[M4] Rheumatologic Drugs

Rheumatology

Encompasses drugs for disorders affecting the musculoskeletal system (joints, bones, muscles, cartilages)

Rheumatologic Disorders

Disorders affecting the musculoskeletal system and is associated with autoimmune, degenerative, and inflammation presentations

Inflammation

Non-specific immune response against an adverse stimulus (e.g., microbial invasion, physical injury) which occurs for protection and as part of the healing process

Calor

One of the cardinal signs of inflammation referring to heat

Rubor

One of the cardinal signs of inflammation referring to redness

Tumor

One of the cardinal signs of inflammation referring to swelling

Dolor

One of the cardinal signs of inflammation referring to pain

Functio laesa

One of the cardinal signs of inflammation referring to loss of function

Autoimmune Diseases

Arise from overreactive immune responses from the B and T cells which normally target substances foreign to the body, now targeting body cells instead

Rheumatoid Arthritis

Chronic autoimmune disorder characterized by inflammation affecting the synovium with bone erosion; (+) hand deformities

Young women

Rheumatoid Arthritis is more common in:

Symmetrical polyarthritis

RA is described to be an inflammation affecting both sides and occurring in multiple joints

> 30 mins

Morning stiffness in RA

Rheumatoid Factor

Diagnosis of RA

Osteoarthritis

Degenerative non-inflammatory disease; "Wear and Tear," it affects the weight-bearing joints, and is regarded as the most common joint disease

Age, Recreational Activities, Obesity

Risk factors for osteoarthritis

< 30 mins

Morning stiffness of OA

Systemic Lupus Erythematosus

SLE, "lupus," an autoimmune disease which is more common in women characterized by a butterfly rash in the face; (+) photosensitivity, renal complications

Nephritis

Most common renal complication of SLE

Malar Rash

Cutaneous presentation of Acute SLE

Discoid Rash

Cutaneous presentation of Chronic SLE

Antinuclear Antibodies, Anti-Double Stranded DNA

Diagnosis of SLE

Ankylosing Spondylitis

An autoimmune disease which is more common in males, characterized by fusion of spine - "bamboo spine"

Enthesitis

Inflammation in the spinal enthesis

Sacroilitis

Inflammation of the sacroiliac joint

Gouty Arthritis

Metabolic disorder that results in excessive uric acid production, increasing the total body stores

Podagra

Acute monoarticular arthritis

Phenacetin, Paracetamol

Para-Aminophenol Derivatives Non-Narcotic Analgesics

Phenacetin

A prodrug of Acetaminophen; withdrawn due to nephrotoxicity, and methemoglobinemia

N-acetyl-para-aminophenol, N-(4-hydroxyphenyl)-acetamide

Paracetamol/Acetaminophen is AKA:

Weak PG inhibitor, reversible COX inhibitor

MOA of Paracetamol

Category B, Class I

FDA Pregnancy Category & BCS Class of Paracetamol

1st line vs Osteoarthritis, Substitute for Aspirin as antipyretic

Indications of Paracetamol

Hepatotoxicity

Toxic effect associated with the excessive use of paracetamol which rarely happens but a pre-existing liver DSE predisposes the patient and with concomitant use of CYP1A2, the oxidative action is increased

N-acetyl-para-benzoquinoneimine

Toxic metabolite of Paracetamol obtained from its oxidation

4 g/day

Toxic Dose of Paracetamol

15 g/day

Lethal Dose of Paracetamol

10-15 mg/kg/day (children), 500 mg/kg/day (adult)

Therapeutic Doses of Paracetamol

Tylenol, Panadol, Tempra

Proprietary Names of Paracetamol

Nabumetone

All NSAIDs are weak acids, EXCEPT:

Ketone prodrug

Nabumetone is a () which gets converted into acetic acid.

Non-Steroidal Anti-Inflammatory Drugs

Act by inhibition of cyclooxygenase in the prostaglandin synthesis pathway; most are nonselective (COX1 > COX2) which results in GI bleeding (in excessive and continual doses)

Cyclooxygenase (COX) 1

Isoform of COX that is a constitutive enzyme and is responsible for the homeostatic functions; it is impt for housekeeping and protection vs gastric acid and in renal vasodilation (it improves filtration rate)

Cyclooxygenase (COX) 2

Isoform of COX that is an inducible enzyme and is only activated in times of injury or infection through which the prostaglandins for inflammation are formed

Acetylsalicylic Acid

Aspirin, the prototype of NSAIDs, is AKA:

Irreversible COX inhibition

MOA of Aspirin

<600 mg/day Aspirin

Indicated for analgesia

3.2-4.0 kg/day Aspirin

Indicated for inflammation

0.3-1.2 g/day

Indicated for fever; it inhibits responses of interleukin-1, an endogenous pyrogen

NMT 325 mg/day Aspirin

Antiplatelet activity; used as blood thinner; achieved through the inhibition of thromboxane which is an impt pro-aggregant in clotting formation (inc. risk of bleeding)

NSAID-Induced Bronchial Asthma

Occurs due to the inhibition of the COX pathway, leading to an increased production of leukotrienes; this manifests as:

Zileuton

LOX Inhibitor

Zafirlukast, Montelukast

Leukotriene Receptor Antagonists

Aspirin, Tolmetin, Salicylates

Contraindicated in gout px taking uricosurics due to decreased renal excretion of urates at doses < 2 g/day

Salicylism

Mild CNS effect of Aspirin characterized by tinnitus, hyperthermia, hyperventilation

Acid-Base Imbalances, hallucinations

Severe CNS effects of Aspirin

Respiratory Depression

Fatal CNS effect of Aspirin

Reye's Syndrome

Characterized by encephalopathy and hepatitis; occurs in children who took aspirin while recovering from a viral infection

Decreased glomerular filtration rate

NSAIDs can interfere with the afferent arteriole resulting in renal vasoconstriction, resulting in their nephrotoxic effects which is characterized by:

5-aminosalicylate

5-ASA or Mesalamine (R); used in the mgt of Inflammatory Bowel Disease

Diflunisal

Salicylate that is also an analgesic, antipyretic, and anti-inflammatory

Methylsalicylate

Salicylate that is applied topically

Phenylbutazone, Dipyrone

NSAIDs that are pyrazolone derivatives which have already been withdrawn due to their toxic effects

Agranulocytosis, Thrombocytopenia, Aplastic Anemia

Hematoxicities caused by pyrazolone derivatives

Aplastic Anemia

Most serious blood dyscrasia wherein there is depleted RBCs, WBCs, and platelets count

Acute tubular necrosis, Anasarca, Nephrotic Syndrome

Nephrotoxicities caused by pyrazolone derivatives

Anasarca

Massive edema

Nephrotic Syndrome

Massive albuminuria (proteinuria)

Indomethacin

NSAID of Indole Derivative; used in the treatment of Patent Ductus Arteriosus and mgt of Bartter's Syndrome

Gel topical preparation

Indomethacin is an NSAID indicated for acute gout and is employed as:

Sulfinpyrazone

A pyrazolone derivative but is not an NSAID, it is used as a uricosuric agent in the mgt of chronic gout

Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen

Propionic Acid derivatives which possess an analgesic and anti-inflammatory activity

Ibuprofen, Naproxen

Propionic Acid derivatives with an additional antipyretic activity

Ibuprofen

Has the shortest T1/2 and is safe for children (available in suspension preparation)

Naproxen

DOC for fever of malignancy; when the patient is unresponsive to the first-line antipyretics and only responds to this propionic acid derivative

True Phenylacetates, Acetic Acid Derivatives

Phenylacetic Acid Derivatives are subdivided into two subgroups

Sulindac, Alclofenac, Diclofenac

True Phenylacetates

Sulindac

A sulfa- drug which poses a risk for blood dyscrasias and skin-related toxic effects

Stevens-Johnson Syndrome - Toxic Epidermal Necrolysis

In the skin, Sulindac can cause:

Diclofenac

Available in K salt or Na salt form

Cataflam

Diclofenac Potassium

Voltaren

Diclofenac Sodium

Pharmaceutical Alternatives

Cataflam and Voltaren are:

Ketorolac, Etodolac, Nabumetone

Acetic Acid Derivatives

Ketorolac

Used in the tx of acute post-operative pain

Nabumetone

Ketone prodrug NSAID

Mefenamic Acid, Meclofenamic Acid, Flufenamic Acid

Fenamic Acid Derivatives which possess only analgesic property; must not be given to children under 14 years old

Piroxicam

Oxicam Derivative NSAID which has the longest half-life and the highest risk for GI bleeding

Tolmetin

Pyrrole Alkanoic Acid Derivative NSAID that is contraindicated in gout as it antagonizes the effect of uricosurics

Meloxicam

Preferentially COX-2 selective NSAID

Celecoxib, Etoricoxib

Highly COX-2 selective NSAID whose advantage is less GI effects

Acute thrombotic effects

T/E of Selective COX2 inhibitors

Rofecoxib

COX-2 inhibitor withdrawn due to cardiovascular risk (stroke)

Valdecoxib

COX-2 inhibitor withdrawn due to cardiovascular risk (MI)

Narcosis

Condition marked by stupor and insensibility caused by narcotic analgesics

Mimicry of endogenous opioid peptides

MOA of Direct, Mixed-Acting Opioid Agonists

Increase opioid peptides

MOA of Indirect, Mixed-Acting Opioid Agonists

Mu, Kappa, Delta Receptors

Opioid Receptors

Mu Receptors

Responsible for majority of opioid activity; non-selective

Kappa Receptors

Receptor whose activation provides an additional analgesic effect for women; Enkephalins possess the highest affinity to this receptor