic in certain patients.

A

Triple therapy

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16
Q

Combination Therapy options

A

○ MTX + Hydroxychloroquine
○ MTX + Biologic
○ MTX + Small molecule
○ MTX + Hydroxychloroquine + Sulfasalazine (Triple therapy)

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17
Q

Leflunomide (Arava) - T-cell Antiproliferative MOA

A

○ Anti-inflammatory and
immunomodulatory effects (reduction
in T lymphocytes)
■ Exact mechanism unknown
■ Long half-life (avg 15.5 days)
● Can remain in the blood for
2-3 years

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18
Q

Leflunomide (Arava) Indications

A

○ Rheumatoid arthritis
○ Other rheumatic diseases: Systemic Lupus Erythematosus, Psoriatic arthritis,
Ankylosing Spondylitis (effective on peripheral arthritis, but not on axial
improvement), Granulomatosis with Polyangiitis, Juvenile Idiopathic Arthritis

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19
Q

Leflunomide (Arava) and Pregnancy

A

○ Category X (Contraindicated), preferably no risk of pregnancy when used as
Arava can remain in the blood for 2-3 years

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20
Q

Due to its long half-life, if the _____ needs to be stopped it is washed out using charcoal or cholestyramine.

A

Leflunomide

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21
Q

Minocycline MOA

A

○ Inhibits bacterial protein synthesis
by binding with the 30S and
possibly the 50S ribosomal
subunit(s) of susceptible bacteria;
cell wall synthesis is not affected.

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22
Q

Minocycline Indications

A

○ Rheumatoid Arthritis (Off Label), Acne, Cellulitis, Chlamydia, Gonorrhea,
Syphilis, Leprosy

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23
Q

Minocycline side effects

A

● Minor side effects:
○ Pruritus, Urticaria, Dizziness, Fatigue, Malaise, Drowsiness, Arthralgia,Tinnitus
● Major side effects:
○ Autoimmune syndromes: drug induced lupus, hepatitis, and vasculitis autoimmune syndromes have been reported (the medication is discontinued if these occur)

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24
Q

Azathioprine (Imuran) MOA

A

○ Decreases synthesis of purine
nucleotides

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25
Azathioprine (Imuran) Indications
○ Rheumatoid Arthritis, Systemic lupus erythematosus, Dermatomyositis, Polymyositis, MCTD, Sarcoidosis, Vasculitis (GPA, Takayasu, Polyarteritis nodosa - off label), Sjogren’s, Pericarditis
26
TNF Inhibitors - Adalimumab (Humira) MOA
○ Human anti-TNF IgG 1 κ monoclonal antibody ■ Neutralizes biologic activity by binding to soluble and transmembrane TNF-�
27
Indicated for Uveitis
TNF - Inhibitors - Adalimumab (Humira)
28
TNF Inhibitors - Etanercept (Enbrel) MOA
○ Recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR-𝛂) linked to the Fc portion of human IgG1
29
Etanercept (Enbrel) - TNF Inhibitor PEARL
● NOT effective in treating uveitis (Humira and other TNF Inhibitors are more effective)
30
TNF Inhibitors - Infliximab (Remicade/Renflexis) MOA
○ Chimeric monoclonal antibody that binds to human tumor necrosis factor alpha (TNFα) ■ Renflexis is biosimilar
31
TNF Inhibitors - Infliximab (Remicade/Renflexis) PEARL
Infliximab is typically more effective for Enteropathic arthritis and GI related autoimmune disease
32
Infliximab (Remicade, Renflexis) - TNF Inhibitor PEARL
● Infliximab can be used to treat Kawasaki’s disease refractory to IVIG ● Pregnancy: Category B
33
Certolizumab pegol (Cimzia) - TNF Inhibitor and Pregnancy
○ Placental transfer is minimal due to lack of functional Fc fragment.
34
Abatacept (Orencia) - T-cell Therapy MOA
○ Selective costimulation modulator; inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86 on antigen presenting cells
35
Abatacept (Orencia) - T-cell Therapy PEARL
● No increased risk of congestive heart failure or non-melanomatous skin cancers (Squamous cell or Basal cell carcinoma)
36
Rituximab (Rituxan) - B-cell Therapy (anti-CD20) MOA
○ monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes. ■ Biosimilar: Truxima
37
Rituximab (Rituxan) - B-cell Therapy (anti-CD20) Side effecs
○ Serious infection, Bowel obstruction, Bowel perforation, Stevens-Johnson Syndrome, Cytopenias, Hepatitis B reactivation ○ NEW: eliminates efficacy of COVID-19 vaccines - Therefore medications like Evusheld (monoclonal antibody) are currently being used
38
Tocilizumab (Actemra) - IL-6 receptor antagonist Indications
Giant cell arteritis, Rheumatoid arthritis, Cytokine release syndrome
39
Sarilumab (Kevzara) - IL-6 receptor antagonist Indications
○ Rheumatoid Arthritis, Polymyalgia Rheumatica, COVID-19 (Hospitalized patients)
40
Black Box Warning for JAK Inhibitors: Small molecule “Jakinibs”
Increased risk of blood clots in susceptible patients
41
Biologic DMARD Therapy side effects
● Minor side effects: ○ Infection, Headache, Injection site reaction, Rash ● Major side effects: ○ Reactivation of TB, **Serious Infection**, Reactivation of Hepatitis B, Malignancy (e.g. increased risk for Lymphoma, Cytopenias
42
Alcohol Use and DMARD Therapy
○ Avoided in patients using MTX as concomitant use can irritate the liver ■ Patients that cannot give up alcohol should be started on a different therapy
43
Steroid MSK indications
- Osteoarthritis - Inflammatory Arthritis (eg. RA) - Gout, Pseudogout
44
Contraindications for steroid injections
- Do not inject Septic Arthritis/Bursa etc. - Can present similar to non-septic inflammation - Do not inject fractures - Do not inject prosthetic joints (eg.s/p TKA) - Do not inject through cellulitis - Do not inject into a tendon - Caution with diabetes
45
Side Effects with steroid injections
- Localized pain - Facial flushing - Skin depigmentation - Fat atrophy - Tendon weakening/ rupture - Routine injections linked to decrease chondrocytes, maybe the anesthetic? - Possible joint infection
46
Contraindications for steroids in general
- Active serious infection - Systemic fungal infections - Bacteremia - Cerebral Malaria - TB infections - Psoriasis - Use shortest duration possible, and consider co-morbid conditions: diabetes, HF, osteoporosis, etc
47
Side Effects of steroids
- Many exist In relationship to bone and long term use - Osteoporosis which increase risk of fractures - Osteonecrosis - suppressed osteoblastic activity - Myopathy - muscle breakdown
48
Glucocorticoid Therapy and Psoriatic arthritis
○ Glucocorticoid therapy is generally avoided due to an increased chance of developing erythroderma or pustular psoriasis. ○ If glucocorticoid therapy is necessary, higher doses are generally required.
49
Glucocorticoid Therapy and RA
○ RA is sensitive to glucocorticoids. A dose of prednisone 10 mg daily can be beneficial to patients (15 mg daily with medium and large joint involvement, rarely 20 mg). ○ It should also be noted that prednisone may need to be withdrawn to identify disease
50
Glucocorticoid Therapy and Polymyalgia Rheumatica
○ Oral prednisone starting at an initial dose of 15-20 mg daily then weaning slowly by 1 mg every once every month. ■ Coverage with a bisphosphonate or other medications for osteoporosis prophylaxis is generally recommended.
51
Prednisone MOA
○ Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability and suppressing the immune system by reducing activity and volume of the lymphatic system
52
Prednisone Side effects
○ Cushing’s syndrome, Osteoporosis, Avascular necrosis of bones, Pathological fracture, Tendon rupture, Steroid myopathy, Wound healing impairment
53
Glucocorticoid Joint Injection Medications:
● Kenalog / Triamcinolone Acetonide (40 mg/mL) ○ Used in large joints, more necrotic to skin (used for deeper injection) ● Depo-Medrol / Methylprednisolone (80 mg/mL) ○ Used in small joints, less necrotic to skin (used for more superficial injections)
54
An increased FRAX score is indicated by:
○ >20% 10 year risk for a major osteoporosis related fracture ○ >3% risk for a hip fracture
55
Bisphosphonate - Alendronate MOA
○ Inhibits the rate of bone resorption by acting on osteoclasts or on osteoclast precursors
56
Alendronate Side effects
○ Osteonecrosis of the jaw, Atypical femur fracture, Erosive esophagitis, Esophageal ulceration, Esophageal perforation, Hypersensitivity reaction, Symptomatic hypocalcemia
57
Monoclonal Antibody (Prolia / Denosumab) indications
○ Osteoporosis/bone loss, ■ The duration of use is not established. If fracture risk remains high after 5 to 10 years of therapy and alternative therapy is considered. There are no data on use beyond 10 years ○ Bone metastases from solid tumors, Giant cell tumor of bone, Hypercalcemia of malignancy, Multiple myeloma
58
Anabolic Agents: Romosozumab (Evenity) side effects
○ Arthralgia, Increased risk of MI and CVA, Peripheral edema, Insomnia, Rash, Headache
59
Prostaglandins (PGH2) function and NSAIDs
- Formed when arachidonic acid is converted by COX enzyme to PGH2 - Released from mast cells, granulocytes, basophils - NSAIDs block prostaglandin biosynthesis by inhibiting cyclooxygenase enzyme (COX)
60
NSAIDs MOA
NSAIDs are a group of medications with differing chemical structures, but all share the property of blocking prostaglandins. This occurs through inhibiting the activity of the enzyme PG G/H synthase (PGHS), which is also called cyclooxygenase (COX).
61
NSAID Indications
- Anti-Inflammatory - Analgesics- impeding PGE2 - Antipyretic- impeding PGE2 synthesis - Can be given topically
62
NSAID side effects
- Dyspepsia - Peptic ulcers- common cause of GI bleeds - Risk of heart attack and stroke - Fluid retention- loss of renal prostaglandins - Asthma- has been associated with acute flares - Nephrotoxic- loss of vasodilatory effects of renal prostaglandins - Hepatotoxic- with long-term use, monitor Liver enzymes - Delayed or nonunion- Fracture healing
63
the original NSAID
Aspirin
64
Aspirin Indications
- Pain/ Fever- role has significantly diminished overtime - Acute Coronary Syndrome - CVD risk reduction - TIA/ CVA risk reduction - Decreased incidence of cancer with daily ASA use. (Colon cancer)
65
Aspirin side effects
- Bleeding - Ecchym - Anaphylaxis - Angioedema - Bronchospasm - Nephrotoxicity - Hepatotoxicity - Salicylism - Reye Syndrome
66
Ibuprofen uses
- Anti-inflammatory - Analgesic - Oral - IV - Topical - Can be used for patent ductus arteriosus - Antagonizes the anti-platelet effect of ASA
67
Ketorolac Uses
- Short term analgesic - Used to replace opiates as an injectable - Can be given IV IM Oral- more rare Renal toxicity with chronic use
68
Indomethacin (Indocin) uses
- Often used for gout - NSAIDs inhibit urate crystal phagocytosis - Inhibiting inflammatory response - Potent non-selective NSAID - Similar side effects to other NSAID - Pancreatitis - Can be used for patent ductus arteriosus
69
Meloxicam uses
- Preference for COX-2 at lower doses - Not as selective as Celecoxib - Fewer GI side effects - Although all NSAID warnings still apply
70
Celecoxib uses
- Attempt to not mess with the “housekeeping” of COX-1 - Less GI side effects - Can still be nephrotoxic - Potentially higher risk of CVD compared to other NSAIDs
71
Black Box Warning for NSAIDS
- “The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.” - “NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease” - Increased risk of serious or potentially fatal GI adverse events. Increased bleeding, peptic ulcer, perforation.
72
All patients should be screened for _____ prior to administration of NSAIDs
cardiovascular, gastrointestinal, and renal diseases
73
NSAIDs contraindications
● For high risk patients with cardiovascular disease, GI ulcers, or renal disease consider an alternative therapy like Acetaminophen. ● If NSAIDs need to be used consider the addition of a PPI, misoprostol, and elimination of H. pylori when necessary. ● Avoid concomitant use of NSAIDs with corticosteroids (increased risk for GI ulceration).
74
Non-Opioids Analgesics indications
- Analgesic effects - Antipyretic agent - Headache - Postpartum pain - No effect on uric acid - Not effective for RA - No platelet inhibiting effect
75
Non-Opioids Analgesics side effects
- Elevated liver enzymes with therapeutic dose (Adult max 4gm/day) - Caution in liver disease - Anemia - Allergic Reactions or Steven Johnsons has occurred
76
Capsaicin
(Non-Opioids Analgesics) - Chili pepper extract - Used as a counter irritant - Reduces pain by desensitizing the afferent axons - Induces release of substance P - a chemomediator of pain - With repeated use Capsaicin depletes the neuron of substance P - Topically used, although oral preparation exist - Wash your hands after use
77
Non-Opioids Analgesics Indications
- Neuropathic pain - Postherpetic neuralgia - Osteoarthritis - Musculoskeletal pain - Pruritus
78
Non-Opioids Analgesics side effects
- Dermatologic - Localized skin irritation, Rash, Pruritus - Nausea - Nasopharyngeal irritation - Coughing, eye irritant - Hypertension
79
Neuromuscular blocking drugs
- Used in surgery or for sedation - eg. Succinylcholine, Pancuronium - Not covered during this learning unit
80
Antispasmodics
- Meant to improve clinical spasticity - Inhibits the stretch reflex arc - Majority cause sedation, potential for abuse - Benzodiazepine, Baclofen, Cyclobenzaprine, Carisoprodol, etc
81
Muscle Relaxants
Cyclobenzaprine (Flexeril) - Prototype Drug - Carisoprodol (Soma) Schedule IV - Metaxalone (Skelaxin) - Methocarbamol (Robaxin)
82
MOA of the antispasmodics
- Not completely defined - Inhibits stretch reflex arc, centrally acting - Medication used for local muscle spasm - Cyclobenzaprine is related to TCA - Meant for treatment of localized tissue trauma and muscle strains - Currently on FDA watch list for possible relationship to serotonin syndrome
83
Muscle Relaxants indications
- Skeletal muscle spasm - Fibromyalgia - Musculoskeletal pain
84
Cyclobenzaprine
- Related to tricyclic antidepressants - Presumed to be helpful with - muscle injury and inflammation - reduce muscle hyperactivity - Antimuscarinic side effects - Dry mouth, ileus, tachycardia, mydriasis, confusion - Overdoses do occur- tachycardia, seizures - Hepatic Metabolism- CYP1A2
85
Carisoprodol (Soma)
- Often referred to as a sedative - Schedule IV - Abuse potential - Withdrawls after discontinuation - Anxiety, tremors, muscle twitching - Also has antimuscarinic side effects - Hepatic Metabolism- CYP2C19
86
Muscle Relaxants Side effects
- Antimuscarinic effects- all have some - Drug interactions- there is a lot - Avoid use with alcohol and sedatives - Confusion - Do not drive or operate machinery - Abuse potential - Avoid long term use - Given these and contraindications, these become tricky medications to use
87
Drugs for Gout flare
○ NSAIDs (Indomethacin - Classical treatment)/Naproxen/Other NSAIDs, Intra-articular steroids, Systemic Glucocorticoid (Prednisone), Adrenocorticotropic Hormone
88
Drugs for Gout - Long term
○ Allopurinol (Zyloprim), Colchicine (Colcrys), Uloric (Febuxostat)
89
Xanthine oxidase inhibitor: Allopurinol (Zyloprim) MOA
○ Inhibition of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. ○ This medication also acts on purine catabolism and reduces the production of uric acid without disrupting the biosynthesis of vital purines
90
Xanthine oxidase inhibitor: Allopurinol (Zyloprim) Indications
○ Gout treatment (Chronic urate-lowering therapy), Nephrolithiasis (prevention of recurrent calcium or uric acid stones), Tumor lysis syndrome prevention
91
Xanthine oxidase inhibitor: Allopurinol (Zyloprim) side effects
○ Gout (acute), Hypersensitivity reaction, Hepatotoxicity, Agranulocytosis ■ Starting urate-lowering therapy can precipitate acute flares. For this reason colchicine or a NSAID is also started
92
Xanthine oxidase inhibitor: Febuxostat (Uloric) contraindications
○ Concurrent use with azathioprine or mercaptopurine ○ Hypersensitivity ○ History of heart attack
93
Xanthine oxidase inhibitor: Febuxostat (Uloric) side effects
○ Gout (acute), Hepatic insufficiency, Agranulocytosis
94
Colchicine (Colcrys) MOA
○ Disrupts cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils associated with mediating some gout symptoms
95
Colchicine (Colcrys) indications
○ Gout (prophylaxis, acute flare), Familial Mediterranean Fever (FMF) ○ Off label: Behçet syndrome, Epidermolysis bullosa acquisita, Pericarditis, acute or recurrent treatment, Postpericardiotomy syndrome, Sweet syndrome (acute febrile neutrophilic dermatosis)

MSK Exam 4 (6 decks)

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