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208 Cards in this Set

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Describe RA
- Chronic progressive autoimmune inflammatory disease
- Unknown etiology
- Attacks synovial tissue
- Leading to irreversible joint damage, chronic pain and functional impairment
- Ages 30-60 years old, 75 % women
Is there a cure for RA
No, but progression of disease can be stopped with DMARDS
Describe genetic component of RA
- Association with HLA-DR4, chromosome 6 - strong association with RA and juvenile diabetes
RA symptoms
- Inflammation of joints
- Swelling
- Difficulty moving and pain
- Loss of appetite
- Fever
- Loss of energy
- Anemia (10-20% mild anemia)
RF
Rheumatoid factor - immunologic complex - binds to IgG - most patients with RA have it
Negative RF test with RA symptoms means _
Mild disease
Describe progression of RA
RF antigen presents to IgG or other antibody - inflammatory response - PMN's, leukocytes , monocytes, lymphocytes congregate - phagocytosis of immune complexes - release of lysosomal enzymes - destruction of cartilage and subchondral bone erosion
At the same time inflammatory response causes angiogenesis in synovium, synovial cell proliferation and pannus invasion, which also leads to destruction of the joint
Pannus
1. B cell activity
2. Plasma cell activity
3. Activation of synovial fibroblasts
Synovitis in RA can be attributed to _
Pro-inflammatory cytokines - IL1, TNF alpha and other cytokines
In addition to joint problems RA patients should also be checked for _
Osteopenia due to increased bone resorption by osteoclasts
One of the most common extra-articular manifestations of RA
Nodules - associated with presence of RF (occurs in high titer RF)
What do you see on x ray in people with RA
- Decreased joint space
- Bony erosions (overproduction of TNF alpha, IL1)
- Joint deformities
- Thinning of bones around joints - juxtarticular osteoporosis
- Soft tissue swelling (early RA)
How do you prevent radiological damage in RA
Early RA - major window of opportunity for disease control - apply DMARDS in this phase
Radiographic damage occurs in 1-2 years after disease onset
Which enzyme is inhibited by corticosteroids
Phospholipase A2
Which enzyme is inhibited by NSAIDS
Cyclooxygenase
NSAIDS side effects
-GI IRRITATION - most common
- Skin reactions and rashes
- Increased blood coagulation time (PT test)
- Reversible hepatocellular toxicity (check liver enzymes)
- Impaired renal function (especially if patient is on diuretics - check BUN + creatinine)
Are NSAIDS effective in treatment of RA
While NSAIDS relieve pain and inflammation of RA, they do nothing to halt loss of bone associated with this disease
Corticosteroid side effects
- Diabetes (long time users)
- Weight gain
- Osteoporosis
- Hypertension
- Mood changes (very common, 95%)
- Increased risk of infection
- Bone damage - osteonecrosis
Major classes of DMARDS
- Antimalarial drugs
- Gold compounds
- Penicilamine
- Sulfasalazine
- BRM - biologic response modifiers
IL1 role in RA
- Dominant cytokine associated with RA
- Produced in response to inflammatory stimuli
- Mediates inflammatory and immunological responses
- Broad range of activity including cartilage degeneration and stimulation of bone resorption
- Abundant in synovial fluid of RA patients
Relationship of IL1 and TNF alpha
IL 1 and TNF alpha induce production of each other and they act synergistically
Functions of IL1
- Activates monocytes and macrophages - inflammation
- Induces fibroblast proliferation - synovial pannus formation
- Activates chondrocytes - cartilage breakdown
- Activates osteoclasts - bone resorption
Name drug that is recombinant version of human IL1 receptor antagonist (IL1- Ra)
ANAKINRA - blocks biologic activity of IL1, identical to normal human IL1 - Ra - a single aa methionine has been added at N terminus which stabilizes it
How long does it take for Anakinra to work
2-4 weeks
Pharmokinetics of Anakinra
- Well absorbed after subcutaneous injection
- T 1/2 4-6 hours
Indication for Anakinra
For the reduction of signs and symptoms of moderately to severe active RA in patients 18 or older who have failed AT LEAST 1 or more DMARDS
Adverse effects for Anakinra
- The most common adverse event is transient mild local injection site reaction which lasts 14-28 days
How is ANAKINRA used (alone, combination, etc)
ANAKINRA can be used alone or in combination with DMARDS other then TNF alpha blocking agents
Describe AZATHIOPRINE
- Has been used since mid 1960's to treat RA and SLE
- Derivative of mercaptopurine - functions as structural analog or antimetabolite (acts on precursors of DNA and RNA)
- Alters Ab production and suppression of T cell effects (immunosuppressive)
Adverse effects for AZATHIOPRINE
- Nausea, vomitting
- Leukopenia
- Thrombocytopenia
- Hepatotoxicity (High serum APT and mild jaundice)
- SEVERE BM SUPPRESSION - particularly in patients with renal insufficiency
Drug interactions for AZATHIOPRINE
- Allopurinol - increases serum levels 3-4 folds
- ACE inhibitors (enalapril, captopril) - can cause severe leukopenia
Contraindications for AZATHIOPRINE
- Contraindicated in pregnancy
- Severe leukopenia and thrombocytopenia may occur during treatment - CBC!!!
- Risk of infection during treatment
- May increase risk of neoplasia
Describe HYDROXYCHLOROQUINE
- Antimalarial drug discovered in early 50's
- Decreases inflammation of RA
- Decreases joint pain and inflammation in 60% patients with RA
Drug which most rheumatologists consider to be "safe but weaker second line drugs"
HYDROXYCHLOROQUINE (PLAQUENIL)
Adverse effects of HYDROXYCHLOROQUINE
- Headache
- Dizziness
- Abnormal skin pigmentation
- Visual disturbances
- Edema
- Blood dyscrasia
- Nervousness
- Anorexia
- Weight loss
Most important toxicity of HYDROXYCHLOROQUINE
OCULAR - should see ophthalmologist every 3 months
Describe LEFLUNOMIDE
- FDA approval October 1998
- Similar efficacy to MTX
- Used for patients with definite active RA when aggressive treatment is needed
- Usual time to effect - 4-8 weeks
LEFLUNOMIDE MOA
- Decreases inflammation by inhibition of enzymes necessary for production of pyrimidines - tyrosine kinase and dihydropteorate dehydrogenase
T1/2 - 15 days
Toxicities for LEFLUNOMIDE
- Elevation of liver enzymes with some risk of liver damage
- Renal impairment
- Teratogenic effect
- Low frequency of cardiovascular effects ( angina, tachycardia) was reported in clinical trials
Drug interactions for LEFLUNOMIDE
- RIFAMPIN - blood levels of leflunomide can increase to toxic levels
- TOLBUTAMINE - blodd levels of leflunomide may increase to toxic levels
SULFASALAZINE FDA indications
- Mildly to moderately acute ulcerative colitis - DOC
- Treatment of RA in patients who have not responded to salicylates or other NSAID's
- Treatment of children with polyarticular juvenile RA that have not responded to salicylates or other NSAIDs
Describe SULFASALAZINE
- Combination of 2 different medications - 5-aminosalicylic acid and sulfapyridine, starts working 6-12 weeks, 1/3 of people starting it have to stop because of side effects
SULFASALAZINE MOA
- Split by intestinal bacteria into active metabolies sulfapyridine and mesalamine - BLOCK CYCLOOXYGENASE and inhibit prostaglandin formation which would decrease formation of AA metabolites
SULFASALAZINE adverse effects
- Anorexia
- Headache
- Reversible oligospermia
- CAN CAUSE HYPERSENSITIVITY reactions due to sulfa allergy - allergic reactions include fever and rash
SULFASALAZINE drug interactions
May reduce absorption of DIGOXIN and FOLIC ACID
Contraindications for SULFASALAZINE
- Contraindicated in patients with hypersensitivity to salicylates
- Use with caution in patients with renal and hepatic dysfunction, blood dyscrasias and bronchial asthma
PENICILLAMINE - describe
- For acute and severe RA (seldom used)
- Unknown MOA
- Response delayed (4-12 weeks)
- Can also chelate copper and so used to treat Wilsons disease, mercury or lead poisoning
Common side effects for PENICILLAMINE
- Rashes+ dermatitis - most common
- Severe nausea and vomitting
- Mild to moderate thrombocytopenia and leukopenia
- Mild proteinuria which can progress to nephrotic syndrome - DO UA!!!
Side effects rapidly disappear if therapy discontinued
Most widely prescribed and most commonly used DMARD
MTX - methotrexate
MTX indications
- RA
- Psoriasis
- Psoriatic arthritis
- SLE
- Sarcoidosis

ADDITIONAL USE - anticancer and immunosuppressive if used in high doses
Why MTX is the first line DMARD
- Early onset of action (4-6 weeks)
- Good efficacy
- Favorable toxicity profile
- Ease of administration
- Low cost
Describe MOA of MTX
- FOLATE ANTIMETABOLITE - inhibits dihydrofolate reductase
- Inhibits folate-dependent enzymes involved in ADENOSINE degeneration increasing concentration of extracellular ADENOSINE which inhibits formation of pro-inflammatory cytokines - TNF alpha and IL1
Adverse effects of MTX
- Usually mild and can be managed by temporarily stopping the drug or reducing dose
- Nausea
- STOMATITIS
- GI DISCOMFORT
- MILD ALOPECIA
Those three related to folic acid antagonism
- RASH - common
- Diarrhea
- Headache
SEVERE BUT RARE SE
- Hepatotoxicity progressing to cirrhosis
- Pneumonitis progressing to pulmonary fibrosis
- Bone marrow depression - anemia, leukopenia, thrombocytopenia
Why is it recommended to use folic acid supplementation together with MTX
Stomatitis, GI discomfort and mild alopecia are connected to folic acid antagonism, so folic acid supplementation can help to reduce those side effects
Which population is at higher risk for toxicity from MTX
Elderly due to decreased renal and hepatic function
Contraindications for MTX
- TERATOGENIC - contraindicated during pregnancy or breast feeding
- Kidney disease
- Lung disease
- Liver disease
- Immunodefficiency
- Blood dyscrasias
- Type III hypersensitivity
Drug interactions for MTX
MTX clearance can be decreased by administration of NSAIDS - not problem with low doses of MTX to treat RA
- Can be displaced from plasma protein binding by phenylbutazone, phenytoin and sulfonylureas
Two IM preps of GOLD COMPOUNDS available in US
- Gold sodium thiomalate
- Aurothioglucose
The only oral prep GOLD COMPOUND available in US
AURANOFIN - limited efficacy
GOLD COMPOUNDS MOA
- Not fully understood
- Suppresses increased phagocytic activity - either inhibits macrophages or prevents release of LYSOSOMAL ENZYMES in the joint - main thing responsible for erosion
Most common adverse reaction with GOLD COMPOUNDS IS
RASH
Adverse effects for GOLD COMPOUNDS
- DERMATITIS - accompanied by pruritus
- STOMATITIS - may be preceded by metallic taste in mouth
- BLUE OR GRAY SKIN DISCOLORATION - from gold deposition in that tissue, PHOTOSENSITIVITY may also occur
- Mild proteinuria - if severe may indicate toxic nephritis
In what case GOLD COMPOUND therapy should be stopped
If proteinuria exceeds 500 mg in 24 hours - glomerular filtration is down - can lead to renal failure, hepatotoxicity and CNS toxicity
Most common hematologic abnormality with GOLD COMPOUNDS is _
EOSINOPHILIA
if this or any other hematologic abnormalities occur - discontinue therapy
How do you alleviate signs and symptoms of toxicity with GOLD COMPOUNDS
Chelating agents - DIMERCARPOL and PENICILLAMINE
Contraindications for GOLD COMPOUNDS
Patients with
- SLE
- Sjogren syndrome
- Severe debilitation
- Uncontrolled CHF and hypertension
- Should be used cautiously in patients receiving drugs that can cause NEPHROTOXICITY
Criteria for diagnosis of RA
- Morning stiffness
- Arthritis of 3 or more joint areas - at least 6 weeks
- Arthritis of hand joints - at least 6 weeks
- Symmetrical arthritis - at least 6 weeks
- Rheumatic nodules
- Serum RF
- X ray changes
DMARDS that are MODERATELY EFFECTIVE and employed in milder disease
- Hydroxychloroquine
- Sulfasalazine
- Auranofin
- Minocycline
DMARDS that are VERY EFFECTIVE and are used in moderate to severe RA
MTX - most popular
- Leflunomide
- TNF blockers - Remicade, Humira, Enbrel
- IL 1 blocker - Anakinra
- Azathioprine
- IM Gold compound
- Cyclosporine (immunosuppressive)
Which lab tests are important when assessing for RA
- CBC
- RF
- C-reactive protein - indicaiton of inflammation
- ESR - erythrocyte sedimentation rate
- X ray
Primary palliative agents in treatment of RA
NSAIDS - do not significantly alter course of disease - analgesic and anti-inflammatory
What is the problem with conventional DMARDs
Long term tolerability
Name Biological Response Modifiers (BRM)
ETANERCEPT - reduces circulatory TNF alpha levels, for patients who are treatment-naive, with DMARD-refractory RA and those with moderately to severe active RA, not recommended in patients with CHF or with demyelinating disease
INFLIXIMAB - monoclonal Ab, for use in refractory DMARD RA, combination with MTX, associated with cytokine release syndrome - fever, chills, headache - infusion related
How do you ensure clinical outcome with DMARDS
- Radiologic evidence of clinical efficacy
- Improvement of clinical symptoms
At low doses aspirin plays what role
ANTI PLATELET AGENT - widely used to reduce risk of MI and stroke - targets cyclooxygenase - non selective - both COX 1 and COX 2
At moderate doses NSAID's are effective as what
- Mild analgesics for conditions such as headache and muscle aches and also reduce fever
At high doses NSAID's are used as what _
- Anti -inflammatory and are heavily used for arthritis
NSAIDS DO NOT SLOW PROGRESSION OF JOINT DISEASE (use DMARD's for that)
Describe steps of inflammation
- Exudation of fluid from vessels to site of injury
- Attraction of leukocytes to the site of injury for destruction of bacteria, tissue debris, etc
- Activation of chemical mediators
- Restoration of injured tissue to normal structure and function
Cardinal signs of inflammation
Rubor = redness
Dolor = pain
Calor = heat
Tumor =swelling
Functio laesa = loss of function
Major causes of inflammation
- Infection
- Trauma
- Physical injuries
- Chemical injuries
- Immunologic injuries
- Tissue death (necrosis, not apoptosis)
3 types of inflammation
- Acute (neutrophils)
- Immune response
- Chronic (macrophage)
Mediators of acute inflammation
- Histamine
- Leukotrienes (can block with corticosteroids)
- Bradykinin
- Prostaglandin (block with aspirin)
- Serotonin
Immune response inflammation provides two outcomes _
- Beneficial - invading organisms can be eliminated by phagocytosis and neutralization
- Harmful - can lead to chronic inflammation without resolution of underlying infectious process
Mediators of chronic inflammation
- IL1, 2, 3 - activate lymphocytes and prostaglandin production
- Granulocyte-macrophage-colony stimulating factors for activation of macrophages and granulocytes
Cyclooxygenase (COX) pathway of AA metabolism produces _
- Prostaglandins
- Thromboxane
COX 1
- More involved in homeostatic function and is non-selective
COX 2
Induced during inflammation and cause facilitation of inflammatory response
Lipooxygenase pathway of AA metabolism produces _
Leuotrienes - effect eosinophils, neutrophils, macrophages, cause bronchoconstriction and alteration in vascular permeability
Most widely prescribed corticosteroid
Prednisone
Agents that reduce inflammation and relieve pain
- NSAIDS
- Non-opioid analgesics
- Glucocorticoids
Major adverse effects of salicylates
- Hepatotoxicity
- Nephrotoxicity
- GI irritation
SHOULD NOT BE COMBINED WITH NSAIDS
Name non- selective COX inhibitors
- Aspirin
- Ibuprofen
- Indomethacin
- Ketoprofen
- Ketorolac
- Naproxen
- Diclofenac
Selective COX 2 inhibitors
- Celecoxib (CELEBREX) - only one that is still on market but can be prescribed only by specialists
- BEXTRA and others have been removed off market because of serious cardiac complications
Historically _ has been DOC against inflammatory condition but now _ is DOC
Aspirin
Ibuprofen
3 effects of aspirin
- Analgesic - reduces mild to moderate pain
- Antipyretic - reducing fever
- Antiplatelet
Selective property of aspirin
- Decreases incidence of TIA, unstable angina, coronary artery thrombosis with MI and colon cancer
- Incidence of MI can be reduced by giving 325 mg every other day
Which drug should be discontinued week prior to surgery to avoid bleding complication
ASPIRIN
Why is aspirin contraindicated in viral infections in kids
REYES SYNDROME
Adverse effects of aspirin
- Gastritis (take with meal or water)
- increase incidence of gastric ulcers
- Vomitting, tinnitus, vertigo - in case of overdose - SALICYLISM
- Unnoticed fecal blood loss
- Respiratory alkalosis due to increased ventilation
Aspirin is contraindicated in _
Hemophilic patients
Ketoprofen MOA
Inhibits COX and lipooxygenase activity - can also be used for gout and dysmenorrhea
Ketoprofen adverse effects
GI dyscomfort + nervous system effects
Which NSAID is like aspirin - has analgesic, anti-inflammatory and antipyretic activity - BUT DOES NOT ACT ON PLATELETS
DICLOFENAC
Non selective COX inhibitor that may affect TNF
FLURBIPROFEN
Which NSAID is used as topical ophthalmic preparation for inhibition of intraoperative miosis
FLURBIPROFEN
Ibuprofen is contraindicated in patients with _
- Nasal polyps
- Angioedema
- Bronchospastic reactivity to aspirin
Indomethacin
- Gout
- Ankylosing spondylitis
- RA
- Patent ductus arteriosus
Adverse effects of INDOMETHACIN
- ABDOMINAL PAIN
- HEMORRHAGE
- PANCREATITIS
- DEPRESSION
- Diarrhea
- Headache
- Dizzines, confusion

RARE - hyperkalemia, thrombocytopenia, aplastic anemia
Ketorolac is mainly used as _
ANALGESIC
Where is KETOROLAC used
- To replace morphine in situations with mild to moderate post surgical pain
- Ophtalmic preparation
KETOROLAC adverse effect
- Increased incidence of peptic ulcer
- Renal failure if used for postsurgical pain for more then 5 days
FENOPROFEN is less used due to _
Association with interstitial nephritis
DICLOFENAC is associated with _ toxicity
LIVER
DMARD with shortest half life
ANAKINRA - 4-6 hours
DMARD with longest half life
LEFLUNOMIDE - 15 days
SULFASALAZINE should not be used in people with _
G6PD defficiency
Which DMARD can chelate copper so can be used to treat Wilsons disease
PENICILLAMINE
Neuromuscular blocking drugs
Used to produce muscle paralysis in order to FACILITATE SURGERY or ARTIFICIAL VENTILLATION
Spasmolytic drugs
A drug that reduces abnormally elevated MUSCLE TONE (SPASM)without paralysis - Baclofen, dentrolene
Describe pathophysiology of spasms
SPASMS - sudden violent painful involuntary CONTRACTIONS of muscle or group of muscles
- Involvement of MOTOR NEURONS (balance between muskuloskeletal movement and body posture)
- ACTION POTENTIALS by motor neurons are conducted directly to nerve terminals in muscle fibers that form synapses called NEUROMUSCULAR JUNCTIONS (NMJ)
- ACH is released from nerve terminal and stimulated NICOTINIC RECEPTORS ON MUSCLE producing CONTRACTION
Describe pathophysiology of spacsticity
- In contrast to spasm spasticity is INCREASE IN PASSIVE STRETCH RESISTANCE of muscle or muscle group - INCREASED MUSCLE TONE OR CONTRACTIONS cause movement to be STIFF AND AWKWARD
- SPASTICITY IS CONSIDERED TO BE PERMANENT CONDITION and may progress to disabling condition of therapy is not instituted
Common causes of spasticity
- Close head injuries
- Cerebral palsy
- MS
- Stroke
Two major classes of skeletal muscle relaxants
- Neuromuscular blockers
- Spasmolytics
How do neuromuscular blockers act
Interfere with TRANSMISSION at neuromuscular end plate and ARE NOT CENTRALLY ACTING DRUGS
Spasmolytics are centrally acting muscle relaxants EXCEPT _ which is peripheral drug
DANTROLENE
Major use of skeletal muscle relaxants
Muscle strains
Back pain
Name centrally acting muscle relaxants used to treat spasticity
Baclofen
Botulinum toxin type A (BOTOX)
Diazepam (VALIUM)
Tizanidine
Peripherally acting drug for spasticity
DANTROLENE
Name centrally acting drugs for spasms
Carisoprodol
Chlorphenesin
Chlorzoxazone
Cyclobenzoprine
Diazepam
Metaxalone
Methocarbamol
Vigabatrin
Spasm is mediated by _ while spasticity is mediated by _
Spasm - LOWER MOTOR NEURONS

Spasticity - UPPER MOTOR NEURONS
BACLOFEN MOA
- Acts within spinal cord to SUPPRESS HYPERACTIVE REFLEXES involved in regulation of muscle movement
- Structural analog of GABA (mimics action of GABA on spinal neurons)

ACTS ON THE LEVEL OF SPINAL CORD TO RESTORE INHIBITING TONE!!!
Therapeutic use of BACLOFEN
- Can REDUCE SPASTICITY associated with MS, spinal cord injury and cerebral palsy
- Not effective in stroke
- Drug decreases FLEXOR AND EXTENSOR SPASMS and suppresses resistance to passive movement - reduces discomfort of spasticity and allows increased performance
- PREFERRED TO DANTROLENE in patients whose spasticity is associated with significant muscle weakness
- DOES NOT relieve spasticity of Parkinsons disease
Adverse effects of BACLOFEN
- MOST COMMON - GI and CNS effects
- CNS effects - CNS depressant, causes DROWSINESS AND DIZZINESS (should not be driving), weakness and fatigue - especially in early stage
Contraindications for BACLOFEN
- SHOULD NOT BE USED WITH ALCOHOL AND OTHER CNS DEPRESSORS
Max amount of BACLOFEN
80 mg/D (20 qid)
Overdose with BACLOFEN can lead to _
COMA and RESPIRATORY DEPRESSION - no antidote, supportive treatment
DIAZEPAM
- ANTI-ANXIETY DRUG
- Member of BENZODIAZEPINE family
- Acts within CNS by facilitating GABA mediated PRESYNAPTIC INHIBITION (mimics action of GABA in spinal cord and brain)
- Can be used in patients with muscle spasm of almost any origin including local muscle trauma
- Produces SEDATION
Side effects of DIAZEPAM
SEDATION (MOST COMMON)- to minimize sedation initiate therapy at lower dose
MOA DANTROLENE
Suppression of Ca release from SR - decrease in ability of skeletal muscle to contract
Therapeutic advantage of DANTROLENE
Minimal effect on smooth and cardiac muscle
Therapeutic use of DANTROLENE
- Spasticity
- MALIGNANT HYPERTHERMIA
Describe malignant hyperthermia
- Life threatening syndrome that can be triggered by any general anesthetic and by succinylcholine - neuromuscular blocker.
- Prominent symptoms - muscle rigidity and profound elevation of temp
- Heat of malignant hyperthermia is generated by muscle contraction occuring secondary to massive release of Ca from SR
- DANTROLENE relieves symptoms by acting on SR to block Ca release
DANTROLENE adverse effects
- HEPATIC - dose related liver damage - MOST SERIOUS TOXICITY (1/1000) - test liver function before and during treatment
- Also CNS effects
- Increased urinary frequency
Drug interaction of DANTROLENE
Increased toxicity:
- Estrogen
-Warfarin
- CNS depressants
- Clindamycin
- Verapamil
- Tolbutamine
Which drug used for local acute muscle spasms has longest half life and most protein binding
CYCLOBENZAPRINE
DANTROLENE
CYCLOBENZAPRINE IS CONTRAINDICATED IN PATIENTS WITH HISTORY OF _
PORPHYRIA
Arachidonic acid is derived from _
CELL MEMBRANE LIPIDS
Name natural EICOSANOIDS
Prostaglandins
Thromboxanes
Leukotrienes
Lipoxins
Lipid derived autocoids derived from AA formed from _
DIETARY LINOLEIC ACID
EICOSANOIDS are stored in cells - T/F
FALSE - they are not stored in cells, synthesis depends on release of AA from membrane lipids by phospholipases that are activated by physical, chemical or hormonal stimuli
Prostaglandin chemical structure
Modified fatty acid attached to 5 membered ring
Therapeutic use of prostaglandinds
- Obstetric
- Cytoprotection of stomach
- Pediatrics (patent ductus arteriosus)
- Impotence
- Glaucoma (relieve intraocular pressure)
- Pulmonary hypertension
Which prostaglandin has most broad multiorgan application
PGE2
Describe use of PGE2
- CYTOPROTECTIVE - inhibits gastric acid secretion, increases bicarbonate
- VASODILATOR - maintains kidney function by increasing glomerular filtration and increasing sodium and H2O excretion
- RELAXES RESPIRATORY SMOOTH MUSCLE
- INHIBITS PLATELET AGGREGATION
- CAUSES STRONG UTERINE CONTRACTION - labor induction
- INCREASES BODY TEMP - increases cAMP and triggers hypothalamus to increase body temp
- INFLAMMATORY MEDIATOR
Describe use of PGI2
- INHIBITS PLATELET AGGREGATION and causes hypotension
- VASODILATOR
- RELAXES UTERINE MUSCLE
- CYTOPROTECTION
Describe main function of TXA2
- Potent STIMULATOR OF PLATELET AGGREGATION
- Potent VASOCONSTRICTOR
- Potent BRONCHOCONSTRICTOR
TXA 2 can be blocked by _ which will cause _
Aspirin
Inhibition of platelet aggregation
Name EICOSANOIDS as therapeutic agents
- Alprostadil
- Carboprost
- Caverject
- Dinoprostone
- Prostacycline
- Misoprostol
Which two EICOSANOIDS are used for 1st and 2nd trimester abortions
CARBOPROST - IM
DINOPROSTONE - intravaginally
Which EICOSANOID is used to control postpartum hemorrhage and uterine atony
CARBOPROST
Which EICOSANOID is used in pediatrics to maintain patency of ductus arteriosus in neonates with congenital heart defects - pulmonary atresia, tetralogy of Fallot, transposition of great vessels, aortic coarctation, interruption of aortic arch
ALPROSTADIL - IV infusion can be used until surgery can be performed, only temporarily, has toxic effects
Forms of DINOPROSTONE
PROSTIN E2 - vaginal suppository used for abortions, also used to induce labor, causes cervical ripening and also to control postpartum hemorrhage and uterine atony
PREPEDIL GEL - gel used to ripen cervix and induce labor
CERVIDIL - vaginal insert
Which EICOSANOID is used orally to prevent peptic ulcers in patients on chronic NSAIDS toxicity
MISOPROSTOL
Adverse effects of ALPROSTADIL
- Prolonged treatment can rupture ductus
- APNEA - 10-20% of neonates
- Other SE - flushing, hypotension, fever, seizures, diarrhea, hemorrhage, rarely cardiac arrest
Which EICOSANOID is used for treatment of impotence
Alprostadil (CAVERJECT) - naturally occuring from PGE1, ACTS AS SMOOTH MUSCLE RELAXANT LOCALLY, injected via cavernous arteries - PRODUCES ERECTION with 5-20 min lasting about 1 hour
Side effects of CAVERJECT (Alprostadil)
PROLONGED ERECTION
Bleeding at injection site
Penile pain
CONTINUED USE CAN CAUSE PENILE FIBROSIS
Which APROSTADIL form is used for treatment of OPEN ANGLE GLAUCOMA
XALATAN - PGF2 analog that reduces elevated IOP
- PRODRUG hydrolyzed by esterases in cornea to active LATANOPROST ACID
Which EICOSANOID is used IV for treatment of PRIMARY PULMONARY HYPERTENSION
EPOPROSTENOL (high pulmonary artery pressure causes R ventricular hypertrophy)
- Causes vasodilation and inhibition of platelet aggregation
EPOPROSTENOL adverse effects
BROAD ADVERSE EFFECT PROFILE
FLUSHING - common, headache, nausea, diarrhea, vomitting, tachycardia, jaw pain, fever, hypotension, anxiety, etc
Name drugs that inhibit LEUKOTRIENES
5-LO INHIBITORS - ZILEUTIN

Lekotriene receptor antagonists - anti-asthmatics - ZAFIRLEUKAST and MONTELEUKAST
- Also corticosteroids
Which drugs inhibits prostaglandins
NSAIDS - inhibit COX

CORTICOSTEROIDS - inhibit PLA2 - NOT DIRECTLY - stimulate synthesis of lipocortins that inhibit phospholipase A2
Describe GOUT
Clinical syndrome - deposition of monosodium urate monohydrate crystals in tissue - accompanying inflammation - degeneration of joints and soft tissues
Gout in men vs women
Women have lower incidence and later onset of gout - attributed to better urate excretion, attack before age 30 is rare and suggests genetic metabolic disorder
GOUT is associated with
HYPERURICEMIA
Drugs used for treatment of acute gout
COLCHICINE
NSAIDS
GLUCOCORTICOIDS
ANALGESICS
Drugs used in treatment of chronic gout
URICOSURICS
ALLOPURINOL
Drug of choice for treatment of chronic gout
ALLOPURINOL
Why does uric acid deposit in tissues
URIC ACID is the end product of purine metabolism and is POORLY SOLUBLE especially in acidic environment
TOPHI
URIC ACID DEPOSITS under the skin around affected joint, cartilage of ear, tendons or other tissues (can also deposit in kidney resulting in chronic kidney failure)
Tophi are a sign of _ gout
CHRONIC
Symptoms of gout
- Appears as ACUTE ATTACK often coming overnight
- Within 12-24 hours there is SEVERE PAIN and swelling in affected joint
- SKIN over joint may be RED AND SHINY
What is the concentration of uric acid necessary for DIAGNOSIS OF GOUT to be made
- More then 7 mg/dL in men

- More then 6 mg/dL in women
Manifestations of Hyperuricemia
- Subcutaneous tophaceous deposits
- Urolithiasis - crystals in urine combine to form stones
- Nephrolithiasis - kidney stones
- Renal diseases involving tubules, interstitium, glomeruli
4 clinical phases of GOUT
- Asymptomatic hyperuricemia
- Acute gouty arthritis
- Intercritical gout (intervals between acute attacks)
- Chronic tophaceous (UA deposits) gout
Gouty arthritis
- Arthritis especially of BIG TOE as a result of gout, often precipitated by TRAUMA, INFECTION, SURGERY.
- Initial attacks are usually monoarticular but later attacks are polyarticular
Causes of GOUT
- EXCESS OF URIC ACID due to either decreased excretion or increased production
- HYPERURICEMIA - high levels of uric acid in blood
- RECURRENT ATTACKS OF GOUTY ARTHRITIS - deposition of uric acid crystals in joints

URIC ACID DEPOSITS CAN ALSO OCCUR IN KIDNEY CAUSING KIDNEY STONES

- OBESITY
- High ALCOHOL intake
- High intake of food containing PURINES
- DIURETICS - cause volume depletion
- Longstanding KIDNEY DISEASE
Foods that are high in purines
- Offal foods such as liver, kidney, tripe, sweetbreads and tongue
- Excessive amounts of red meet
- Shellfish, fish roe and scallops
- Peas, lentils and beans
Hyperuricemia ALWAYS LEADS to GOUT - T/F
FALSE - hyperuricemia DOES NOT always lead to gout, but GOUT is ALWAYS preceded by hyperuricemia
How does uric acid form
Purine is converted to HYPOXANTHINE by XANTHINE OXIDASE and the HYPOXANTHINE is converted to XANTHINE by XANTHINE OXIDASE and XANTHINE is converted to URIC ACID
Therapeutic strategies for treatment of gout
- Interfere with uric acid synthesis with ALLOPURINOL
- Increasing uric acid secretion with PROBENECID or SULFINPYRAZONE
- Inhibiting leukocyte entry into affected joints with COLCHICINE
- Anti- inflammation - NSAIDS
Goals of drug therapy of GOUT
- To PREVENT OR REDUCE INFLAMMATION and pain of acute attack
- To REDUCE BLOOD URATE LEVELS either by increasing urate excretion or by decreasing urate production
DOC for treatment of acute gout
COLCHICINE
Drugs that INCREASE URATE EXCRETION
PROBENECID
SULFINPYRAZONE
Drugs that DECREASE URIC ACID PRODUCTION
ALLOPURINOL
MOA of COLCHICINE
BINDS TO TUBULIN AND INHIBITS MICROTUBULE ASSEMBLY - microtubules in granulocytes and inflammatory cells are affected and granulocytes cannot migrate to inflamed area
NET EFFECT - decrease release of LACTIC ACID - decreases inflammation and further urate deposit caused by lactate-induced low pH is prevented
Use of COLCHICINE in treatment of GOUT
- DIAGNOSTIC - results in dramatic relief
- PROPHYLACTIC - very low doses to decrease risk of acute attacks
- TREATMENT OF ACUTE GOUT
COLCHICINE toxicity
- GI symptoms of nausea, vomitting, abdominal pain,diarrhea are common - 80% of patients get those
- HEMORRHAGIC GASTROENTERITIS in case of OVERDOSE - if not stopped can progress to vascular damage, renal toxicity, muscular depression and depression of CNS
MAXIMUM AMOUNT OF COLCHICINE PER DAY
6 MG !!!!!!!!!!
DRUG OF CHOICE FROM NSAIDS for treatment of acute gout attacks
INDOMETHACIN
MOA URICOSURICS
BLOCK REABSORPTION OF URATE IN RENAL PROXIMAL TUBULE - also block urate tubular secretion
NET RESULT - INCREASED URATE EXCRETION IN URINE
NAME URICOSURICS
PROBENECID
SULFINPYRAZONE
Adverse effects of URICOSURICS
- Initiation of therapy may precipitate acute gout attack - prevent by prophylactic use of colchicine or NSAID
- Best not to start treatment with uricosuric until 1-2 weeks after acute gout attack
- Strongly bound to plasma albumin - potential for drug-drug interaction
- Tend to PRODUCE URIC ACID STONES - should be taken with plenty of water
Sulfinylpyrazone should be taken with _
FOOD OR MILK to avoid common GI irritation
Other then for treatment of gout PROBENECID is also used where?
- As adjunct in penicillin therapy - doubles levels of penicillin
MOA of ALLOPURINOL
- INHIBITS XANTHINE OXIDASE which converts hypoxanthine to xanthine and xanthine to uric acid
- Drug is oxidized to OXYPURINOL - which is an irreversible "suicide substrate" inhibitor of XO
- RESULT IN INCREASED CONCENTRATIONS OF MORE WATER SOLUBLE HYPOXANTHINE - less likely that uric acid crystals will precipitate in joints and tissues
Therapeutic uses of ALLOPURINOL
- Generally used in SEVERE CHRONIC GOUT
- Also valuable in PREVENTION OF HYPERURICEMIA in patients with leukemia and some other cancers undergoing chemotherapy with cytotoxic agents
- Also used TO PREVENT RECURRENCE OF URIC ACID KIDNEY STONES
ALLOPURINOL side effects
- SKIN RASH - can become serious if therapy is continued - higher incidence of rash when used with AMPICILLIN
- Rare BM depression, hepatotoxicity, interstitial nephritis, peripheral neuritis and cataracts
Drug interactions for ALLOPURINOL
- Xanthine oxidase inactivates 6-MERCAPTOPURINE AND AZATHIOPRINE - doses of these drugs must be reduced to 1/3 or 1/4 of usual dose
- In some patients it may interfere with hepatic inactivation of ORAL ANTICOAGULANTS - MONITOR PT
- May increase concentration of THEOPHYLLINE metabolite (anti-asthmatic drug)