What is the primary Mech of Action (MOA) for NSAIDS

Inhibition of COX enzymes via reversible competitive inhibition

ONLY Aspirin has Irreversible Inactivation

Anti-Inflamm

Analgesic

Antipyretic

Inhibition of Prostaglandin and thromboxane synthesis; stabalize lysosomal enzymes; Inhibit plasmin; inhibit activation and function of neutrophils, macrophages and mast cels

*Note: NSAIDS HAVE NO EFFECT ON SPECIFIC IMMUNE RESPONSE*

Narcotic- opiate, central, & morphine-like

Antipyrectic- peripheral, non-opiod, aspirin-like analgesics

NSAIDs mediate the inhibition of PG synthesis which promotes the return of the body to normal set-point, causes dilation and sweating to reduce body temp

*Note PG's are responsible for the rise in body temp set-point

Aspirin- 70%

Salicylic acid- 100%

Low Dose: Central antipyrectic effects & depression of hypothalamic circuits involved in pain modulation

High Doses: stim chemoreceptor trigger zone & afferent stim of CN VIII

Low Dose: No effect

Mod/High: Stim respiration directly on the medulla resp center

Toxic Dose: Direct depression of resp center

Low/Mod Dose: No effect

High Dose: Direct dilation of peripheral BV & increase in circulatory plasma volume

Low/Mod Dose: Inhibition of tubular uric acid excretion & Small decrease in GFR

High Dose: Inhibition of tubular uric acid reabsorption; Decrease in GFR (can cause ARF in pts with renal disease, hypovolemia or cardiac failure)

Chronic Doses: Renal Lesions

Low/Mod Dose: Decrease platelet Aggregation (aspirin cause to last 7-8 dys due to irreversible inhibtion).

*Due to reduced Thromboxane (promotes aggregation) and increase PGI2 (inhibits aggregation)

High Dose: Sideropenia (low iron level) & Hypoprothrombinemia

Stomach: Erosive Gastritis.

*Via local effects: Irritation of mucosa, increased [IC] of salicylate & prolonged gastric emptying

*Via systemic effects: increased gastric secretion and decreased bicarb/mucous production resulting from the inhibition of PG synthesis

Liver: Direct stim of bile secretion & Severe hepatic Injury (Reyes Syndrome)

High Dose: Compensated Resp Alky

Toxic Doses: Uncompensated Resp & Met Acidosis

High Doses: Hyperthermia (uncoupling of oxy-phos in sk. muscle); Hypoglycemia (insulin stimulation); Hyperglycemia and glycosuria ( adrenaline release and increased glycogenolysis); Hyerperkalemia (increased K reabsoprtion by kidney)

* Remember 4 H's

Aspirin in: Antiplatelet Dose (80-325); Analgesic/Antipyretic (300-600 or 6-10 in children)

Anti-Inflam (1000 or 10-15 in childrem)

*Doses in mg

Used locally Dermatologically as: Keratolytics, antifungals, and counterirritants

Systemic Use: Antipyresis (in dangerous fevers); Analgesia (non-specific pain)

Inflam Disease: Rheumatic fever, RA, Ankylosing Spondylitis (aspirin least effective); Ulcerative colitis & Crohns  (sulfasalazine only); Thromboembolic Diseases (MI, Stable&unstable angina, A-fib, Arterial thromboembolism, TIA)

Common: Dyspepsia, Heartburn, Naseua, diarrhea, Fecal Blood Loss

Sulfasalazine Only: Arthralgias(joint pain), myagias (muslce pain), bone marrow suppression, malaise (general discomfort)

Folate absorption impairment

OD: Mild= Headache, dizzy, tinnitus, hearing impairment, vision dimness, confusion, sweating, hyperventilation, n/v, diarrhea

Serious OD: Confusion, deafness, vertigo, diplopia, resp depression, change in MS (hallucination, delirium, etc), coma, GI bleed, n/v, Hyperglycemia in adults, Hypoglycemia in children

Hypersensitivity rxns; chronic erosive gastritis

peptic ulcers; liver disease

hypochromic anemia

Reyes Syndrome in Children

Anaphalaxia; Vascular shock

angioneurotic & laryngeal edema

uticaria & rhinitis

Sulfasalazine Only: Fever, exfoliative dermatitis

Pancreatitis, pneumonitis, hepatitis

Pericarditis, hemolytic anemia

Prev: Mostly females in 4th & 5th decade of life

Etio: due to chronic us (6-8mths) leads to drug accummulation

Patho: Chronic inhibition of PG synthesis

S/S: Back pain, hematuria, kidney [] ability affected

Prognosis: Remove drug early = good recovery

If drug not removed in good time= renal insufficiency

Prev: Children & young adults

Etio: Unknown

Patho: Microvesicular fatty infiltration of liver and other organs & Cerebral Edema

S/S (2 Phases): 1. Resp Infection

2. After 4 dys: N/V, change in mental status suddenly, Lab signs of liver damage

Prognosis: Mild or progression to toxic encephalopathy

Recovery may still lead to mental disturbancs

Ulcers; Alcohol consumption

Coag disorders (i.e. Hemophilia)

G6DH deficiency

Renal disease

Gout

Heart failure

Severe Hypertension

Hepatic disease

Asthma

NSAID Hypersensitivity

Viral Fever in children

Pregnacey or Breast feeding

Use along with: Methotrexate, Anticoags, Bilirubin, Corticosteroids, Phenytoin, or Probenecid

Less pronounced CNS & GI effects

Minimal to no effect on Acid/Base and uric acid secretion

Oral, Topical, & Parenteral (IV)

2hours

Closing DA in pre-term infants

Osteoarthritis of knee (Topical form)

Post-surgical dental pain

Aseptic Meningitis

Fluid retention

Nasal polyps

Angiodema

Bronchopastic reactivity

Admin with aspirin

Oral, Parenteral (IM or IV), opthalmic

4-10 hours

40% undergoes metabolism

Primarily used for analgesic action

replace morphine post-surgical

decreases opiod req by 25-50% when given together

Ocular inflammation

Oral, Rectal, Opthalmic, Parental, Topical

4-5 hours

~85% metabolized

Non-selective COX inhibitor

Inhibits PLA & PLC

Reduces neutrophil migration

Decreases T & B cell proliferation

Gout

Ankylosing Spondylitis

Closure of DA

Gingivitis

Analgesia in epidural injection

Headache, dizziness, and confusion as well as depression

Pancreatitis, thrombocytopenia, aplastic anemia, renal papillary necrosis

Use with Probenecid (prolongs the half-life of clearance)

Pregnacy 3rd trimester (risk of DA closing prematurely, bleeding disorder, and kidney failure)

Oral ONLY

57 Hours!!!

Metabolism is > 90%

Nonselective COX inhibitor

Inhibits polymorohonuclear leukocyte migration @ high dose

Decrease ROS @ high dose

Inhibits Lymphocyte function @ high dose

Increased incidence of peptic ulcer & bleeding

9.5 X higher than any other NSAID

ORAL ONLY

11 hours

CV Risk= Most important; carries FDA Label

Rash

Ulcers but less then other drugs in class

Interactions with Warfarin

Pregnancy (can inhibit labor)

Oral & Rectal

2-3 hours (increase x 2 with toxic doses or patients with liver disease)

Potent inhibitor of COX enzyme in the CNS

Weak inhibitor in inflammed tissue

Analgesic and Antipyretic

*Effects related to peripheral PG inhibition are absent

*Few Adverse effects at therapeutic doses

Antipyretic

Analgesic (in mild/mod pain not due to inflammation of or when NSAIDS contraindicated)

Hemophiliacs

Patients with peptic ulcers

Pts with adverse effects to aspirin

Increase in Hepatic enzymes, dizziness, excitement

disorientation(@high dose)

Poisoining: Can occur @ doses of (150-250 mg/kg in adults; 250 in children = fatal)

*due to NAPQUI- reacts iwth sulfyhdryl groups because glutathione gets depleted at high doses leaving the groups open for rxn

Patho: Centrilobular necrosis; 10-20 = death due to hepatic failure

S/S: first two days = n/v, and abd pain

clinical indications of liver damage after 2 days

Therapy: NAC - needs to be admin within 16 hours; replenishes glutathione stores which promotes metabolism of NAPQI

What should you never use Acetominophen to treat

hint: Med students

These act like transcription factors and alter gene expression;

They can also influence funtion of other transcription factors

Important dose-related effects on carbs, proteins, and fat metabolism

GCC's are required for gluconeogenesis and glycogenogenesis

GCCs increase serum glucose and insulin release

GCC inhibit muscle uptake of glucose

GCC stimulate lypolysis via lipase

Have effects on lymphoid and connective tissue, muscle, fat, bone, & skin

Large amounts lead to decreased muscle mass and weakness as well as thinnin of the skin

Osteoporosis in Cushings syndrome due to GC induced effects on bone

In Children, reduced growth

reduces effects of inflamm dramatically

they inhibit the [], distribution, and function of leukocytes and have suppressive effects on cytokines and chemokines

They inhibit the function of tissue macrophages and antigen-presenting cells

Can produce behaivoral disturbances i.e. Insomnia, depression

Can increase intracranial pressure with large doses

Can suppress the release of pituitary hormones with chronic use

What effect does GCCs have on the kidneys

Dx & Tx of adrenal disfunction:

Addisons: given as supplement

Congenital Adrenal hyperplasia: given to induce feedback inhibition of ACTH

Cushings: giving during and after tumor remova

Aldosteronism

Acute Adrenocortical insufficiency: supplement

Stimulate fetal lung maturation

Tx of nonadrenal disorders i.e. Allergic rxns, Collagen vascular disorders, Eye disease, etc

MOST EFFECTIVE in Skin Disease i.e. dermatitis

What should be avoided in prolonged high dose therapy of GCCs? Why?

Hint: Withdrawal

Lead to Cushings like features:

Moon face, fat redistribution, increased fine hair growth over thighs and trunk

Increase insulin need due to glucose production increase; leads to weight gain, muscle wastes, thinning of skin

Diabetes

Insomnia, ulcers, pancreatitis, behaivoral changes (early effects)

Myopathy, weight loss, depression (late effects)

Peptic ulcer

Heart disease

Hypertension

TB, Varicella

Psychoses

Diabetes

Osteoporosi

Glaucoma

Beta-Blockers, Anticonvulsants (valproic acid), & NSAIDs

Calcium Channel Blockers (varapamil, diltiazem) & Trycyclic Antidepressants (amitriptyline & doxepin) can be used but are not FDA approved for migrains