PHARMA ● PHARMA-THERAPEUTICS SHIFT

NSAIDs, DMARDs, ANTI-GOUT, & NON-OPIOID ANALGESICS 01

Maria Minerva P. Calimag, MD, MSCE, PhD, FPBA, FPSECP 06/09/22

LECTURE OUTLINE 1. PAIN

1. Pain 01 1.1. DEFINITION OF PAIN
1.1. Definition
1.2. 2020 Revised Definition of Pain Notes 1.1.1. DEFINITION (IASP, 1979)
1.3. Classification of Pain
1.4. Common Pain Complaints ● An unpleasant sensory and emotional experience associated with actual
1.5. COX-2 and Sensitization to Pain or potential tissue damage, or described in terms of such damage
1.6. Pre-Emptive Analgesia (International Association for the Study Pain)
1.7. Multimodal Analgesia
1.8. Pre-Emptive Analgesia 1.1.2. REVISED DEFINITION (IASP, 2020)
1.9. Congenital Insensitivity to Pain with Anhidrosis
1.10. Complex Regional Pain Syndrome ● An unpleasant sensory and emotional experience associated with, or
1.11. Prostaglandins resembling that associated with, actual or potential tissue damage.

2. Inflammation 03 ● 📝 A distressing feeling often caused by intense or damaging stimuli

2.1. Cardinal Signs of Inflammation ● 📝 Regarded as a symptom of an underlying condition
2.2. Common Causes of Inflammation ● 📝 Motivates the person to withdraw from a damaging situation
2.3. Types of Inflammation
2.4. Goals of Treatment
● 📝 Protects a damaged body part while it heals
3. Nonsteroidal Anti-Inflammatory Drugs 04 1.2. 2020 REVISED DEFINITION OF PAIN NOTES
3.1. Pharmacokinetics
3.2. Pharmacodynamics 1 ● Pain is always a personal experience that is influenced to varying
3.3. Indications for NSAIDs degrees by biological, psychological and social factors.
3.4. Pharmacologic Actions ○ It is not only subjective.
3.5. Adverse Effects
3.6. Spectrum of COX-2 Selectivity 2 ● Pain and nociception are different phenomena. Pain cannot be
3.7. Aspirin inferred solely from the activity in sensory neurons.
3.8. Non-Acetylated Salicylates ○ Due to the presence of peripheral and central sensitization.
3.9. COX-2 Selective Inhibitors ■ Pain mediators travel through humoral mechanisms and not
3.10. Non-Selective COX Inhibitors through nerve endings. Tra
3.11. Choice of NSAIDs: Its Use and Its Comorbidities ■ Ex. Patient with spinal anesthesia
4. Disease Modifying Anti-Rheumatic Drugs (DMARDs) 08 ● Even after blocking the nerves, anesthesiologists still
4.1. Rheumatoid Arthritis administer anti-inflammatory drugs that counteract the
4.2. DMARDs humoral mechanisms of pain mediators that travel centrally
4.2.1. Prescription of DMARDs and tell the brain of an ongoing inflammation.
4.2.2. Conventional Synthetic DMARDs ● After the effects of local anesthetics are gone, the patient will
(csDMARDs)/Non-Biologicals still not feel any pain.
4.2.3. Combination Therapy with DMARDs 3 ● Through their life experiences, individuals learn pain.
4.2.4. Targeted Synthetic DMARDs/Biologicals
4.2.5. TNF Inhibitors 4 ● A person’s report of an experience of pain should be respected.
4.2.6. IL-12 and IL-23 Blockade ○ Just because we’ve been through a similar painful experience, we
4.2.7. IL-17 Inhibition should invalidate the pain of others (e.g. saying “Di na masakit
4.2.8. Kinase Inhibition ‘yan! Pinagdaanan ko na rin yan!”)
4.2.9. IL-1 Inhibition 5 ● Although pain usually serves an adaptive role, it may have adverse
4.2.10. B-Cell Depletion and Inhibition effects on function and social and psychological well-being.
4.2.11. Co-Stimulation Blockade
4.2.12. IL-6 Inhibition 6 ● Verbal description (“ouch”, “aray!”) is only one of several behaviors
5. Glucocorticoids 13 to express pain; Inability to communicate does not negate the
6. Non-Opioid Analgesics 13 possibility that a human or a nonhuman animal experiences pain
6.1. Acetaminophen ○ Non-verbal
7. Drugs Used in Gout 13 ■ E.g. facial expressions, hand movements, fist clenching
7.1. Anti-Inflammatory Drugs ○ Inability to communicate pain in children may manifest as crying.
7.2. NSAIDs in Gout
7.3. Xanthine Oxidase Inhibitors
7.4. Uricosuric Drugs/Agents
7.5. Uricase
8. APA References 16
9. Freedom Wall 16

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DISCLAIMER: A lot of information in this trans are additional information
coming from the previous trans or book, as some were not included in the
main lecture. You may opt to skip these during your review, when found using
the symbols above.

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 1
 📝
1.4. COMMON PAIN COMPLAINTS
● Neck pain
● Shoulder pain
● Back pain
● Neuropathic pain
● Joint pain
● Migraine
● Despite different symptoms and kinds of pain, a commonality would be:
○ Inflammatory Profile
■ Varies from person to person
■ Can be different in a person at different time periods
○ Unifying Theory of Pain
■ All pain originates with inflammation and the inflammatory response

1.5. COX-2 AND SENSITIZATION TO PAIN

● Peripheral Sensitization
The IASP Revised Definition of Pain ○ COX-2 is expressed following tissue injury
(Source: Pain Management Collaboratory) ○ ○ Prostaglandins produced increase nociceptor sensitivity to pain
The changes in the definition of pain is brought about by the shift of ● Central Sensitization
quantitative research towards qualitative research in conducting pain studies. ○ Peripheral inflammation leads to induction of COX-2 in the CNS
Qualitative methods provide techniques to access the pain experience of ○ Occurs even with complete sensory nerve block, possibly due to a
patients in ways that provide explanation for apparent contradictions and humoral signal
idiosyncrasies that are difficult to access. ■ Even with the use of local anesthetics (e.g. spinal anesthesia), still
administer anti-inflammatory drugs to dampen the pain mediators that
1.3. CLASSIFICATION OF PAIN may still travel centrally through the humoral response
○ Prostaglandins produced by COX-2 in the CNS cause further
1.3.1. DURATION sensitization to pain
● Acute – Pain for less than a month
● Chronic – Pain extends beyond 3 months 1.6. PRE-EMPTIVE ANALGESIA
○ Example: Post-surgical pain ● Timing
■ Starts as an acute pain but may progress into chronic pain if it prolongs ○ Administration of analgesia before a nociceptive stimulus (e.g. before
beyond 3 months
cutting or making incision wounds) reduces the degree of sensitization
■ Reason: Plasticity of the brain
● In the clinical setting, the recommendation is to treat pain immediately. If produced in the CNS and facilities subsequent relief of symptoms
there is an onset of Acute pain, it must be treated promptly. ● Effect: Patient is pain-free through out post operative period
● Never let pain last for a long time or “Huwag tiisin ang sakit” because it can ● Also known as preoperative dosing and preventive analgesia
progress to chronic pain. ○ We preempt pain and give preoperative dosing to prevent chronic pain
○ As to its effect, it is pre-emptive.
ACUTE CHRONIC ○ As to its timing, we give a preoperative dose.
Duration <1 month >3 months ○ As to its goal, it prevents sensitization to pain.

Cause Obvious tissue damage Pain beyond expected period

1.7. MULTIMODAL ANALGESIA
↑ nervous system activity of tissue healing
● Strategy/Technique
Resolution Upon tissue healing -
○ Giving two drugs at the same time
Function Protective Degrades health and function ○ 3L’s
■ Lowest Dose
■ Longest Duration
1.3.2. PATHOPHYSIOLOGY ■ Least Side Effects
● Nociceptive – requires a nociceptive stimulus ○ Synergistic Combination
● Neuropathic – caused by brain spasticity and damage in nervous system ■ Non-opioids: NSAIDs, Paracetamol, COXIBS
■ Opioids: Codeine, Morphine, Fentanyl, Tramadol (weak opioid)
■ Adjuvants: Antidepressants, Anticonvulsants, Corticosteroids, NMDA
NOCICEPTIVE NEUROPATHIC antagonists
Cause Develops in response to a Due to brain plasticity; primary
specific stimulus outside the lesion or dysfunction in the 1.8. PRE-EMPTIVE ANALGESIA
nervous system (e.g. Pinprick, nervous system (e.g. nerve ● Multimodal and Pre-emptive Analgesia Prevents
incision wounds, fire, damage) ○ The algesic flare prior to surgery
chemicals, acids burns) ○ The hyperalgesic states after surgery
Nociceptive Present Absent ■ The feeling where the sickness could be mild, but the pain is great
Stimulus
1.9. CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS
Degree Proportionate to receptor Disproportionate to receptor
stimulation stimulation ● This condition has two characteristics:
○ Inability to feel pain and temperature
○ Decreased or absent sweating (anhidrosis)
1.3.3. LOCATION ■ It is also known as hereditary sensory and autonomic neuropathy type
IV (HSAN IV)
SOMATIC VISCERAL ■ Inability to feel pain may lead to unintentional self injury
■ Inability to cool the body by sweating leads to recurrent, extremely high
Receptor Superficial – skin Internal organs (viscera) and fevers (hyperpyrexia) that may lead to death due to hyperthermia
Location Deep – muscles, joints, and blood vessels ■ There may be an ongoing infection in the body and the patient would
tendons not be aware since they cannot feel pain
Localization More localized due to more Vague; Poorly localized due to ○ There is no treatment for CIPA. Attention to prevent injuries and prevent
density of nerve supply fewer receptors; Responsible infection is necessary
for referred pain ● Inherited as an autosomal recessive pattern
○ Both copies of the gene in each cell have mutations

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 2
 ○ The parents of an individual with an autosomal recessive condition each
carry one copy of the mutated gene, but typically do not show signs and
symptoms of the condition
● Cause is a mutation in the NTRK1
○ This gene encodes the neurotrophic tyrosine kinase receptor
○ A receptor for nerve growth factor (NGF
○ The mutation does not allow NGF to bind properly which cause defects in
development and function of nociceptive reception
○ Nerve biopsies show a lack of small myelinated and unmyelinated fibers
○ COX-2
■ Expressed in certain areas of the kidney and brain
■ Induced in the endothelial cells by laminar shear forces
● Spliced variant of COX-1 has been identified known as COX-3:
○ It has COX like enzymatic activity
○ Known to be involved in pain perception and fever
○ Not involved in inflammation
■ Paracetamol is a selective COX-3 inhibitor

1.10. COMPLEX REGIONAL PAIN SYNDROME CYCLOOXYGENASE ENZYMES

● A rare condition that occurs when a person experiences severe and lasting
pain in a limb Properties COX-1 COX-2
● It could be in the arm/hand or leg/foot Site of Action ● Found in many tissues ● Induced by inflammatory
● Typically occurs after an injury ● Important for homeostasis stimuli at the site of
● So rare that its cause has not yet been determined and is not clearly inflammation
understood
Effects if ● Converts arachidonic acid ● Increases pain,
1.11. PROSTAGLANDINS Activation to inflammatory inflammation
prostaglandins ● Vasodilatory effects
● Prostaglandins, thromboxanes & Leukotrienes are collectively known as ● Maintains renal function ● Blocks platelet clumping
eicosanoids ● Provide integrity to gastric
● Most are produced from arachidonic acid mucosa (cytoprotective)
○ A 20 carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) ● Promotes vascular
homeostasis
● Autocrine effects cause
fever
Effects of ● Decreases swelling, pain ● Decreases pain and
blocking and inflammation inflammation
Effects of ● Damage to renal system ● Prevents protective
blocking for a (acute tubular necrosis vasodilation, allows
Arachidonic Acid prolonged may occur) platelet clumping, which
(Source: ResearchGate.com) period leads to ● Sodium retention, edema, can lead to myocardial
Structural composition of Arachidonic Acid adverse effects increased blood pressure infarction,
like ● Gastrointestinal erosions cerebrovascular
(ulcer) and bleeding accidents
1.11.1 SYNTHESIS OF PROSTAGLANDINS ● Decreases fever
● Prostaglandins have two major actions: Source: Lecture of Doctor Calimag
○ They are mediators of inflammation, stimulate sensory nerve endings and
cause pain
○ They allow the movement of other inflammatory mediators like histamine
and bradykinins to the site of inflammation and aggravate pain 📝
2. INFLAMMATION
● The underlying origin of pain is inflammation
● Local response and protective response whose ultimate goal is to rid the
organism of both the initial cause of cell injury (microbes or toxins) and the
consequences of such injury

2.1. CARDINAL SIGNS OF INFLAMMATION

● Pain
● Heat
● Redness
● Swelling
● Loss of function

2.2. COMMON CAUSES OF INFLAMMATION

● Infective agents - bacteria, viruses, or toxins
● Immunological agents - cell mediated and antigen-antibody reactions
● Physical agents - heat, cold, radiation and trauma
● Chemical agents
Synthesis of Prostaglandins ● Inert materials - foreign bodies
(Source: Lecture of Doc Calimag)
The membrane phospholipids would increase the action of phospholipase A2 2.3. TYPES OF INFLAMMATION
which in turn would increase the production of arachidonic acid as well.
Increase in arachidonic acid would produce prostaglandin H2 which will allow ● Acute Inflammation
this to differentiate into different enzymes, your E2, I2, D2, F2 and TXA2 ○ Short duration
(thromboxane). Prostaglandin E2 works in vasodilation, gastric cytoprotection ○ Lasting for a few minutes, several hours or a few days
and fever. Thromboxane would work in platelet aggregation and ○ Has 1 out of 4 outcomes:
vasoconstriction. ■ Complete resolution
■ Healing by scarring
■ Abscess formation
1.11.2 TYPES OF CYCLOOXYGENASE ENZYMES ■ Progression to chronic inflammation
● Two main types of Cyclooxygenase Enzymes found in the periphery:
○ COX-1 ● Chronic Inflammation
■ Expressed in most normal cells and tissues ○ Longer duration
■ Cytokines and inflammatory mediators that accompany inflammation ○ Causative agent of acute inflammation persists for a long time
which induce COX-2 production
■ Housekeeping enzyme

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 3
2.4. GOALS OF TREATMENT ○ 📝 Parexocib also a prodrug of Valdecoxib
● Highly protein-bound in plasma (typically >95%), usually to albumin.
● Relieve pain
○ 📝 Able to displace other drugs with lower binding capacity
● Reduce inflammation
● Prevent/slow damage
○ 📝 Patients with Hypoalbuminemia or Cirrhosis may have a higher free
serum concentration of the drug
● Improve quality of life
● Most NSAIDS are metabolized in the liver by oxidation and conjugation.
● The medications we should prescribe to patients must be of the lowest
● Most of these drugs are well absorbed, and food does not substantially
dose, can be used for the longest duration with the least side effects (that is
change their bioavailability
why NSAIDs are the most prescribed drugs)
○ Technique in giving drugs: 3Ls (Lowest dose, Longest duration, Least
○ 📝 Acidic nature → easily pass through gastric mucosa
○ Because they are weak acids, they are absorbed in the stomach for as
side effect)
long as they have been disintegrated and dispersed
● Two primary goals in the treatment of patients with inflammatory
■ e.g. Enteric coated drugs are not disintegrated → less dispersion →
response:
less absorption
○ Relief of symptoms and maintenance of function
○ Because they are weak acids they are lipid soluble in the stomach and
○ Slowing or arrest of the tissue damaging process
are therefore absorbed
● Most of the NSAIDS are highly metabolized, some by phase I followed by
3. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS phase II mechanisms and others by direct glucuronidation (phase II) alone.
● Almost all NSAIDs are metabolized by CYP3A or CYP2C families of P450
LIST OF COX INHIBITOR DRUGS enzymes in the liver.
COX-1 Nonselective COX-2 Selective More COX-2 ● Renal excretion is the most important route for final elimination, nearly
Selective COX Inhibitors Selective all undergo varying degrees of biliary excretion and reabsorption
Inhibitors Inhibitors Inhibitors (enterohepatic circulation).
○ First-pass effect
● Acetylsali- ● Acetylsalicylic ● Celecoxib ● Nimesulide ● In fact, the degree of lower gastrointestinal (GI) tract irritation
cylic acid at acid at high ● Etoricoxib ● Etodolac correlates with the amount of enterohepatic circulation
low doses doses ● Valdecoxib ● Medoxicam ○ The longer it stays in the GI tract is dependent on the amount of
● Sulindac ● Diclofenac ● Nabumetone enterohepatic circulation
● Ibuprofen
● Ketoprofen
● 📝 Racemic mixtures
○ Naproxen - single enantiomer
● Flurbiprofen ○ Diclofenac - no chiral center
● Indomethacin
● Piroxicam
● 📝 Found in synovial fluid after repeated dosing
○ Drugs with short half-lives remain the joints longer
● Naproxen ○ Drugs with longer half-lives disappear at a rate proportionate to their
half-lives
● Valdecoxib has been removed from the market because of possible ● 📝 Nonsteroidal, have similar eicosanoid-depressing, antiinflammatory
reaction as steroids
adverse events
○ Usually used for long periods of time ● 📝 As analgesics, NSAIDs are non-narcotic and are used as nonaddictive
alternatives
● Parecoxib (prodrug) is still available because usually the IV formulation is
given only for about 1 to 2 days for post-operative pain ● 📝 Most NSAIDs inhibit the activity of COX-1 and COX-2 , and thereby the
synthesis of prostaglandins and thromboxanes
● Another drug that has been removed from the market is Rofecoxib
○ Also because of adverse cardiovascular effects ● 📝 Main mechanism in providing pain relief:
● Etodolac has the least cardiovascular event in terms of odds ratio ○ Inhibition of formation of PGs and other inflammatory mediators, which is
achieved by inhibiting the enzymes involved in their synthesis
(Phospholipase A, COX enzyme, LOX enzyme)
3.0.1. PHARMACOTHERAPY OF PAIN ● 📝 Most prominent members: Aspirin, Ibuprofen, and Naproxen
● COX-1, not COX-2, is expressed as dominant, constitutive isoform in gastric ○ Cause IgE mediated anaphylaxis
epithelial cells ○ Sometimes not IgE mediated
○ Major source of cytoprotective prostaglandin formation ■ Ibuprofen mediates releases of histamine leading to an anaphylactoid
reaction (pseudo-allergy)
● The inhibition of COX-1 can lead to gastric adverse events that complicate
therapy with tNSAIDs ● 📝 Over the counter medications given to relieve pain and reduce
inflammation
○ This provides rationale for the development of NSAIDs specific for the
inhibition of COX-2 ● 📝 One of the most used medications in adults
○ Important to know its proper dosage and potential side effects
3.0.2. PRODUCTS OF PROSTAGLANDINS
3.2. PHARMACODYNAMICS
● PG12 (prostacyclin) ● NSAID anti-inflammatory activity is mediated chiefly through inhibition of
○ Located predominantly in vascular endothelium prostaglandin biosynthesis.
○ Main effects:
■ Vasodilation
○ 📝 Primary mechanism: inhibition of prostaglandin biosynthesis through
inhibition of cyclooxygenase (COX-2) isoform of arachidonic acid (COX)
■ Inhibition of platelet aggregation
● TXA2 (thromboxane A2)
○ 📝 Via enhanced edema formation and leukocyte infiltration to promote
blood flow to the inflamed area
○ Found in platelets
○ Main effects:
○ 📝 Increased vascular permeability and leukocyte infiltration through
activation of EP2 and IP1
■ Platelet aggregation
■ Vasoconstriction
○ 📝 TXA2 - increased platelet-leukocyte interaction
● Some other mechanisms of action of NSAIDS
● PGE2 ○ Inhibition of chemotaxis
○ inhibition of gastric acid secretions ○ Down-regulation of interleukin-1 production
○ Contraction of pregnant uterus ○ Decreased production of free radicals and superoxide
○ Contraction of GI smooth muscles ○ Interference with calcium-mediated intracellular events
● PGF2a ● Aspirin irreversibly acetylates and blocks platelet cyclooxygenase,
○ Contraction of bronchi while the non-COX-selective NSAIDs are reversible inhibitors.
○ Contraction of myometrium ○ If a patient is on aspirin, there is a chance that the patient may have
■ Which is why NSAIDs are not given during the third trimester of prolonged bleeding during surgery
pregnancy ■ Stop aspirin for 7-10 days before surgery
○ 📝 Stop intake for 1-2 weeks if patient has surgery in order to unblock
3.1. PHARMACOKINETICS platelet COX (may cause bleeding)
● Most nonsteroidal anti-inflammatory drugs are weak acids, except, ○ 📝 Ask for herbal drug intake (has anti-platelet effects) → synergistic drug
nabumetone, which is a prodrug, which is metabolized through acidic interactions
medium

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 4
● Selectivity for COX-1 versus COX-2 is variable and incomplete for the older
NSAIDs, but selective COX-2 inhibitors have been synthesized.
● Selective COX-2 inhibitors may increase the incidence of edema and
hypertension
○ 📝 Patients with increased water retention
■ Post-pregnancy
○ 📝 Contraindications: patients post-eclampsia
■ Increased blood pressure
● Rofecoxib and valdecoxib, selective COX-2 inhibitors, were withdrawn
from the market because of their association with increased
cardiovascular thrombotic events.
○ 📝 Used at high doses in prevention for cancer
○ 📝 Do not give drugs beyond their therapeutic concentrations → toxic
effects
● In 2011, celecoxib and the less selective meloxicam were the only COX-2
inhibitors, which is available in market
○ Etoricoxib, parecoxib, and valdecoxib were introduced much later
● All NSAIDs are gastric irritants and can be associated with GI ulcers
and bleeds as well, although as a group the newer agents tend to cause
less GI irritation than aspirin.
● NSAIDs are also associated with nephrotoxicity, which is due to the
interference with the autoregulation of renal blood flow, which is modulated
by prostaglandins.
○ 📝 NSAIDs can worsen comorbidities of patients with pain (diabetic
nephropathy, gouty nephropathy, hypertensive nephropathy)
○ 📝 Intake of excess NSAIDs
■ Renal shutdown → dialysis or transplant
● Hepatotoxicity can also occur with any NSAID
○ Although these drugs effectively inhibit inflammation
● Several NSAIDs (including aspirin) reduce the incidence of colon cancer
when taken chronically.
○ Reason why rofecoxib ran into major adverse cardiovascular events
■ Usual dose for rofecoxib is 25mg
■ Because of the pharmacodynamic effects of NSAIDs in reducing
familial polyposis, there is a mechanistic effect in preventing familial
polyposis
■ Experimented with rofecoxib at 50mg and 75mg (which is 3x the usual
therapeutic concentration)
■ Result:
● Colon cancer was not prevented but it increased toxicity of rofecoxib
● Patients with low-risk for cardiovascular events were developing
thrombotic events
■ Rofecoxib was withdrawn from the market
● Several large epidemiologic studies have shown a 50% reduction in relative
risk when the drugs are taken for 5 years or longer.
3.3. INDICATIONS FOR NSAIDS
● NSAIDs have a number of commonalities
● Various Indications of NSAIDs by FDA
○ Rheumatoid arthritis
○ Seronegative spondyloarthropathies (ex. psoriatic arthritis and arthritis
associated with inflammatory bowel disease)
○ Osteoarthritis
○ Localized musculoskeletal syndromes (ex. sprain, strain, low back pain)
○ Gout (except tolmetin, which appears to be ineffective in gout)
■ NSAIDs have nephrotoxic effect (“gouty nephropathy”)
■ Treatment with NSAIDs for long periods of time could lead to CKD
3.4. PHARMACOLOGIC ACTIONS
3.4.1. ANALGESIC EFFECTS
OPIATES NSAIDs
Static Pain Dynamic Pain
Target Pain
(Pain At Rest) (Pain On Motion)
Central action in the Peripheral action
Pathway
brain and spinal cord through COX inhibition
3.4.2. ANTIPYRETIC EFFECTS
● Fever may reflect inflection or result from tissue damage, inflammation, graft
rejection, or malignancy
○ All enhance cytokine formation (IL-1B, IL-6, interferons, TNF-alpha)
■ Increase synthesis of PGE2 in circumventricular organs in and
adjacent to the preoptic hypothalamic area
PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD
● PGE2 increases cyclic AMP and triggers elevation of body
temperature via the hypothalamus through these mechanisms:
○ Increase in heat generation
○ Decrease in heat loss
3.4.3. RESPIRATORY EFFECTS
● Salicylates increase O2 consumption and CO2 production (especially in
skeletal muscle) at full therapeutic doses
○ Result of uncoupling oxidative phosphorylation
○ Increased production of CO2 stimulates respiration
○ Increased alveolar ventilation balances increased CO2 production
■ Reason why the plasma CO2 tension (PCO2) does not change or
decreases slightly
3.4.4. ACID BASE AND ELECTROLYTE EFFECTS
● Therapeutic doses of salicylate produce definite changes in the acid base
balance and electrolyte pattern
● DOSE DEPENDENT of salicylate or aspirin
○ Low dose: Stimulation of respiratory center leads to respiratory alkalosis
○ Moderate high dose: metabolic acidosis
○ High dose: Depression of respiratory center leads to accumulation of
CO2 and causes respiratory acidosis
3.4.5. CARDIOVASCULAR EFFECTS
● Low doses of aspirin (<100 mg daily) are used widely for their
cardioprotective effects
○ Reduce thrombus potential
● At high therapeutic doses (> 3g daily), as might be given for acute
rheumatic fever, salt and water retention can lead to an increase (up to
20%) in circulating plasma volume and decreased hematocrit
cardioprotective effects
3.4.6. UTERINE EFFECTS
● Increased levels of PG in menstrual blood flow, endometrial biopsies
and their metabolites is seen in dysmenorrheic women leading to
myometrial ischemia and menstrual cramps
○ Decreased menstrual flow
○ Dysmenorrhea disappears
● NSAIDs lowers uterine PGs and afford relief of menstrual cramps —
menstrual flow also decreases
● Sudden increase in PG synthesis by the uterus triggers labor and
facilitate progression
● NSAIDs delay and retard labor – do not use at term
3.4.7. URICOSURIC EFFECTS
● Effects of salicylates on uric acid excretion are dependent on dose:
○ Low doses (1 or 2g per day): may decrease urate excretion and
elevate plasma urate concentrations
○ Intermediate doses (2 or 3g per day): usually do not alter urate
excretion
○ Large doses (more than 5g per day): induce uricosuria and lower
plasma urate levels
3.4.8. BLOOD EFFECTS
● Patients with severe hepatic damage, hypothrombinemia, vitamin K
deficiency or hemophilia should avoid aspirin because the inhibition of
platelet hemostasis can result in hemorrhage
● Aspirin can cause a mild degree of hemolysis in individuals with a deficiency
of glucose-6-phosphate dehydrogenase
● Anti-platelet aggregation
○ Except COX-2 and non-acetylated salicylates
○ Inhibition of TAX2
3.5. ADVERSE EFFECTS
3.5.1. REYE’S SYNDROME
● Combination of encephalopathy, liver damage, and brain dysfunction
● Can also be due to aspirin in premature infants
(TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 5
 3.7. 📑
ASPIRIN
● Acetylsalicylic acid (ASA)
● Oldest NSAID
● Functions as an analgesic, antipyretic and antiplatelet
○ Reduces the signs and symptoms of inflammation (rarely used today)
and exhibits a broad range of pharmacological activity
○ Antiplatelet property: because of the inhibition of TXA-2 (a potent
vasoconstrictor and platelet activator)
● Introduced by Bayer in 1889
● MOA: irreversible inhibition of COX-1 and COX-2
Reye’s Syndrome ○ Irreversibly inhibits COX1 and alters the enzymatic activity of COX2
(Source: Lecture of Doc Calimag) ● ASA’s antiplatelet action lasts for 8-10 days
● Pharmacokinetics
3.5.2. ACETAMINOPHEN/PARACETAMOL POISONING ○ Simple organic acid, pKa 3.5 absorbed mostly in the ileum
○ Rapidly hydrolyzed in the liver and plasma yielding salicylate
● Medical emergency ● Indications (mainly Cardiovascular)
● Severe liver damage occurs in 90% of patients with plasma concentrations ○ Anti-inflammatory - rarely used today
of acetaminophen greater than 300 g/ml at 4 hours or 45 g/ml at 15 hours ○ Anti-platelet aggregation - decreases the incidence of transient
after ingestion of the drug
ischemic attacks, unstable angina, coronary artery thrombosis with
● Minimal hepatic damage can be anticipated when the drug concentration is
myocardial infarction and thrombosis after CABG
less than 120 g/ml at 4 hours or 30 g/ml at 12 hours after ingestion
● 👉Antidote: N-acetylcysteine (NAC) is indicated for those at risk of
○ Lower doses is associated with decrease incidence of colon cancer
● Contraindications
hepatic injury
○ Pediatric patients on anti-viral treatment
○ NAC therapy should be instituted in suspected cases of
○ Asthmatic patients
acetaminophen poisoning before blood levels become available, with
■ Inhibition of COX pathway increases the substrate available for the
treatment terminated if assay results subsequently indicate that the
LOX pathway → increase production of Leukotrienes →
risk of hepatotoxicity is low
bronchoconstriction
○ Give early even before receiving laboratory results of liver enzymes
● 📑CNS
● Side effects:
○ A: Allergy like reactions
○ Headache
○ S: Susceptibility to bleeding
○ Tinnitus
○ P: Peptic ulcer
○ Dizziness
● 📑 Cardiovascular ○
○
I: Idiosyncratic reactions
R: Reye’s Syndrome/ Post-viral encephalitis
○ Fluid retention ■ Rare but serious condition that results in fatty liver and altered
○ Hypertension
mental status: encephalopathy with hepatic dysfunction
○ Edema
■ Commonly observed in children and teenagers recovering from a
○ Myocardial infarctions
○ CHF (rare) viral illness (ex. Influenza or varicella zoster)
○ Selective COX-2 inhibitors may increase the incidence of edema and ■ Occurs 3-5 days after onset of viral illness with symptoms of
hypertension persistent vomiting, sleepiness, lethargy, and disorientation
● 📑 GIT ■ Labs: elevated ALT, AST, and ammonia
○ I: rInging in the ears (tinnitus)
○ Ulcers
○ Bleeding ○ N: Nephropathy
○ Abdominal pain ○ Other info on side effects of Aspirin:
○ Dyspepsia ■ Therapeutic dose – GIT (GI upset, bleeding)
○ Nausea ■ Large dose – salicylism (tinnitus, deafness, dizziness)
○ Vomiting ■ Toxic dose – uncompensated metabolic acidosis
● 📑 Hematologic (rare)
○ Thrombocytopenia
○ Neutropenia
3.8. 📑 NON-ACETYLATED SALICYLATES
● Magnesium choline salicylate, sodium salicylate, salicyl salicylate
○ Aplastic anemia
● 📑 Hepatic ● Effective anti-inflammatory drugs
○ Anti-inflammatory > Analgesic than ASA
○ Abnormal liver function test
● Does NOT inhibit platelet aggregation
○ Hepatotoxicity can occur with any NSAID
● 📑 Skin ● Uses: preferred when you do not want the effects of COX inhibition
(less effective COX inhibitor):
○ Rashes
○ Patients with asthma
○ Pruritus
● 📑 Renal ○ Those with bleeding tendencies
○ Renal dysfunction
○ Nephrotoxicity is observed for all NSAIDs due to interference with

○
autoregulation of renal blood flow modulated by PGs
Renal insufficiency 3.9. 📑 COX-2 SELECTIVE INHIBITORS
○ Renal failure ● Inhibit inducible COX-2 isoform (decreases inflammation) without having
○ Hyperkalemia a substantial effect on constitutively active “housekeeping” COX-1 isoform
○ Proteinuria found in the GIT, kidneys, and platelets (thereby minimizing toxicity)
● 📑 Pulmonary ● Minimizing gastrointestinal side effects
○ Asthma ● No impact on platelet aggregation
● Does not offer cardioprotective effects
● Can still cause renal toxicities to those associated with traditional NSAIDs
3.6. SPECTRUM OF COX-2 SELECTIVITY
● 📑 Analgesic, antipyretic, and anti-inflammatory effects similar to
Spectrum of COX-2 Selectivity nonselective NSAIDs but having no GIT adverse effects

COX-1 > COX-2

Aspirin
COX-1 = COX-2
Ibuprofen
COX-1 < COX-2
Celecoxib
3.9.1. 📑 CELECOXIB (Celebrex)
Indomethacin, Piroxicam Meclofenamate Etoricoxib ● Selective COX2 inhibitor (10-20 more times selective for COX-2)
Sulindac Mefenamic acid Parecovib ● Approved by the FDA based upon the results of clinical trials involving
Valdecoxib more than 5,000 patients with osteoarthritis and rheumatoid arthritis

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 6
● Half-life: 11 hours
● Associated with fewer endoscopic ulcers than most other NSAIDs •
● Do not affect platelet aggregation at usual doses
● Occasionally interacts with Warfarin – as would be expected of drug
metabolized via CYP2C9
● Adverse reactions: peripheral edema, GI disturbance, increased liver
enzymes
● Allergy because of its sulfa content → Half the GI side effects of
nonselective NSAIDs
● The FDA approved product labeling for medications containing
● Combination of diclofenac and omeprazole was also effective with respect
to the prevention of recurrent bleeding, but renal adverse effects were
common in high-risk patients.
● A 0.1% ophthalmic preparation is promoted for prevention of postoperative
ophthalmic inflammation and can be used after intraocular lens implantation
and strabismus surgery.
● A topical gel containing 3% diclofenac is effective for solar keratoses.
● Diclofenac in rectal suppository form can be considered for preemptive
analgesia and postoperative nausea

●
sulfonamides chemical group.
Patients with prior allergic reaction to sulfonamides should take precaution 3.10.2. 📑 IBUPROFEN (Advil, Alaxan, Dolan)
before taking it due to its sulfa content. ● Most commonly used OTC and prescribed NSAID
○ Widely used as an analgesic, anti-inflammatory, and antipyretic
3.9.2. 📑 ETORICOXIB (Arcoxia) ● Used to manage mild to moderate pain related to dysmenorrhea, headache,
migraine, and postoperative dental pain
● Newer COX-2 selective inhibitor ● Derivative of phenylpropionic acid
● Bipyridine derivative ● Preparation: 200 mg (soft gel or tablet); 100 mg/5 mL oral suspension (q6-8)
● 106 times more selective for COX-2 inhibition than to COX-1 ● A 2400 mg daily dose is equivalent to 4 g of aspirin in antiinflammatory
● Half-life: 22 hours effect
● Bioavailability is 100% after oral administration ● Analgesic dose is given at a lower dose at <1600 mg/day
● Metabolized by hepatic P450 enzymes followed by renal excretion ● Effective medication for closure of the PDA among preterm infants – same
● Used in osteoarthritis, rheumatoid arthritis, chronic low back pain efficacy and safety as indomethacin
● Approved in many countries but not in US ● Lesser effect in urine output and fluid retention as compared with
indomethacin
3.9.3. 📑 MELOXICAM (Mobic) ● Decreases the anti-platelet activity of aspirin
○ Antagonizes the irreversible platelet inhibition induced by aspirin and can
● Enol Carbamide related to piroxicam limit its cardioprotective effects
● It is not as selective as celecoxib and may be considered as “preferentially” ○ Concomitant use with aspirin may also decrease the total
selective rather than “highly” selective antiinflammatory effect
● Half-life: 20 hours (considerably longer than most other NSAIDs) → Can be ● Relatively contraindicated in individuals with nasal polyps, angioedema, and
dosed without the need for slow release formulations bronchospastic reactivity to aspirin
● Although it preferentially inhibits COX-2, it also exerts activity against ● Rare hematologic effects include agranulocytosis and aplastic anemia
COX-1 causing GI irritation
● Associated with fewer clinical GI symptoms and complications than
piroxicam, diclofenac, and naproxen
3.10.3. 📑 INDOMETHACIN
● Known to inhibit TXA2 synthesis; even at supratherapeutic doses, its ● Indole derivative • Discovered in 1963 and made available in 1965
blockade of TXA2 does not reach levels that result in decrease in vivo ● It has antipyretic, analgesic and anti-inflammatory properties
platelet function ● Inhibit phospholipase A and C, reduce neutrophil migration, and decrease T
cell and B cell proliferation
3.9.4. 📑 VALDECOXIB ● Labeled indications for use are mild to moderate pain, ankylosing
spondylitis, bursitis, tendonitis, acute gout flares, osteoarthritis
● Highly selective COX-2 inhibitor ● IV use is for closure of hemodynamically significant patent ductus arteriosus
● Diaryl-substituted isoxazole, no effect on platelet aggregation or bleeding in premature infants
time ● GI side effect may include pancreatitis
● Made available in 2001 in the US to treat arthritis and menstrual cramps ● Headache in 15-25% of patients
● Withdrawn from the market in 2005 due to increased risk of heart attack, ● Renal papillary necrosis
stroke, and sometimes fatal skin reactions ● May cause thrombocytopenia, aplastic anemia, and hyperkalemia
● Patients with sulfonamide allergy should also take precaution before ● An ophthalmic preparation is efficacious for conjunctival inflammation
taking it and to reduce pain after traumatic corneal abrasion.

3.9.5. 📑 PARECOXIB (Dynastat) 3.10.4. 📑 KETOPROFEN (Fastum Gel)

● Water-soluble prodrug of valdecoxib ● Propionic acid derivative that inhibits both COX (nonselective) and
● Administered via IV and available in Europe but not in US lipoxygenase
● (IV or IM) short term use for post-operative pain ● Half-life: 1.8 hours
● Also inhibits platelet aggregation by decreasing TXA2 synthesis
3.10. 📑 NON-SELECTIVE COX INHIBITORS ● Can cause GI upset and ulceration
● Inhibit both types of the COX enzyme
● Associated with an increased risk of gastric ulceration 3.10.5. 📑 KETOROLAC (Toradol)
● Also inhibit platelet aggregation ● Indicated for shorter management of acute pain that requires the caliber
of pain management offered by opioids
3.10.1. 📑 DICLOFENAC (Voltaren, Cataflam) ● Commercially available as an oral tablet, injectable, nasal spray, and as an
ophthalmic solution
● Another NSAID with relative COX- 2 selectivity at recommended doses ● Systemic use mainly as an analgesic, not as antiinflammatory drug
● Phenylacetic acid derivative that is relatively nonselective as a COX inhibitor ● Manage postoperative pain, spinal and soft tissue pain, rheumatoid arthritis,
● Half-life: 1.1 hours osteoarthritis, ankylosing spondylitis, menstrual disorders, and headaches
● Dosage: 50-75 mg qid ● Half-life: 4-10 hours
● GI ulceration may occur frequently than with some other NSAIDs ● Classified as a pregnancy category C drug since there is lack of evidence
● >150 mg/day can impair renal blood flow and GFR demonstrating safety among pregnant women
● May elevate serum transferases ● Given at the lowest possible dose
● Approved in the US for treatment of osteoarthritis, rheumatoid arthritis, and ● Advised to avoid use for an extended period of time (ideally ≤ 5 days)
ankylosing spondylitis ● Ophthalmic preparation for ocular inflammatory conditions
● One of the most commonly used NSAID worldwide for variety of conditions
● A preparation combining diclofenac and misoprostol decreases upper GI
ulceration but may result in diarrhea.

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 7
3.10.6. 📑
MECLOFENAMATE & MEFENAMIC ACID (Ponstan, ○ Chronic kidney disease and disease risk
○ Aspirin-exacerbated respiratory disease
Dolfenal, & Gardan)
○ Chronic liver disease and hepatic cirrhosis
● Members of the anthranilic acid derivatives
● Half-life: 3 hours
4. DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (DMARDs)
● May cause hypersensitivity reaction to some patients
● Also inhibits phospholipase A2 4.1. 📝 RHEUMATOID ARTHRITIS
3.10.7. 📑 NAPROXEN (Flanax, Skelan) ● 📕 Progressive immunologic disease that causes significant systemic
● Initially approved for prescription in 1976 and for OTC (over-the-counter) effects, shortens life, and reduces mobility and quantity of life
use in 1994 ● Chronic systemic inflammatory disorder of unknown etiology that primarily
● Naphthylpropionic acid derivative involves the synovial joints
● Only NSAID presently marketed as a single enantiomer • Half-life: 14 hours ● Arthritis is typically symmetrical and usually leads to uncontrolled
● Effective for the usual rheumatologic indications and is available in a destruction of joints due to erosion of the cartilage and bone, causing joint
slow-release formulation and as an oral suspension and OTC drug deformity
● A topical preparation and an ophthalmic solution are also available ● Bilateral swelling of the MCP joints
● May still cause GI bleeding ● Other features include: mild swan neck deformity present in several fingers
particularly in the middle and 5th fingers
○ Incidence of upper GI bleeding in OTC use is low but still double than
● It can affect the patient’s capacity to perform activities of daily living,
that of OTC use of ibuprofen including those related to his/her job
● Adverse effects: allergic pneumonitis, leukocytoclastic vasculitis, and ● The effects of disease-modifying therapies may take 2 weeks to 6 months to
pseudoporphyria become clinically evident

3.10.8. 📑 PIROXICAM (Feldene, Feldene Flash & Feldene Gel)
● An oxicam, at high concentrations also inhibits PMN leukocyte migration,
decreases oxygen radical production, and inhibits lymphocyte function
● Long half-life: 57 hours (permits it to be given once a day)
● Used for the usual rheumatic conditions
● When used >20 mg/day, it is associated with increased incidence of peptic
ulcer and bleeding (9.5 times higher risk as compared with other NSAIDs)
3.10.9. 📑 SULINDAC
● Sulfoxide prodrug
● Reversibly metabolized to the active sulfide metabolite and has
enterohepatic cycling which prolongs the duration of action to 12- 16 hours
● Used for osteoarthritis, and rheumatoid arthritis
● May suppress familial intestinal polyposis
● Associated with regression of colorectal adenomas in familial
adenomatous polyposis
○ Used in combination with ornithine decarboxylase inhibitor,
difluoromethylornithine (DFMO) for the prevention of adenomas (it
looks like it has synergistic action)
● Inhibit the development of colon, breast, and prostate cancer
● Adverse effects: Stevens-Johnson epidermal necrolysis syndrome,
thrombocytopenia, agranulocytosis, nephrotic syndrome, and cholestatic
liver damage
3.10.10. 📑 NABUMETONE
● Prodrug that upon hepatic catalysis is converted into the active moiety
6-methoxy-2-naphthylacetic acid (6MNA)
○ 6MNA inhibits the activity of COX-1 and COX-2
○ Decreased formation of prostaglandin and thromboxane precursors
○ Minimal activity against COX-2
● Only nonacid NSAID in current use
● Long acting NSAID used for therapy for chronic conditions (e.g. chronic
arthritis)
● Mean half-life: 24 hours (with range of 19-36 hours; permits once-daily
dosing)
● Does not appear to undergo enterohepatic circulation
● Renal impairment leads to doubling of its half-life and a 30% increase in the
AUC
● Higher dosages (1500-2000 mg/d) are often needed
● Very expensive drug
● Causes pseudoporphyria and photosensitivity in some patients
4.1.1. 📝 PATHOGENESIS OF RHEUMATOID ARTHRITIS
● Environmental factors (e.g. infection and smoking) along with susceptibility
genes (HLA-DR4 haplotype) induce T-cell (Th1 and Th17) and B-cell
responses (formation of antibodies directed against self-antigens).
● Lymphocytes, antibodies, and immune complexes then enter the joint.
● Once in the joint, there will be synoviocyte activation, cytokine production,
and inflammation.
● Eventually it will lead to destruction of cartilage and bone.
4.1.2. 📝 TREATMENT
● Directed towards the control of synovitis and prevention of joint injury
● Choice of therapy will depend on
○ Severity of the disease
○ When will the therapy be initiated
○ Response of the patient to prior therapeutic interventions
● Common medications for rheumatoid arthritis include:
○ Glucocorticoids
■ Reserved for temporary control of severe exacerbations and long-term
use in patients with severe disease not controlled by other agents
■ Non-specific immune suppression
■ Rapid systemic disease-modifying effects
■ Its use is too toxic for routine chronic use due to long-term side effects
○ NSAIDs
■ Rapid onset of action
■ Used in acute cases to relieve inflammation and pain
■ Provide partial relief of pain and stiffness (symptom improvement)
■ No influence on disease progression
○ DMARDs
■ Interferes with signs and symptoms of rheumatoid arthritis
■ Target inflammation and prevent further joint damage
■ Its use has a good prognosis
■ It cannot treat any previous deformity present prior to the treatment
4.2. 📝 DMARDS
● Indicated for the treatment of inflammatory arthritis including rheumatoid
arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS)
● Immunosuppressive and immunomodulatory agents
● Arrest the progression of the disease
● Prevent formation of new deformity
○ DMARDs are grouped into biologics and synthetic which is further
divided into conventional and targeted DMARDs.
○ Biologicals are composed of TNF inhibitors, IL-6 inhibitors, B-cell
depletion, and inhibitors of T-cell co-stimulation.

3.10.11. 📑 TOLMETIN 4.2.1. 📝 PRESCRIPTION OF DMARDs

● Non-selective COX inhibitor ● DMARDs should be prescribed as soon as patient is diagnosed with RA
● Short half-life: 1-2 hours • Not often used ● RA should be monitored every 1-3 months
● Ineffective in the treatment for gout ● Treatment should be adjusted if there is no improvement after 3 months or if
the target has not been reached by 6 months
3.11. 📑 CHOICE OF NSAIDs ● According to EULAR recommendations for the management of rheumatoid
arthritis, MTX should be part of first treatment strategy for patients with RA
● When prescribing NSAIDs, the following must be considered:
○ GI diseases
○ CV disease and disease risk

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 8
4.2.2. 📝
CONVENTIONALLY-SYNTHETIC DMARDs (cDMARDs)/ ● Mechanism of Action
○ An antibiotic and non-biologic DMARD
NON-BIOLOGICALS
○ Calcineurin inhibitor (along with FK 506 tacrolimus)
● Methotrexate ○ Regulation of gene transcription
● Cyclophosphamide ■ Inhibits transcription of certain genes in T cells, most notably
● Cyclosporine those encoding cytokines such as IL-1 and IL-2 receptor
● Chloroquine and Hydroxychloroquine
● 📝 Azathioprine
production and secondarily inhibits macrophage-T cell

● 📝 Leflunomide
interaction, and T-cell responsiveness

● 📝 Mycophenolate mofetil
■ T cell-dependent B cell function is also affected.

● 📝 Sulfasalazine
● Pharmacokinetics
○ Erratic absorption
○ Grapefruit increases its bioavailability (62%)
4.2.2.1. METHOTREXATE ■ food-drug interaction (remove grapefruit or reduce dose of drug)
■ It metabolizes Cyclosporine faster than usual
● Anti-metabolite
● 📝 Commonly used for the treatment of patients with rheumatoid arthritis
○
○
Metabolized by CYP3A
Retards the appearance of new bony erosions
and in several forms of inflammatory arthritis and autoimmune diseases 📝Subject to a large number of drug interactions
●
●
First-line csDMARD for treating RA
Used in up to 60% of patients
● 📝 Indications
○ Approve for use in rheumatoid arthritis and retards the appearance of
● Mechanism of Action: Enzyme Inhibition new bony erosions
○ Inhibition of amino-imidazole carboxamide ribonucleotide (AICAR) ○ 3-5mg/kg/day
transformylase and thymidylate synthetase
■ 📝 AICAR inhibits AMP deaminase leading to increase
● 📝 Toxicity
○ Leukopenia, thrombocytopenia, anemia
adenosine
● 📝 Adenosine is a potent inhibitor of inflammation
○
○
High doses can be cardiotoxic, neurotoxic
Prolonged use can result into bladder cancer even after cessation of
● Has an effects on polymorphonuclear chemotaxis use
● Some effect on dihydrofolate reductase (lymphocyte and macrophage in
the inflammatory response)
● Decrease the rate of appearance of new erosions 4.2.2.4.CHLOROQUINE AND HYDROXYCHLOROQUINE
○ 📝 Suppression of the inflammatory, function of neutrophils, ● Mechanism of Action
macrophages, dendritic cells and Lymphocytes ○ Suppression of T-lymphocyte responses to mitogens, inhibition of
● Adverse Effects leukocyte chemotaxis, stabilization of lysosomal enzymes, processing
○ Nausea and mucosal ulcers through the FC-receptor, inhibition of DNA and RNA synthesis, and
■ Most common toxicities the trapping of free radicals
○ Dose-related hepatotoxicity in the form of enzyme elevations but cirrhosis ● Not considered very efficacious DMARDs
is rare (<1%) ● No evidence that it alters bony damage in rheumatoid arthritis
○ Pseudolymphomatous reactions ● Takes 3-6 months to obtain a response
○ GI and liver function test abnormalities reduced by leucovorin or daily folic ● Adverse effects
acid
■ 📝 All patients are required to take folic acid or folinic acid or
○ Ocular toxicity (most common) may occur at doses greater than
250mg/day for chloroquine and greater than 6.4mg/kg/day for
Leucovorin with MTX hydroxychloroquine
○ Contraindicated in pregnancy ○ Ophthalmologic monitoring every 6-12 months is advised.
○ Oral probenecid increases levels of methotrexate sodium injection by
acidic drugs competing for the same pathway through the kidneys
■ If these drugs must be taken together, decrease methotrexate dose 4.2.2.5. 📝 AZATHIOPRINE
○ MTX also increases uric acid production and risk for uric acid ● Mechanism of Action
nephropathy ○ Acts through its major metabolite, 6-thioguanine
■ 📕 6-thioguanine suppresses inosinic acid synthesis, B-cell and
4.2.2.2. CYCLOPHOSPHAMIDE T-cell function, immunoglobulin production, and IL-2 secretion.

● 📝 One of the most potent immunosuppressive therapies available
● Major alkylating agent
○ Phosphoramide mustard
● Mechanisms by which Cyclophosphamide modify rheumatic
diseases:
○ Cross-links DNA to prevent cell replication
○ Transfer of their alkyl groups to various cellular constituents
○ Alkylation of DNA within the nucleus lead to cell death
■ Impairs DNA replication and transcription, ultimately leading
either to cell death or altered cellular function
○ Intramolecular cyclization to form an ethyleneimonium ion and
formation of a carbonium ion transfer an alkyl group to a cellular
constituent
○ Carbamoylation of lysine residues of proteins through formation of
isocyanates
● T cell and B cell function by 30-40%
● T cell suppression correlates with clinical response in the rheumatic
diseases
● 📝 Used as an antineoplastic agent
● Indications
○ Used at 2mg/kg/day but not when given intravenously
■ Be careful when computing for the dosage
○ Treat systemic lupus erythematosus (SLE), vasculitis, Wegener’s
granulomatosis, and other severe rheumatic diseases.
● 📝 Toxicity
○ Cumulative dose is a major risk for toxicity and duration exposure
○ The inhibition of purine synthesis will now lead to the inhibition of
RNA and DNA incorporation
● Pharmacokinetics
○ Can be given orally or parenterally
○ Well-absorbed from the GI tract
● Metabolism
○ Rapid metabolizers clear the drug four times faster than slow
metabolizers
■ The toxicity of AZA and 6-MP is predominantly related to the
activity of thiopurine methyltransferase (TPMT)
● Deficiency of TMPT causes 6-MP to be preferentially
metabolized toward 6-TG nucleotides, which appear to
account for much of the hematologic toxicity related to AZA
and 6-MP.
● 📕 patients with low or absent TPMT activity (0.3% of the
population) are at particularly high risk of myelosuppression
by excess concentrations of the parent drug, if dosage is
not adjusted
● Indications
○ Approved for use in rheumatoid arthritis at 2mg/kg/day
○ Used for the prevention of kidney transplant rejection
● Adverse Effects
○ Bone marrow suppression, GI disturbances and increase risk of
infection
○
○
Lymphomas may be increased
Rarely, fever, rash, and hepatotoxicity signal acute allergic reactions

4.2.2.3. CYCLOSPORINE
4.2.2.6. 📝 LEFLUNOMIDE
● Mechanism of Action
● Immunosuppressant ○ Its active metabolite, A77-1726 inhibits DHODH

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 9
 ○ Inhibits T cell proliferation and reduces
autoantibodies by B cells
the production of 4.2.4. 📝 TARGETED SYNTHETIC DMARD/ BIOLOGICALS
● Pharmacokinetics ● Includes the targeted, TNF inhibitors, IL-6 inhibitors, B-cell depletion, and
○ Well absorbed during oral administration inhibitors of T-cell co-stimulation
○ Plasma half-life: 19 days ● In the late 1980s and early 1990s, the cytokine profile in rheumatoid
○ Elimination is via kidneys and GI tract arthritis was first being defined using precise molecular methods
● Indications ● One of the surprises in these studies was that the anticipated high
○ Effective as MTX in rheumatoid arthritis concentration of T cell-cytokines was not really found. Instead, the
dominant cytokines that were detected in the joints were those made of
● Adverse Effects your macrophages and fibroblasts
○ Diarrhea, elevation in liver enzymes, mild alopecia, weight gain, and ● The acute inflammation can develop within minutes to hours and days, and
hypertension then chronic inflammation will ensue
● Contraindicated in pregnancy ● It will lead to the recruitment and activation of monocytes and lymphocytes
● There is a high concentration of pro-inflammatory cytokines that contribute
4.2.2.7. 📝 MYCOPHENOLATE MOFETIL to the systemic effects but are also responsible for many clinical signs of
infections and inflammatory diseases
● Powerful inhibitor of lymphocyte proliferation ● TNF, IL-1, and IL-6 are the pro-inflammatory cytokines
● Widely used as a glucocorticoid sparing agent for the treatment of patients ● Antagonists for these pro-inflammatory cytokines are used in rheumatoid
with a variety of rheumatic diseases arthritis, inflammatory bowel diseases and psoriasis
● Mechanism of Action
○ Converted to mycophenolic acid (active form)
■ Inhibits IMP dehydrogenase
■ Leading to suppressed T and B lymphocyte suppression
● Indications
○ Renal disease due to SLE, vasculitis, and Wegener’s granulomatosis
○ No controlled data regarding its efficacy on rheumatoid arthritis
● Adverse Effects
○ Nausea, dyspepsia and abdominal pain Biological Drugs
○ Contraindicated in pregnancy (Source: 2024 Trans)
■
■
Increased risk of first trimester pregnancy loss
Not advised for mothers who are breastfeeding
4.2.5.📝 TNF-α- INHIBITORS
4.2.5.1. 📝 ADALIMUMAB
○ May lead to active infection

4.2.2.8. 📝 SULFASALAZINE ● Mechanism of Action

○ Anti-TNF monoclonal antibody
● Non biologic disease-modifying antirheumatic drug which is originally ○ Complexes with soluble TNF-alpha and prevents its interaction with
proposed as a treatment for rheumatoid arthritis because of its p55 and p75 cell surface receptors → Downregulation of macrophage
anti-inflammatory and antimicrobial properties and T-cell function → Decreases the rate of bony erosion
● A prodrug composed of 5-aminosalicylic acid (5-ASA) linked to ● Pharmacokinetics
sulfapyridine through an azo bond ○ Given subcutaneously
● Mechanism of Action ○ Half-life: 10-20 days
○ Probably the parent compound, sulfasalazine suppresses T-cell ○ Clearance is decreased if given with MTX
responses to concanavalin and inhibition of in vitro B-cell proliferation ○ Usual dose: 40mg every other week
○ Inhibit the release of inflammatory cytokines produced by monocytes
or macrophages (IL-1, IL-6 and TNF-a) ● Indications
● Pharmacokinetics ○ Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
○ 10-20% of orally administered is absorbed by the small bowel and is juvenile idiopathic arthritis, plaque psoriasis, Crohn’s disease, and
returned unaltered via the enterohepatic circulation into the bile ulcerative colitis
○ Half-life is 6-17 hours ○ Effective both as a monotherapy and combination with MTX or other
● Indications nonbiologic csDMARDS
○ Used in rheumatoid arthritis and reduces radiologic disease

○
progression
Usual regimen is 2-3 g/day
4.2.5.2. 📝 CERTOLIZUMAB
● Adverse Effects ● Mechanism of Action
○ Nausea, vomiting, headache and rash ○ Recombinant, humanized antibody Fab fragment conjugated to
○ Sulfasalazine may cause reversible oligospermia and reduced male polyethylene glycol (PEG)
fertility ■ PEGylation of certolizumab allows for delayed elimination
○ Generally considered safe during pregnancy and breastfeeding ○ Neutralizes membrane-bound and soluble TNF-alpha in a
dose-dependent manner
● Pharmacokinetics
4.2.3. COMBINATION THERAPY WITH DMARDs
○ Given subcutaneously
● Exhibits either synergistic or no pharmacodynamic reaction with ○ Half-life: 14 days
Methotrexate ○ Given with MTX - decreases the appearance of antibodies
● Improved with Methotrexate (CIRCLE) ○ Usual dose: 400 mg initially, 200 mg for weeks 2 and 4 or 400 mg
○ Cyclosporine every 4 weeks
○ Infliximab ● Indications
○ Rituximab ○ Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, uveitis,
○ Chloroquine and inflammatory bowel disease
○ Leflunomide
○ Etanercept
● No additional benefit (ASA)
4.2.5.3. 📝 ETANERCEPT
○ Azathioprine ● Mechanism of Action
○ Sulfasalazine ○ Soluble p75 TNF receptor fusion protein that consists of two p75 TNF
○ Auranofin receptors bound to the Fc portion of immunoglobulin G (IgG)
● CASE IN POINT: Probenecid ○ Binds to TNF-a and also inhibits lymphotoxin alpha
○ Drugs mentioned above (CIRCLE) have a synergistic ○ Decreases rate of formation of new erosions relative to MTX alone
PHARMACODYNAMIC effect with Methotrexate. While on the other ● Pharmacokinetics
hand, Probenecid has a PHARMACOKINETIC effect with Methotrexate ○ Given subcutaneously as 25 mg twice a week or 50 mg weekly
because it alters its excretion. ○ Slowly absorbed, with peak concentration 72 hours after given
■ Anything that has something to do with ADME is Pharmacokinetic ○ Half-life: 4.5 days

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 10
● Indications the IL-12 receptor b1 found on the surface of CD4 T cells and NK cells
○ Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis ○ Interferes with IL-12 and 23 signal transduction and suppresses the
○ Not effective for inflammatory bowel disease formation of proinflammatory TH1 and TH17 cells
○ Also interferes with the expression of monocyte chemotactic protein,
4.2.5.4. 📝 GOLIMUMAB ● 📕
TNF-α, and IFN-γ inducible protein 10
Pharmacokinetics
● Mechanism of Action ○ Given as 45- and 90- mg SC injection (PsA and plaque psoriasis)
○ Human monoclonal antibody with high affinity for soluble and ○ Given as 130 mg dose IV infusion (Crohn’s disease)
membrane-bound TNF-alpha ○ Maintenance every 12 weeks
● Pharmacokinetics ○ Bioavailability: 57% (SC)
○ Given subcutaneously ○ Time to peak plasma concentration (half-life): 7-13.5 days
○ Half-life: approximately 14 days ○ Elimination half-life: 10-126 days
○ If given with MTX, increased golimumab serum levels and
anti-golimumab Abs decreased
● 📕 Indications
○ PsA, Crohn’s disease, plaque psoriasis
● Indications ○ Can be used as monotherapy or in combination with MTX
○ Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
ulcerative colitis
● 📕 Adverse Effects
○ Most common: URTI
○ Golimumab with MTX is indicated for the treatment of moderate to ○ Rare: Severe infection, malignancy, reversible posterior
severely active rheumatoid arthritis in adult patients leukoencephalopathy syndrome
○ Indicated in the treatment for moderate to severe ulcerative colitis ○ Should be discontinued at least 15 weeks before live vaccines are
administered and can be resumed at least 2 weeks after
4.2.5.5. 📝 INFLIXIMAB
● Mechanism of Action 4.2.7. 📝 IL-17 INHIBITORS
○ Chimeric (25% mouse, 75% human) monoclonal antibody (mAb) ● IL-17A is involved in normal inflammatory and immune responses
directed against TNF-alpha
○ 📕MOA is probably the same as that of adalimumab
● Elevated concentrations of IL-17A are found in psoriatic plaques and PsA

● Pharmacokinetics
○ Given IV 4.2.7.1. 📝 SECUKINUMAB
○ Induction: 0,2, and 6 weeks ● 📕 Mechanism of Action
○ Maintenance: every 8 weeks ○ Human IgG monoclonal antibody that selectively binds to the IL-17A
○ Half-life: 9-12 days cytokine, inhibiting its interaction with the IL-17A receptor
○ Intermittent therapy may elicit human anti-chimeric Abs ● 📕 Pharmacokinetics
○ If given with MTX, the prevalence of Abs decreases ○ Given as 150- and 300-mg SC injection or lyophilized powder for
● Indications injection
○ Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ○ Peak plasma concentration: 13.7 mcg/mL (150 mg dose) and 27.3
inflammatory bowel diseases mcg/mL (300 mg dose)
○ If used with MTX, decreases the formation of new erosions ○ Elimination half-life: 22-31 days
○ May also be used as monotherapy ● 📕 Indications
○ Modern to severe plaque psoriasis, PsA, AS, investigated for uveitis
4.2.5.6. 📝 ADVERSE EFFECTS OF TNF-α-BLOCKING AGENTS ● 📕 Adverse Effects
○ Infection (28.7%), nasopharyngitis (about 12%)
● The decision to use these agents must be based on the specific clinical ○ TB status should be evaluated prior to therapy
features and the unique risk profile of a given patient ○ May exacerbate Crohn’s disease
○ Injection site reactions (common)
■ Itching, pain, redness, irritation, bruising, or swelling at the side of
medication injection 4.2.8. 📝 KINASE INHIBITORS
○ Infusion reactions ● JAK-STAT signaling is responsible for the ligation of receptors for cytokines
○ 📕 Neutropenia, leukopenia, thrombocytopenia, pancytopenia that results in the activation of JAK tyrosine kinase
■ Check CBC prior to therapy ● The recruited STAT is activated by JAK phosphorylation and leads to gene
○ Opportunistic infections transcription
■ Pneumonia, tuberculosis, Zoster
○ Demyelinating diseases 📝 TOFACITINIB
4.2.8.1.
■ Confusion, ataxia, paresthesia
○ Heart failure ● 📕 Mechanism of Action
■ Often associated with etanercept or infliximab ○ Targeted synthetic small molecule (sDMARD) that selectively inhibits all
■ Cardiology consultation is advised members of the JAK family
● 📕 Cutaneous reactions ○ Mainly inhibits JAK3, and to a lesser extent JAK1, interrupting the
JAK-STAT family signaling pathway
○ Dermatitis, psoriasis-like lesions, alopecia, hypertrichosis
● 📕 Malignancy ■ JAK-STAT signaling: ligation of receptors for cytokines → activation of
JAK tyrosine kinase
● 📕
○ Skin cancer
Induction of autoimmunity ● 📕Pharmacokinetics
○ Formation of dsDNA antibodies and antinuclear antibodies ○ Recommended dose: 5 mg/tab twice daily
○ Infection reactions ○ Extended release (XR) dose: 11 mg/tab OD
○ Category B drugs for pregnancy ○ Patients taking CYP enzyme inhibitors or with moderate hepatic or renal
● 📕 HBV reactivation impairment: 5 mg/tab OD
● 📕 Gastrointestinal ulcers and large bowel perforation ○ Oral bioavailability: 74%
○ Elimination half-life: 3 hours
4.2.6. 📝 IL-12 AND IL-23 BLOCKING AGENTS ○ Metabolism:
■ 70%: In the liver, mainly by CYP3A4, and to a lesser extent CYP2C19
● Biologic effects of IL-12 and IL-23 include natural killer cell activation and ■ 30%: Excreted unchanged by the kidneys
CD4 T cell differentiation and activation ○ Not for patients with severe hepatic disease
● 📕 IL-12 and IL-23 are also contributors to the chronic inflammation in ● 📕Indications
plaque psoriasis, PsA, and Crohn’s disease ○ Moderately to severely active RA patients who have failed or are
intolerant to MTX
4.2.6.1.📝 USTEKINUMAB ○ Solid organ allograft rejection (originally), inflammatory bowel disease,
● 📕 Mechanism of Action ●
spondyloarthritis, psoriasis, dry eyes
📕Adverse Effects
○ Fully human IgG monoclonal antibody to the p40 protein subunit of ○ Most common: URTI and UTI
IL-12 and IL-23 ○ Pneumonia, cellulitis, esophageal candidiasis, and other opportunistic
○ Prevents the binding of the p40 subunit shared by IL-12 and IL-23 to

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 11
 infections
○ Increase in LDL, HDL, and total cholesterol levels 4.2.10.1.📝 RITUXIMAB (B-CELL DEPLETION)
○ Neutropenia and anemia
○ Headache, diarrhea, elevation of liver enzymes, and GI perforation ● 📕 Mechanism of Action
○ Screen for latent TB ○ Chimeric monoclonal antibody that targets CD20 lymphocytes
○ Depletion takes place through cell-mediated and complement-dependent

4.2.9. 📝 IL-1 INHIBITORS cytotoxicity and stimulation of cell apoptosis

○ B cell depletion reduces inflammation by decreasing the presentation of
● IL-1 is a mediator of inflammation via activation of monocytes and antigens to T lymphocytes and inhibiting the secretion of proinflammatory
cytokines
●
macrophages
Induces fibroblast formation that results in pannus formation ● 📕Pharmacokinetics
● Activates chondrocytes, leading to cartilage breakdown and osteoclast ○ Given at two IV infusions of 1000 mg, separated by two weeks (may be
repeated every 6-9 months as needed)
activation responsible for bone resorption
● 📕Indications
4.2.9.1. 📝 ANAKINRA ○ In combination with MTX in patients with inadequate response to TNF-α
antagonists: moderately to severely active RA
● Oldest drug in the family ○ In combination with glucocorticoids: granulomatosis with polyangiitis
● 📕 Mechanism of Action (Wegener’s granulomatosis), microscopic polyangiitis, and other forms of
○ Competes and blocks the IL-1β receptor vasculitis
● Pharmacokinetics ● 📕Adverse effects
○ Given subcutaneously ○ Infusion reactions (rash development)
○ Bioavailability: 95% ○ Fatal bacterial, fungal, and viral infections
○ Half-life: 4-6 hours ○ Reactivation of HBV infection
○ Reduction in administration to every other day for patients with renal ○ Mucocutaneous reactions
insufficiency ○ Different cytopenias
● 📕 Indications
○ Moderately to severely active RA (rarely used)
■ Significantly less potent in most patients with RA as compared to
4.2.10.2. 📝 BELIMUMAB (B-CELL INHIBITION)
TNF-α inhibitors ● Mechanism of Action
○ Inhibits B lymphocyte stimulator (BLyS)
○ More effective in the treatment of other inflammatory conditions
■ CAPS, TRAPS, systemic juvenile idiopathic arthritis, Adult-onset ● 📕Pharmacokinetics
Still’s Disease (AOSD), gout, and Behçet’s Disease ○ Given IV
■ Drug of choice for CAPS (NOMID subtype) ○ Recommended dose: 10 mg/kg at weeks 0, 2, and 4 and every 4 weeks
thereafter

4.2.9.2. 📝 CANAKINUMAB ○ Distribution half-life: 1.75 days

○ Terminal half-life: 19.4 days
● Approved for four types of periodic fever syndromes in adults and children ● 📕Indications
in the European Union ○ Patients with active, seropositive SLE who are receiving standard
● 📕 Mechanism of Action treatment
○ Should not be used in patients with active renal or neurological
○ Human IgG/κ anti-IL-1β monoclonal antibody
manifestations
●
○ Forms a complex with IL-1β, preventing its binding to IL-1 receptors
📕 Pharmacokinetics ● 📕Adverse effects
○ Given subcutaneously ○ Nausea, diarrhea
○ Peak serum concentration: 7 days ○ Respiratory tract infection
○ Bioavailability: 66%

●
○ Half-life: Mean of 26 days
📕 Indications
4.2.11. 📝 CO-STIMULATION BLOCKADE
○ Systemic juvenile idiopathic arthritis ● The best characterized costimulatory pathway in T-cell activation involves
■ Still’s disease in children aged 2 and above the T-cell surface receptor CD28 which binds the costimulatory molecules
○ AOSD, gouty arthritis, TRAPS, CAPS, hyperimmunoglobulin D syndrome B7-1 (CD80) and B7-2 (CD86) expressed on activated APCs.
(HIDS), mevalonate kinase deficiency (MKD), familial Mediterranean ● After a T-cell has engaged an APC, CD28 produces a second signal on the
fever T cell that interacts with CD80 or CD86 on the APC, leading to T cell
activation.

4.2.9.3. 📝 RILONACEPT 📝 ABATACEPT

4.2.11.1.
● 📕 Mechanism of Action ● 📕 Mechanism of Action
○ Antibody with bispecific arms
○ Binds to CD80 and CD86 → inhibiting the binding to CD28 → preventing
○ Binds mainly to IL-1β and with lower affinity to IL-1α and IL-1RA
the activation of T cells
○ Neutralizes IL-1β and prevents its attachment to IL-1 receptors
● 📕Pharmacokinetics
● Pharmacokinetics
○ Given IV or SC
○ Given subcutaneously
○ Steady-state plasma concentration: 6 weeks
● 📕Indications
● 📕Indications
○ Monotherapy or in combination with MTX or other DMARDs: moderate to
severe RA or severe PJIA
○ Given subcutaneously
○ PsA, SLE, primary Sjögren’s syndrome, type 1 diabetes, inflammatory
○ Steady-state plasma concentration: 6 weeks
bowel disease, psoriasis vulgaris

4.2.9.4. 📝 ADVERSE EFFECTS OF IL-1 INHIBITION ● 📕Adverse effects

○ URTI, UTI, infusion-related reactions, hypersensitivity reactions
● Injection site reactions (40%) ○ Screen for latent TB and viral hepatitis
● URTI ○ Avoid live vaccines while taking and up to 3 months after discontinuation
● Headache
●
●
Abdominal pain, nausea, and diarrhea
Arthralgia
4.2.12. 📝 IL-6 INHIBITION
● Flu-like illness ● IL-6 is a proinflammatory cytokine that has local and systemic effects
● Hypersensitivity reactions ● Involved in T-cell activation, hepatic acute-phase protein synthesis, and
● Transient neutropenia stimulation of the inflammatory processes involved in RA and systemic
sclerosis

4.2.10. 📝 B-CELL DEPLETION AND INHIBITION ● IL-6 can lead to inflammatory storm

● Biologic agents that can deplete B cells or inhibit factors that activate B
cells

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 12
4.2.11.1. 📝 TOCILIZUMAB ■ with hemophilia
● 📕 Mechanism of Action ■ with history of peptic ulcer
■ wherein bronchospasm is precipitated by aspirin
○ Biologic humanized anti-human IL-6 receptor antibody ● Adverse effects
○ Binds to soluble and membrane-bound IL-6 receptors → inhibiting the ○ 📝 Hepatotoxicity may develop under several circumstances
●
IL-6 mediated signaling via these receptors
📕Pharmacokinetics
○ 📝 Concomitant use of alcohol or other drugs, comorbid illnesses,
advancing age, genetic makeup, and nutritional status
○ Half-life is dose dependent: 11 days (4 mg/kg dose) and 13 days (8 ○ Acetaminophen/Paracetamol poisoning
mg/kg dose)
○ IL-6 suppress several CYP450 isoenzymes
7. DRUGS USED IN GOUT
■ Inhibition may restore CYP450 activities to higher levels
■ Clinically relevant for drugs that are CYP450 substrates and have a ● 📝 Gout
narrow therapeutic window (e.g. warfarin and cyclosporine) ○ Associated with increased serum concentration of uric acid
○ Can be given as monotherapy or in combination with nonbiologic ○ Acute attacks involved joint inflammation initiated by precipitation of
DMARDs uric acid crystals
● Indications ○ 3.9% of adults (8.3 million) in the United States have had a diagnosis
○ Patients with moderately to severely active RA who have had an of gout
inadequate response to one or more DMARDs ■ Most common in patients > age 65
○ Patients who are older than 2 years old with active SJIA or active PJIA ○ Primarily affects men starting in their 20s, women mostly of those who
● 📕Adverse effects
○
are postmenopausal
Gout is the most prevalent form of arthritis afflicting Filipinos
○ Serious infections
■ Tuberculosis, fungal, viral, and other opportunistic infections ○ When left untreated, becomes more severe and attacks are more
○ URTI, headache, hypertension, elevated liver enzymes, neutropenia, frequent
thrombocytopenia, and anaphylactic reactions ○ Serum uric acid level is > 6 mg/dL (hyperuricemia)
○ Screen for TB and URTI ■ For men: > 7 mg/dL (0.42 mmol/L)
■ Premenopausal women: > 6 mg/dL (0.36 mmol/L)
5. GLUCOCORTICOIDS ○ Asymptomatic hyperuricemia
● 📕 Corticosteroids are sometimes used in the treatment of severe
■ Hyperuricemia in the absence of gouty arthritis and uric acid
nephrolithiasis
symptomatic gout, by intra-articular, systemic, or subcutaneous routes, ○ Metabolic “6-pack”
depending on the degree of pain and inflammation ■ Obesity
● Symptomatic relief for signs and symptoms of RA ■ Metabolic syndrome
● Capable of slowing the appearance of new bone erosions ■ Type 2 diabetes
● For serious extra-articular manifestations of rheumatoidarthritis suchs as ■ Hypertension
pericarditis or eye involvement or during periods of exacerbation. ■ Chronic kidney disease
● Intra-articular corticosteroids are often helpful to alleviate painful symptoms ■ Diet and lifestyle
● Prednisone: Does not exceed 7.5 mg daily-required dose for long-term ○ Medication that can raise serum urate levels
therapy ■ Aspirin
○ Prolonged use can affect the head of the femur ■ Niacin
● Delayed-release prednisone: treatment of early morning stiffness
○ 📕 Most commonly used oral corticosteroid is prednisone
■
■
Thiazide diuretics
Loop diuretics
● Adverse Effects ○ Risk factors frequently found in association with gout
○ Prolonged use leads to serious and disabling toxic effects
○ 📝 Infections
■ Dyslipidemia
○ 📝 GI manifestations
■ Obesity
○ 📝 Dermatological
■ Metabolic syndrome
○ 📝 Endocrine
■
■
Congestive heart failure
Psoriasis
■ Malignancies
6. NON-OPIOID ANALGESICS ○ Known precipitants
● 📕 Most nonopioid analgesics (aspirin, etc) have anti-inflammatory effects ■
■
Stress
Hospital admission or surgery
→ appropriate for treatment of both acute and chronic inflammatory
conditions ■ Infection
6.1. 📝ACETAMINOPHEN ■
■
Dehydration
Drugs/medication (ASA, pyrazinamide, ethambutol, diuretics)
● Paracetamol/APAP (Para-acetyl-amino-phenol) ■ Irregular intake of urate lowering medications
● Active metabolite of phenacetin and is responsible for its analgesic effect
● 📕 Said to be equivalent to aspirin as an analgesic and antipyretic agent
● No significant anti-inflammatory effects
○ 📕No significant effect on anticoagulant therapy (lacks platelet-inhibiting
effects)
○ Mechanism
■ Weak COX-1 and COX-2 inhibitor in peripheral tissues
■ Evidence suggests that it may inhibit COX-3 in the CNS
● Pharmacokinetics
○ 10-15 mg/kg dose in children
○ 325-1000 mg per dose in adults
○ Given every 4-6 hours
○ Rapidly and completely absorbed from the GI tract (duodenum)
○ Half-life
■ 2-4 hours
■ Elimination phase may be delayed in onset for extended release
preparations due to prolonged tablet dissolution and absorption
● Indications
○ 📕
Used in the treatment of mild to moderate pain (headache,
myalgia, postpartum pain)
○ Inadequate for inflammatory conditions such as rheumatoid arthritis
(RA)
○ Preferred drug in patients:
■ allergic to aspirin (mild analgesia)
Key Checkpoints in Gout Pathogenesis
● Salicylates are poorly tolerated
(Source: 2024 Trans)

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 13
 ● Relieves the pain and inflammation in 12-24 hours without altering
○ Overproduction of urate or underexcretion of uric acid → Hyperuricemia the metabolism or excretion of urates and without other analgesic
→ Formation of MSU crystals: effects
■ Acute gout: resolution of acute gout attack ● Adverse effects:
■ Chronic gout: tophus formation ○ Diarrhea
○ Nausea
○ Vomiting
○ Abdominal pain

● Dosage:
○ Prophylaxis 0.6 mg one to three times daily
○ Attack of gout, 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until
pain is relieved or nausea and diarrhea appear
○ Can be given intravenously
■ Fatal dose: 8 mg in 24 hours
● Should also be used until steady-state serum uric acid is normalized or
decreased to less than 6 mg/dL
● Colchicine or an NSAID should be given during the first weeks of allopurinol
therapy to prevent the gouty arthritis episodes that sometimes occur

Natural History of Gout

(Source: 2024 Trans)

● Stage 1: Asymptomatic Hyperuricemia

○ No medications
○ Monitor for comorbidities and recommend appropriate adjustments to diet
and lifestyle
● Stage 2: Acute Gout Flares
○ Goal of therapy is safe termination of pain and disability
○ Without therapy, gout flares resolve completely within few days to several
weeks particularly if disease is early
○ Rapid short term therapy using:
■ Colchicine
■ NSAIDs
■ Glucocorticoids Mechanism of action of colchicine
○ Upon resolution of gout flares → patient enters interval/ (Source: Batch 2024 Trans)
intercritical/between flares (symptom-free) period
■ Flares recur in majority of px with more frequent episodes, more
7.2. NSAIDs IN GOUT
severe, and prolonged with consequent shortening of asymptomatic
periods ● Effects:
● Stage 3: Asymptomatic Gout with History of Flares & Stage 4: Chronic ○ Inhibiting prostaglandin synthase
Gout ○ Inhibiting urate crystal phagocytosis
○ Identify underlying pathology and initiate long term therapy
■ Increased urate intake
● Adjust diet and lifestyle to reduce urate intake, such as purine and 7.2.1. INDOMETHACIN
fructose consumption ● Dosage: 50 mg, three times daily
■ Urate overproduction
● Treat with xanthine oxidase inhibitors
■ Urate hypo-excretion: most common pathology in gout 7.2.2. ALL OTHER NSAIDs
● Treat with uricosuric drugs such as Probenecid ● Except aspirin, salicylates, and tolmetin
○ 📝
High doses of aspirin may be effective but normally should not be
IMPORTANT. You have to be careful with patients having gout; because of given
severe pain, patients are tempted to relieve pain rather than the primary
condition NSAIDs IN GOUT
○ NSAIDs can cause nephropathy
■ Gout + Nephropathy → chronic kidney disease COX-2 SELECTIVE INHIBITORS NON-SELECTIVE COX INHIBITORS
● Celecoxib (Celebrex) ● Diclofenac (Voltaren,
7.1. ANTI-INFLAMMATORY DRUGS ● Etoricoxib (Arcoxia) Cataflam)
● Meloxicam (Mobic) ● Ibuprofen (Advil, Alaxan,
7.1.1. COLCHICINE ● Valdecoxib Dolan)
● 📝 Primary treatment for acute gout ● Parecoxib (Dynastat) ●
●
Indomethacin
Ketoprofen (Fastum Gel)
● Alkaloid isolated from the autumn crocus, Colchicum autumnale
● Ketorolac (Toradol)
● Absorbed readily after oral administration
● Meclofenamate and
● Peak plasma levels within 2 hours
mefenamic acid (Ponstan,
● Half-life: 9 hours
Dolfenal, Gardan)
● Mechanism of action:
● Naproxen (Flanax, Skelan)
○ Binding to the intracellular protein tubulin
● Piroxicam (Feldene,
○ Prevent polymerization into microtubules and leading to the inhibition
Feldene Flash, Feldene
of leukocyte migration and phagocytosis
Gel)
○ Inhibits the formation of leukotriene B4
● Sulindac
● Used for the prophylaxis of recurrent episodes of gouty arthritis
● Nabumetone
● Can be given intravenously (increased bone marrow toxicity)
● Oxaprozin
● Metabolites are excreted in the intestinal tract and urine
Source: 📝 Batch 2024 Trans

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 14
7.2.3. OXAPROZIN ALLOPURINOL VS FEBUXOSTAT
● Propionic acid derivative NSAID ALLOPURINOL FEBUXOSTAT
● Half-life: 50-60 hours (very long)
● Mildly uricosuric Purine analog Non-purine analog
● Effect: Lowers serum uric acid Inhibitor of xanthine oxidase Selective inhibitor only to xanthine
● Not to be given to patients with uric acid stones because it increases uric oxidase
acid excretion in the urine Inhibits other enzymes involved in
7.3. XANTHINE OXIDASE INHIBITORS purine/pyrimidine synthesis and It has no effect on other enzymes
metabolism involved in purine/pyrimidine
7.3.1. ALLOPURINOL synthesis and metabolism

● A purine analog Eliminated primarily via renal Both hepatic and renal metabolism
● A structural isomer of hypoxanthine (a naturally-occurring purine in the excretion
body) Cannot be given safely to renally Can give to patients with mild to
● An inhibitor of the enzyme xanthine oxidase that is responsible for the impaired (dose adjustment is moderate hepatic renal impairment
successive oxidation of hypoxanthine and xanthine, resulting in the necessary) with no dose adjustment
production of uric acid, the product of human purine metabolism thus
blocking uric acid production
Source: 📝 Batch 2024 Trans
● Also inhibits the enzymatic oxidation of mercaptopurine, the
sulfur-containing analogue of hypoxanthine, to 6-thiouric acid
● The most common adverse effect of allopurinol is the precipitation of an 7.4. URICOSURIC DRUGS
acute flare of gout
○ Due to urate lowering resulting in urate crystals being shed from ● Probenecid and sulfinpyrazone
articular cartilage into the joint pace, resulting in acute inflammation ○ Uricosuric agents that act by competitively inhibiting uric acid
● 📝 Pharmacokinetics: reabsorption in the proximal tubule of the kidney by blocking the
URAT1, an urate transporter, in brush border of renal proximal tubular
○ 80% absorbed after oral administration
○ Half-life = 1-2 hours cells
● 📝 Pharmacodynamics: ● In order to avoid the nephrotoxicity and urolithiasis due to increased urinary
urate excretion during use of uricosuric agents, patients should be
○ Inhibits the last step: xanthine or hypoxanthine oxidized to uric acid
○ Results to: encouraged to:
■ Fall in the plasma urate level ○ Increase water intake to maintain adequate urine volume
■ Decrease in the overall rate burden ○ Aciduria should be corrected when it occurs
● 📝 Indications: ■ Urine should be alkalinized
○ Treatment in between attacks and prolongs the intercritical period
● 📝 Adverse effects:
○ Not given in acute gouty attacks because it can give rise to gouty flares 7.4.1. 📝 PROBENECID & SULFINPYRAZONE
○ Rash, leukopenia or thrombocytopenia, and diarrhea ● Mechanism of action:
○ Severe cutaneous adverse reactions (SCAR) - SJS and TEN ○ Interferes with the organic anion transporter (OAT) which reclaims uric
● 📝 Interactions and cautions: acid from the urine and returns it to the plasma
○ Azathioprine and 6MP, alkylating agents (cyclophosphamide), ○ Blocks urate transporter 1 (URAT1)
ampicillin ■ URAT1: central mediator in the transporter of the uric acid from the
● 📝 Dosage: kidney to the blood
○ 50-100 mg/daily titrated until serum uric acid reaches below 6 m/dL ● Pharmacokinetics:
(300-400 mg/day up to 800 mg/day) ○ Completely reabsorbed by the renal tubules
○ Half-life = 5-8 hours
● Pharmacodynamics:
7.3.2. FEBUXOSTAT ○ Decreased absorption of uric acid in the proximal tubule
● The first non-purine inhibitor of xanthine oxidase ● Indications:
● Potent and selective inhibitor of xanthine oxidase ○ Patients with underexcretion of uric acid when allopurinol or febuxostat
● Reduces the formation of xanthine and uric acid is contraindicated or when tophi is present
● Well-tolerated in patients with a history of allopurinol intolerance ○ Should not be started until 2-3 weeks after an acute attack
● Alternative drug to decrease uric acid for patients with gouty ● Adverse effects:
nephropathy ○ GI irritation
● 📝 Pharmacokinetics:
●
○ Rash
Contraindications and cautions:
○ More than 80% absorbed after oral administration
○ Max concentration is achieved in 1 hour ○ Stone and formation
○ Half-life = 4-18 hours ● Dosage:
○ Once daily dosing ○ Probenecid: start at 0.5 g orally divided doses progressing to 1 g daily
○ Metabolized in the liver after a week
● 📝 Pharmacodynamics: ○ Sulfinpyrazone: start at 200 mg orally daily, progressing to 400-800
mg daily
○ Selective inhibitor of xanthine oxidase
● 📝 Indications: ○ Given with food to decrease GI effect
○ Chronic hyperuricemia
○ Clinical trials suggest that febuxostat is more effective than allopurinol 📝 7.5. URICASE
in lowering serum uric acid
● 📝 Adverse effects: 7.5.1. PEGLOTICASE
○ Risk of gout-flares - NSAIDs or colchicine must be initiated at the
● Chemistry:
beginning of therapy
○ Recombinant mammalian uricase attached to mPEG
○ Liver function abnormalities, GI upset, headache, hypersensitivity
■ mPEG: prolongs the circulating half-life and diminish the
reaction
● 📝 Dosage:
immunogenic response
● Pharmacokinetic and dosage:
○ Starts at 40 mg, daily; with 40 mg, and 80 mg dosing
○ Given 8 mg every 2 weeks IV
○ Rapidly acting with achieving peak decline in uric acid within 24-72
hours
○ Half-life: 6-14 days
● Pharmacodynamics:
○ Maintains low urate levels for up to 21 days after a single dose at 4-12
mg

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 15
● Clinical use:
○ Treatment of refractory chronic gout
● Adverse effects:
○ Flares during treatment
■ Use of prophylaxis with NSAIDs and colchicine is recommended
○ Development of antibodies
○ Risk of anaphylaxis
○ UTRI, peripheral edema, UTI, nephrolithiasis, headache, and diarrhea
○ Concern for hemolytic anemia in G6PD patients: formation of hydrogen
peroxide by uricase (contraindicated)

8. APA REFERENCES
Calimag, M.M. (2022). Lecture on NSAIDs, DMARDs, Anti-Gout, & Non-Opioid
Analgesics. Manila: University of Santo Tomas Faculty of Medicine
and Surgery
Katzung, B.G., Vanderah, T.W., (2021). Basic and Clinical Pharmacology. 15th
ed. McGraw Hill
Batch 2024 Trans, NSAIDs, DMARDs, Anti-Gout, & Non-Opioid Analgesics

9. FREEDOM WALL

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 16
ANNEX A: DRUG SUMMARY TABLE FOR NSAIDs, ACETAMINOPHEN, & DRUGS FOR RHEUMATOID ARTHRITIS & GOUT

SUBCLASS AG/ANTAGONIST MECHANISM OF ACTION CLINICAL APPLICATION PHARMACOKINETICS TOXICITIES, DRUG INTERACTIONS
SALICYLATES
ASPIRIN Antagonist Acetylation of COX-1 and COX-2 results Analgesia, antipyretic, Duration of activity is longer than Gastrointestinal (GI) toxicity, nephrotoxicity, and increased
in decreased prostaglandin synthesis anti-inflammatory, and pharmacokinetic half-life of drug bleeding time at therapeutic levels;
antithrombotic (in low dose) due to irreversible COX inhibition ● Bronchoconstrictor reaction due to increased
leukotrienes
● Tinnitus, hyperventilation, metabolic acidosis,
hyperthermia, coma in overdose
NONSELECTIVE NSAIDS
IBUPROFEN Antagonist Reversible inhibition of the COX-1 and Analgesia, antipyretic, and Rapid metabolism and renal GI toxicity, nephrotoxicity
COX-2 results in decreased anti-inflammatory; closure of elimination ● Reaction due to increased leukotrienes
prostaglandin synthesis patent ductus arteriosus ● Interference with aspirin’s antithrombotic action
COX-2 INHIBITOR
CELECOXIB Antagonist Selective reversible inhibition of COX-2 Analgesia, antipyretic, and Hepatic metabolism Nephrotoxicity
results in the decreased prostaglandin anti-inflammatory ● Reaction due to increased leukotrienes
synthesis ● Less risk of GI toxicity than nonselective NSAIDs
● Greater risk of thrombosis than nonselective
NSAIDs
OTHER ANALGESIC
ACETAMINOPHEN Agonist Mechanism unknown, weak COX Analgesia, antipyretic Hepatic conjugation Hepatotoxicity in overdose (antidote is acetylcysteine)
inhibitor ● Hepatotoxicity more likely with chronic alcohol
consumption, which induces P450 enzymes
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS)
METHOTREXATE Antagonist Conventional synthetic (cs) cytotoxicity to Anticancer, rheumatic Renal elimination Nausea, mucosal ulcers, hematotoxicity, hepatotoxicity,
rapidly dividing immune cells due to disorders teratogenicity
inhibition of dihydrofolate reductase
INFLIXIMAB Antagonist Biologic (b) anti-TNF-alpha Rheumatoid arthritis Opprtunistic infections & reactivation of latent TB & HBV

Increased risk of skin cancer

MICROTUBULE ASSEMBLY INHIBITOR
COLCHICINE Antagonist Inhibition of the microtubule assembly Chronic and acute gout, Oral drug Diarrhea, severe liver and kidney damage in overdose
decreases macrophage migration and familial Mediterranean fever
phagocytosis
URICOSURICS
PROBENECID Antagonist Inhibition of renal reabsorption of uric Chronic gout, prolongation of Oral drug Exacerbation of acute gout, hypersensitivity reactions,
acid antimicrobial drug action inhibits renal tubular secretion of weak acids such as
methotrexate
XANTHINE OXIDASE INHIBITORS
ALLOPURINOL Antagonist Active metabolite irreversibly inhibits Chronic gout, adjunct to Activated by xanthine oxidase GI upset, hypersensitivity, bone marrow suppression
xanthine oxidase and lowers production cancer chemotherapy (oral drug)
of uric acid
FEBUXOSTAT Antagonist Reversible inhibitor of xanthine oxidase
URICASE
PEGLOTICASE Recombinant mammalian uricase Chronic refractory gout IV Rapid change in uric acid levels can precipitate gout flare
converts uric acid to the soluble allantoin ● Prophylaxis with NSAIDs or colchicine

PHARMA (TWG) CLEDERA, CONVENTO, ROLLOM, ROMUALDO, ROQUE, MANGUSSAD (TEG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q., SAMSON 17