Nsaids, Non-Narcotic Analgesics, Anti-Gout Drugs

Front 1

NSAIDs
Classical Non Selective (2)

Back 1

Aspirin
Iuprofen

Front 2

NSAIDs:
Cox II Inhibitors

Back 2

Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Valdecoxib (Bextra)

Front 3

SAARDS/DMARDS:
disease modifying anti-rheumatic drugs

Back 3

- cause an arrest in the progression of RA
Traditional: antimalarials, penicillamine (Tx poisoning), methotrexate (chemo agent), gold compounds (toxic)
- Biologic Agents: leflunomide, infliximab, etanercept, anakinara

Front 4

Anti-Gout Medications

Back 4

Colchine
Allopurinol

Front 5

Anti-Gout:
Colchine

Back 5

- anti-inflammatory specific to gout
- not analgesic or uricosuric
- tx acute gouty attacks, reduces frequency
- high toxicity: n/v, pain, diarrhea, chronic myopathy, agranulocytosis, aplastic anemia, alopecia

Front 6

Anti-Gout:
Colchine
Mechanism of Action

Back 6

inhibits activity of leukocytes by decreasing their migration to the site of inflammation thereby reducing inflammation

Front 7

Anti-Gout:
Allopurinol

Back 7

- inhibits xanthine oxidase to reduce uric acid formation
- prevent gouty arthritis and compliance of urate neuropathy
- reduces uric acid levels
- block active tubular reabsorption of uric acid

Front 8

The Inflammatory Process

Back 8

Signs: erythema, edema, tenderness, pain
Acute Inflammation: transient
Immune Response: delayed
Chronic Inflammation: chronic proliferative stage

Front 9

Acute Inflammation

Back 9

- local vasodilation, increased capillary permeability
- release of autoacids: prostaglandins, histamine, bradykinin, leukotrines
- autocrine: released by cell it comes to attack
- Paraprine hormone: acts on cell in immediate vicinity to one released
- prostaglandins: synthesized and controlled by COX
- Agents sensitize to pain

Front 10

Acute Inflammation:
COX and NSAIDs

Back 10

- NSAIDs inhibit COX which stops production of prostaglandins and therby reduces painful stimuli

Front 11

Immune Response

Back 11

infiltration of leukocytes and phagocytic cells
- outcome beneficial by phagocytosis of foreign bodies

Front 12

Chronic Inflammation

Back 12

- tissue degeneration and fibrosis
- Interleukin, GM-CSF (growth factor at chronic inf.sites), TNF-alpha (tumor necrosis factor), interferons, PDGH (platelet derived growth hormone at chronic inf.sites)
- leukocytes release lysomal enzymes
- best example: RA - bone and cartilage pain and destruction

Front 13

Rheumatoid Arthritis

Back 13

pathogenesis unknown
- autoimmune disease; recognizes own tissue as foreign and attacks
- cytokine release: Interleukin and TNF
- only glucocorticoid block synthesis or actions
- PGE2 elevated in inflammed joints d/t induction of COXII
- normally joint does not have COX

Front 14

Synthesis of Prostaglandins

Back 14

- COX and AA used as substrate
- PGI2: in blood vessel walls
- PGE2: variety of dif tissues and effects
- Thromboxine: produced in platelets
- AA: common precursor for COX to produce prostaglandins

Front 15

Mechanism of NSAIDs
Glucocorticoids on prostaglandin synthesis

Back 15

block corticosteroids and block phospholipidase which produces AA. This leads to better efficacy in blocking COX and prostaglandin production

Front 16

COX1 vs. COX2

Back 16

- inhibition of COX to decrease PG formation
- COX1: constitutional, present in healthy persons (blood, stomach, kidneys)
- COX2: inducible by cytokines and other mediators)

Front 17

Aspirin

Back 17

irreversibly acetylates COX
- platelets can not regenerate COX b/c have no nuclei and have no proteins for synthesis. Cannot regenerate thromboxine A2
- Acetyl comes off of aspirin when sees COX, forms covalent bond that cannot be reversed
- most effective when given before tissue injury (heart prophylaxis)
- DO not block PG receptors and no effect on previously forned PG

Front 18

Most NSAIDs

Back 18

reversible inhibition of COX b/c only acetylsalic acid forms the special covalent bond

Front 19

Prototype NSAID:
Ibuprofen

Back 19

analgeic, antipyretic, anti-inflammatory
- tx of dysmenorrhea and to close a patent ductus arteriosus in infants

Front 20

Prototype NSAID:
Ibuprofen
Side Effects

Back 20

- GI ulceration and intolerance
- blockade of platelet aggregation
- Tocolytic action: relaxes uterus causing longer gestation, delays labor, complicated delivery w/bleeding
-can induce acute renal faiulure b/c reduced renal blood flow and causes retention; hyperkalemia
- hypersensitivity reactions w/ middle aged asthmatics

Front 21

Aspirin and Salicylates

Back 21

- absorption delayed by food
- dose dependent kinetics
- 3hrs low dose, 12hrs anti-inflammatory dose, 15-30hrs high therapeutic dose

Front 22

Aspirin and Salicylates
TDM levels

Back 22

single dose: less than 60
optimal anti-inf: 15-300
peripheral nausea: 270
central nausea: greater than 270
hyperventilation: greater than 350
fatal dose: 20-30gm

Front 23

Aspirin and Salicylates:
Therapeutic Uses

Back 23

shared use w/NSAID
RA: 4-6gm/day
local uses: poorly absorbed to tx IBS, suppository or rectal enema

Front 24

Aspirin:
Undesired Effects

Back 24

- shared NSAID toxicities
- GI especially common
- hepatic injury: dose dependent; no symptoms just elevated hepatic enzymes
- Reye's Syndrome: severe hepatic injury and encephalopathy in children w/ chicken pox or flu. High Mortality

Front 25

Aspirin:
Effects on Blood

Back 25

- 650mg doubles bleeding time for 7 days; stopped b4 surgery
- high caution for pts on anticoagulants
- risk for hemorrhage: hepatic damage, hypoprothrombinemia, vitK def, hemophilia

Front 26

Aspirin:
Salicylism (toxicity)

Back 26

Mild: headache, dizziness, tinnitus, impaired hearing/vision, mental confusion, drowsiness, fever w/sweating, thirst, hyperventilation, n/v/d
Severe: coma, skin eruptions, acid-base balance, fever, dehydration, CNS stimulation, CV collapse, pulmonary edemam resp failure, death

Front 27

Aspirin:
Tx of Salicylism

Back 27

treat CV collapse, assist respiration, correct acid/base balance, increase salicylate excretion via fluids, bicarbonate to alkalinize the urine and hemodialysis

Front 28

COX 2 Inhibitors:
Celebrex

Back 28

- tx of RA in adults, osteoarthritis
- Side Effects: dyspepsia, diarrhea, abdominal pain, headache.
- Adverse: high dose continuous long term use - increased risk of heart attacks, stroke and death, nephrotoxic

Front 29

Acetominophen

Back 29

- APAP (paracetamol)
- analgesic, antipyretic, very weak anti-inflammatory so often given w/NSAID
- useful to pts intolerant to ASA who need analgesic/antipyretic
- synergistic w/opiod: Oxycodone APAP, Codeine APAP

Front 30

Acetominophen:
Adverse Reactions and Toxicity

Back 30

A.R: dose dependent, potentially fatal hepatic or renal necrosis
- highly reactive metabolite depletes hepatic glutathione and reacts w/hepatic proteins leading to hepatic necrosis
Tox: allergic skin reaction, hypersensitivity unrelated to ASA
Tx: antidotal to APAP to replenish glutathione

Front 31

Traditional DMARD:
Gold

Back 31

aurothioglucose, Gold Na thoomalate, usually IM
- Auronofin

Front 32

Traditional DMARD:
Gold
Toxicity

Back 32

skin, mucous membranes have blue-grey pigment b/c accumulation in tissues
- proximal tubule of kidney damage. monitor LFTt/kidney tests
- severe blood dyscrasias

Front 33

Biologic DMARD:
Leflunomide

Back 33

immunomodulatory agent/unique
- inhibits mitochondrial enzyme involved in de novo synthesis of pryimidine ribonucleotide uridine
- active metabolite for 2 weeks
- reduces s/s of inflammatory arthritis, delays radiologic progression

Front 34

SAARD/DMARD - Biologic:
Anti-TNF Alpha drugs
Enbrel

Back 34

- recombinant fusion protein w/2receptors for TNF-a drugs
- approved tx of RA when other drugs fail

Front 35

SAARD/DMARD - Biologic:
Anti-TNF alpha drugs
Infliximan (Remicade)

Back 35

- chimeric monoclonal antibody to TNF-alpha
- approved to tx RA combined w/methotrexate and to tx Crohns Disease in pts unresponsive to conventional txs

Front 36

SAARD/DMARD:
Interleukin 1 Receptor Antagonist
Anakinara (Kineret)

Back 36

- recombinant form of human IL-1 receptor antagonist
- approved for RA tx
- IL1 is primary pro-inflammatory cytokine, therefore antagonist reverses this reaction
- IL1 also involved in cartilage damage and none resportion of RA
- requires SC administration