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238 Cards in this Set

  • Front
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role of sympathetics and parasympathetics in the eye
-Sympathetics: iris dilator muscle=alpha adrenergic; superior tarsal muscle (raise eyelid)=alpha adrenergic; relaxation of ciliary muscle for far vision=beta adrenergic
-Parasympathetic: constrictor muscle in iris=muscarinic; contraction of ciliary muscles for accomodation=muscarinic
Signs of Horner's syndrome
1. Anisocoria: effected eye less dilated; accentuated by darkness; light reaction good
2. Ptosis
3. Raised eyebrow (because need to use voluntary eye muscles to keep eye open)
4. If present for a few years, lighter colored eye (because less sympathetic stimulation of melanocytes)
Describe the sympathetic pathway to the eye
-First order neuron: Cell bodies originate in hypothalamus and descends to C8/T1 in spinal cord
-Second order neuron: Cell bodies in C8/T1...give off preganglionic axons that pass over the apex of the lung and under the subclavian artery...synapses on superior cervical ganglia
-Third order neuron: cell bodies in superior cervical ganglia...give off postganglionic axons that course through cavernous sinus to the eye
What is 10% cocaine solution used for?
To diagnose Horner's syndrome
-Will block reuptake of NE and cause pupil dilation in normal eye
-If have Horner's syndrome, then the effected eye will not dilate because no NE is being released from the third order neuron anyways
-Does not discriminate whether the Horner's syndrome is from dysfunction of the first, second, or third order neuron
What is 1% hydroxyamphetamine (Paredrine) used for?
To determine whether Horners syndrome is caused by dysfunction in third order neurons or first/secodn order neurons
-Paredrine increases the release of NE from nerve terminals, causing normal pupils to dilate
-If have third order nerve dysfunction (i.e. tumor in cavernous sinus), will not effectively caused NE release and will not dilate
-If first or second order neuron dysfunction, hydroxyamphetamine should still be able to elicit NE release from 3rd order neuron, and pupil will dilate
What is Adie's (tonic) Pupil?
-Decreased parasympathetic innervation of the eye causes effected pupil to be more dilated than the other
-The anisocoria is accentuated in response to light
-Pupil is slow to constrict; also slow to dilate
-Many of these patients will have decreased deep tendon reflexes
-Usually caused by damage to the post-ganglionic parasympathetic fibers leaving the ciliary ganglion
-usually seen in young women from teens into 30s
-benign condition
How do you diagnose Addie's (tonic) Pupil?
-If have Addie's pupil for a few weeks, will develop denervation hypersensitivity
-1/8% pilocarpine can cause constriction in only hypersensitive eyes; cannot constrict normal eyes
-1% pilocarpine will constrict any eye, unless it is pharmacologically dilated
What are two commonly used drugs that can inadvertantly cause pharmacological pupil dilation?
-Jimson Weed (bella donna alkaloids)
-Scopolamine (used as transdermal patch for travel sickness prevention)
Effects of cholinergic antagonist drops on the eye
1. Inhibit pupil constriction (i.e. cause dilation)
2. Inhibit ciliary muscle contraction (i.e. inhibit accomodation and can't read)
Atropine eye drops
-MOA
-duration
-uses
-MOA: mAchR antag, causes dilation and cycopegia
-Very potent; lasts for up to 2 weeks
-Used when long term dilation is necessary: following eye surgery, very bad iritis, or very bad uveitis
0.5%-1% Tropicanimide (Mydriacyl) eye drops
-MOA
-duration
-uses
-mAchR antagonist, causes cyclopegia and pupil dilation
-Has shortest duration and is fastest acting of all dilator drops; get max dilation in 30 minutes and lasts for 4-6 hours
-used for eye exams and determining refraction errors in childen
Cyclopentolate (Cyclogyl) drops
-MOA
-duration
-uses
-mAchR antagonist; causes pupil dilation and cyclopegia
-Lasts up to 24 hours
-Used a few times per day for corneal abrasions to ease discomfort from ciliary muscle spasm; can be used in children for accurate refraction correction; can be used in any mild condition where you want the eye relaxed for a few days
Homatropine drops
-MOA
-duration
-uses
-mAchR antagonists; causes pupil dilation and cyclopegia
-Lasts 1-3 days
-Prescribed 4x/day for corneal abrasions, chemical burns, or for iritis, uveitis, and post-op
Scopolamine drops
-MOA
-duration
-adverse effects
-uses
-mAchR antagonist; causes pupil dilation and cycloplegia
-Lasts 2-4 days or about a week
-More toxic reactions than other dilators: psychosis, restlessness, hallucination, confusion, vomiting, urinary incontinence
-used transdermally for motion sickness; can cause unilateral pupil dilation
2.5% Phenylephrine (Neosynephrine)
-MOA
-duration
-uses
-adverse effects
-alpha agonist: causes pupil dilation, inhibits accomodation, and causes eyes to open wider; also causes vasoconstriction
-dilates within 45 minutes, lasts 6 hours
-can be used in eye exam; also added in small amounts to Visine because of its vasoconstricting properties
-causes rebound hyperemia in Visine; if use 10% phenylephrine, can cause hypertensive crisis, occipital headaches, ventricular arrhythmias, and tachycardia
What drugs are used for routine pupil dilation?
Either 0.5-1% Tropicanimide alone, or 1% Tropicanimide with 2.5% Neosynephrine
Diagnosis of open angle glaucoma
-Increased intraocular pressure
-Enlarged optic cup
-Peripheral vision effected first
Signs of closed angle glaucoma
-Severe eye pain or headache
-Redness of sclera
-N/V
-cloudy cornea
-fixed, irregular mid-dilated pupils
-can be instigated by pupil dilation
Pilocarpine drops
-MOA
-uses
-direct Ach agonist; causes pupillary constriction, spasm of accomodation, and reduces intraocular pressure by stretching the trabecular network as the iris in contracted and pulled in
-miotic agent (lasts 1 day) used for anisocoria testing; wide angle glaucoma; narrow-angle glaucoma with physostigmine
Epinephrine drops
-MOA
-adverse effects
-direct alpha and beta agonist; causes conjunctival constriction, slight mydriasis, and reduces intraocular pressure by effecting beta receptors in the trabecular meshwork and increasing outflow
-hypertensive crisis, tachycardia, localized burning and irritation, localized allergic reacton, and accumulation of melanin granules
Dipivefrin (Propine) drops
-MOA
-uses
-lipophilic prodrug of ephinephrine; does not enter tear system and cause side effects; converted to epinephrine in eye
-used to reduce intraocular pressure; more potent and safer than EPI
Timolol drops
-MOA
-uses
-adverse effects
-non-selective beta blocker; decreases aqueous humor production via receptors in the ciliary body
-#1 drug for glaucoma, better than pilocarpine and EPI
-can cause lethargy, lightheadedness, fatigue, memory loss, bradycardia, hypotension, syncope, arrhythmias, wheezing, pulmonary edema, CHF
Levobunolol (Betagan) drops
-same as Timolol, non-selective beta blocker, but cheaper
Betaxolol drops
-MOA
-Uses
-selective beta1 blocker
-used in glaucoma patients with history of CHF or asthma, when Timolol would be contraindicate
3 Properties of NSAIDs
1. Analgesic (mostly peripheral; reduces mild to moderate dull pain)
2. Anti-inflammatory (reduces vasodilation and edema)
3. Antipyretic (reduces fever)
Acute uses of NSAIDs
For acute pain releif, acute inflammation, and fever reduction
-headache
-minor injuries
-dysmenorrhea
-symptoms and fever of cold or flu
-acute bursitis
Chronic uses of NSAIDs
used to relieve symptoms of chronic inflammatory diseases, but do not stop their progression
-Osteoarthritis
-Rheumatoid arthrits
-Ankylosing spondylitis
Functions of COX1
-Constitutively active
-Produced by platelets, endothelial cells, GI, kidney, most cells
-GI protection: PGs decrease acid secretion, etc.
-Regulation of blood flow
-Regulation of platelet function: thromboxanes recruit and aggregate platelets vs. PGs and Pcyclins
-Regulating kidney function: PGs cause vasodilation, etc.
Functions of COX2
-Inducible
-Produced by macros, synoviocytes, endothelial cells
-induced by growth factors, cytokines, and hormones
-mostly involved in inflammation, pain, and fever
Selective COX-1 Inhibitors
-Ketorolac
Relatively COX-1 Selective
-Flurbiprofen
Non-selective COX Inhibitors
-Ketoprofen
-Indomethacin
-Aspirin
-Naproxen
-Ibuprofen
Relatively COX-2 Selective
-Celecoxib
COX-2 Selective
Rofecoxib, Valdecoxib (both withdrawn from the market)
MOA of acetylsalicylic acid (Aspirin)
irreversible acetylation of COX enzymes; non-selective
Uses of aspirin
1. Daily baby aspirin (80 mg) reduces risk of MI and stroke via its anti-coagulant effects (inhibits platelet aggregation). May reduce incidence of colon cancer with long term use
2. To reduce low intensity pain, reduce fever, and anti-inflammatory (325 to 650 mg)
3. Rheumatoid arthritis (1-4 mg/day; more likely to have side effects)
How does salicylic acid effect
1. Inflammation
1. Inhibits PG synthesis of WBCs at inflammatory site; inhibits PG effects of vasodilation and increased PCV permeability
-so it reduces erythema and edema
How does salicylic acid effect
2. Pain
2. PGE2 sensitizes nerve endings to chemical mediators at the site of inflammation
By inhibiting PG synthesis, asprinin reduces sensation of pain
-Can be used in combo with opioids
-Used for low intensity pain, 325-650 mg
How does salicylic acid effect
3. Fever
-reduces production of PGE2, which induces fever in the hypothalamus; doesn't effect body temperature of normal individuals
How does salicylic acid effect
4. Platelets
-Irreversibly inhibits the production of TXA2 from platelets (platelets cannot synthesize new COX), reducing platelet aggregation (80 mg). Its effect on TXA2 is greater than on prostacyclin, which inhibits platelet aggregation
Aspirin
-Absorption
-Aspirin is a weak acid, and is readily absorbed in the low pH of the stomach
-But most absorption occurs through the small intestine because of the larger surface area available for absorption
Aspirin
-Distribution
-Widely distributed, includeing CSF, peritoneal cavity, synovial fluid
-Bound to plasma proteins, which can displace other drugs from these proteins and increase their toxicity
-Aspirin acetylates albumin and can affect drug binding to albumin
Aspirin
-Metabolism
-Deacylated by the liver (and plasma)to salicylic acid, which is also an active NSAID
-T1/2 at low doses (325-650) 3 hours
-T1/2 at high doses (1 gram)=15 hours
-The liver's ability to deacetylate aspirin is limited, so higher doses have much longer half lives and action must be taken for ODs
Aspirin
-Excretion
-Excretion in urine is pH dependent
-At higher pHs, salicylic acid is ionized, and is better excreted
Adverse Reactions to Asprin
1. GI: Bleeding, ulceration, perforation
2. Hypersensitivity: Airway hyperreactivity or rash (may also be allergic to ibuprofen, use acetominophen instead)
3. May cause Reye's Syndrome in children-Liver damage (fatty liver) and encephalopathy; children should take acetiminophen instead
4. Salicysm (OD)
5. Respiratory alkalosis (because stimulates respiratory centers; usually is compensated)
6. Anticoagulant
7. Can cause gout episodes (at low doses, decreases urate excretion; at high doses, increases urate excretion)-don't use aspirin for gout
8. Difficulty breathing and wheezing
9. Can cause acute renal failure if have renal disease, cirrhosis, heart failure, or are on diuretics
How does aspirin cause acute renal failure?
-Prostaglandins are vasodilators and usually counteract vasoconstrictors in the kidney (ang II, catecholamines, ADH)
-In disease states with increased vasoconstrictors and decreased renal blood flow (cirrhosis, nephrosis, heart failure, diuretic use, cardiovascular diseases), NSAIDs will inhibit PG synthesis and potentiate vasoconstriction
Moderate Salicylism (Aspirin toxicity)
-Sweating, vomiting, epigastric pain, tinnitus, and vision blurring
-Early respiratory alkalosis (not seen in children) due to respiratory centor stimulation
-Later metabolic acidosis, due to uncoupling of oxidative phosphorylation, increased oxygen consumption and increased CO2 output, which is compounded by decreased respiratory rate from respiratory alkalosis
-Can progress to severe salicylism
Severe salicylism
-Metabolic acidosis reduces the ionized form of salicylic acid, which enhances tissue penetration
-Increased penetration in the CNS leads to agitation, tremor, coma, and respiratory dperession
Management of salicylate poisoning
-Mild to moderate salicylate poisoning: Use oral or IV rehydration with particular attention to K supplements
-Marked signs/symptoms of salicylism: First=oral activated charcoal, second=Simple alkalinisation (e.g. 1.26% of NaHCO3 over 2 hours and repeated, keep urine greater than pH 7.5); third=hemodialysis if levels greater than 1000 mg, have persisent acidosis, or deteriorating level of consciousness
How does salicylic acid cause GI complications?
Inhibition of PG synthesis decreases gastric mucous ecretion, increases acid secretion, and has an antiplatelet effect which increases GI bleeding
What can you give to reduce the GI complications of NSAIDs?
-Misoprostol (synthetic PGE1): reduces risk of gastric and duodenal ulcers; but causes diarrhea and can cause abortions
-Also can use proton pump inhibitors
Drug interactions of acetylsalicylic acid
-concommitant use of aspirin with other NSAIDs (e.g. ibuprofen) or other salicylates can decrease its anti-inflammatory and anti-platelet effect
-avoid use with alcohol (acidosis will reduce excretion)
Ibuprofen (Advil, Motrin)
-MOA
-non-selective, reversible inhibitor of COX
-at doses less than 2400 mg, works as analgesic; at greater than 2400 mg, is anti-inflammatory
-also anti-pyretic
Naproxen
-non-selective NSAID thats like Ibuprofen
Ibuprofen drug interactions
-Can increase blood levels of Lithium
-Can reduce blood pressure lowering effects of anti-hypertensive drugs
-May increase levels of aminoglycosides
-Should not be taken with anticoagulants (warfarin)
Adverse effects of Ibuprofen
-Hypersensitivity (esp. if allergic to aspirin)
-GI complications
-acute renal failure
-dizziness and orthostatic hypotension
Uses of Ibuprofen
-Rheumatoid arthritis
-Osteoarthritis
-Patent Ductus Arteriosus (also can use Indomethican)
Indomethacin
-MOA
-Very potent non-selective COX inhibitor
-Causes significant GI toxicity
Indomethacin
-Uses
-Reserved for moderate to severe arthritic pain
-gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip
-Also used for patent ductus arteriosus
Sulindac
Prodrug related to Indomethacin; GI side effects are less severe because it's activated in the liver
Ketorolac
-MOA
-administration
-COX-1 selective inhibitor
-ONLY NSAID available for IM administration
Ketorolac
-Uses
-Moderate to severe pain (i.e. post operative) because has strong analgesic properties
-Not used as an anti-inflammatory
-Not used before surgery because of GI upset, renal effects, and increased risk of bleeding
Aceteminophen (Tylenol)
-Uses
-Analgesic and anti-pyretic
-Not anti-inflammatory
Acetaminophen toxicity
-Metabolized by cytP450 into benzoquinone imine...the formed benzoquinone imine normally reacts with glutathione to form non-toxic metabolite
-If have insufficient Glutathione or take too much, the benzoquinone imine can cause liver necrosis
-Treatment=provide free sulfhydryl groups, e.e Mucomyst (N-acetyl cysteine)
-Avoid drugs affecting liver metabolism (carbamezepine, isoniazid, rifampin), alcohol
Celecoxib (Celebrex)
-MOA
-relatively COX-II selective inhibitor
Inidications of Celecoxib
-relief of osteoartrhtitis and rheumatoid arthritis in adult patients; chronic inflammatory states
-acute pain management in adults
-Treatment of primary dysmenorrhea
-Management of familial adenomatous polyposis (FAP) to reduce the number of adenomatous colorectal polyps
Cardiovascular and GI Black box warnings on Celecoxib and other prescription NSAIDs
-Cardiovascular: May increase risk of cardiovascular thrombotic events, MI, and stroke
-GI: increase risk of bleeding, ulceration, or perforation; elderly patients at greatest risk of GI event
Why do COXII inhibitors cause CV events?
COXII inhibitors may effect PGI2 synthesis in endothelial cells more than TXA2 synthesis in platelets
What is the FDA recommended therapy for arthritis?
-Naproxen with a proton pump inhibitor
Tramadol (Ultram)
-MOA
-Used as analgesic, NOT anti-inflammatory and NOT anti-pyretic
-Weak opiod agonist and inhibits NE and 5HT reuptake
Adverse reactions of Celebrex other than usual NSAID side effects
-Increased URT infections
-Back pain
-insomnia
-peripheral edema
Drugs that can induce gout in those who are susceptible
-diuretics
-aspirin
-niacin
-cyclosporine
-L-DOPA
Most common treatments for acute gout attacks
-Indomethacin or naproxen (NSAIDs)
-Prednisone (intra-articular corticosteroid)
Colchicine MOA
-Inhibits microtubule polymerization
-Inhibits leukocyte migration and phagocytosis
-Inhibits LTB4 formation
-Reduces the inflammation and pain associated with gouty arthritis
Colchicine uses
-At low doses, used for prophylaxis of an attack
-Given for acute treatment of gout if not responsive to NSAIDs or corticosteroids
Colchicine administration
-Onset of action=1 day;
-Give every hour until develop nausea, vomiting, and diarrhea, then taper off
-Use daily in small doses if using for prophylaxis
Adverse effects of colchicine
-Nausea
-Vomiting
-Diarrhea
What drugs are used prophylactically to prevent gout attacks?
-NSAIDs
-Small daily doses of cochicine
MOA of Probenecid
-Competes with uric acid for reabsorption in the kidney via the anion transporter
-Decreases total body urate pool in gout patients
Uses of Probenecid
-Used to prevent gout attack in patients with impaired urate excretion
-Also inhibits secretion of weak acids such as penicillin, and can be used to increase penicillin t1/2
Adverse effects of Probenecid
-GI irration (take with food or antacids)
-Rash
-May aggravate gout at first (treat concurrently with colchicine, introduce drug slowly, keep patient well hydrated)
What are the limitations of using Probenecid in patients with impaired uric acid secretion?
-Many patients already have reduced renal function
-Uricosuric agents may cause crystallization of uric acid in the kidney if hydration is ot maintained
-Many drug interactions: alters clearance of Methotrexate, oral hypoglycemic agents, and zidovudine
What are the drug interactions with Probenecid?
-Alters clearance of methotrexate, oral hypoglycemic agents, and zidovudine
MOA of Allopurinol
-Irreversibly inhibits Xanthine oxidase; reduces plasma urate levels and increases hypoxanthine and xanthine levels, which are more soluble
Allopurinol
-Metabolism
-Administration
-It is converted by the liver to a more potent metabolite, alloxanthin, which also has a longer t1/2
-Can be given 1x per day, unlike probenicid
Uses of Allopurinol
-Reduce serum uric acid in overproducers, people with impiared urate excretion
-Can be used in patients with recurring renal urate stones and renal dysfunction (with caution)
-Also used for secondary hyperuricemia associated with melignancies
Adverse effects of Allopurinol
-Increased risk of gout early in therapy (can prevent by increasing dose slowly)
-Skin rash or allergic reactions
-GI disturbances
-Rarely causes hepatic toxicity and interstitial nephritis, but need to monitor liver and kidney function
-rare: peripheral neuropathy and bone marrow suppression
Drug interactions with allopurinol
-Increases levels of Azathioprine and Mercaptopurine, which are metabolized by XO
-Can be dangerous in people with reduced activity of TPMT, leaving no other method of metabolizing azothioprines except by hypozanthine phosphoribosyl transferase into a highly toxic 6 thioguanine nucleotide
MOA of uricase enzymes
-metabolize uric acid to allantoin
MOA of Febuxostat
Nonpurine selctive inhibitor of XO
-Can be tolerated by patients with an allergy to allopurinol
-Can be used in patients with renal insufficiency because metabolized by liver
Blood vessels
-Histamine receptor type
-Effect
-H1 and H2
-Vasodilation
Heart (SA Node)
-Histamine receptor type
-Effect
-H2
-Increases heart rate
Myocardium
-Histamine receptor type
-Effect
-H2
-Increased contraction
GI secretory tissue
-Histamine receptor type
-Effect
-H2
-Increased production of acid and pepsin secretion in stomach
Capillaries
-Histamine receptor type
-Effect
-H1
-Increased permeability...edema and hives
Bronchioles
-Histamine receptor type
-Effect
-H1
-Bronchoconstriction
Uterus
-Histamine receptor type
-Effect
-H1
-Uterus contractions
Nerves
-Histamine receptor type
-Effect
-H1
-Increases pain and pruritus
Brain/thalamus
-Histamine receptor type
-Effect
-H3
-Increases pain
MOA of anti-histamines
-Competetive antagonists of Histamine receptors (H1 and H2)
Name six First Generation H1 Blockers
1. Tripelenamine (PBZ)
2. Diphenhydramine (Benadryl)
3. Dimenhydrinate (Dramamine)
4. Chlorpheniramine (ChlorTrimemton)
5. Meclizine (Antivert)
6. Promethazine (Phenargan)
Name four Second Generation H1 Blockers
1. Loratadine (Claritin)
2. Fexofenadine (Allegra)
3. Cetirizine (Zertec)
4. Terfenadine (Seldane; removed from market)
Name 4 H2 Blockers
1. Cimetidine (Tagamet)
2. Rantidine (Zantac)
3. Famotidine (Pepcid)
4. Nizatidine (Axid)
Methotrexate MOA
-Folic acid analogue that inhibits dihyrofolate reductase, thus decreasing dTMP and DNA synthesis
-Or may work my increasing levels of adenosine, which acts as an anti-inflammatory mediator [therapeutic effect of methotextrate is not reversed by folic acid]
Methotrexate administration
-Give once a week
-Orally or IM or IV
Methotrexate pharmacokinetics
-Converted to active metabolite in the liver, 7-hydroxymethotrexate
-Also poly glutamated, and the polyglutamated methotrexate has a longer half life; only needs to be given once a week
Methotrexate elimination
-Eliminated by the kidney via the same pathway as aspirin and probenecid are eliminated in the proximal tubule
-Therefore can compete with high dose aspirin and probenecid for excretion
Adverse effects of methotrexate
-Mucosal ulcers
-Nausea
-Diarrhea
-Can reverse the above effects with leucovorin, a folate acid analog
-Hepatotoxicity and abnormal LFTs, esp. if alcoholic or already have reduced liver function; Need to monitor hepatic function
-Bone marrow suppression at higher concentrations
-Do not use in pregnant women
Clinical uses of methotrexate
- first line for Rheumatoid arthritis; slows disease progression
-Psoriasis
-Chemotherapy
-Immunosuppression
MOA of Hydroxychloriquine
-Drug is basic and accumulates in lysosomes; Eventually increases lysosomal pH and inhibits sphingomyelase; this increases ceramide levels, which then inhibits TNF transduction and the production of proinflammatory mediators
Pharmacokinetics of Hydroxychloriquine
-Given orally, once a day
-Half life=40 days, a steady state is not reached in months
-Has long latency period (12-24 weeks) before it exerts its action
Adverse effects of Hydroxychloroquine
-Rash
-GI upset (can be avoided by taking with food)
-Leukopenia
-Peripheral neuropathy
-Ocular effects; should do baseline eye exam before administration
Clinical uses of hydroxychloroquine
-Second line for Rheumatoid arthritis; used if not responding to NSAIDs; slows disease progression
-Malaria
Sulfasalazine MOA
-Unknown; may prevent antigen absorption from the gut
Sulfasalazine Pharmacokinetics
-Administered orally
-For rheumatoid arthritis, sulfapyridine is the active moeity: sulfasalazine is converted to sulfapyridine by bacteria in the colon
Sulfasalazine Adverse effects
-GI upset
-CNS complications
-Skin rashes
-Neutropenia: should do routine full blood counts
-Heptatoxicity: should do routine liver function tests
Clinical uses of Sulfasalazine
-Second line for Rheumatoid arthritis; slows disease progression
Pro-inflammatory effects of IL-1 and TNFa
-Increase COX2
-Increase PGE2
-Increase NO
-Increase adhesion
-Increase chemokines
-Increase collagenases
-Increase osteoclast activation
-Increase angiogenesis
What are some common properties of Biological response modifiers used in Rheumatoid arthritis? (i.e. TNF and IL-1 inhibitors)
-Proteins; need to be injected
-Can be used with methotrexate
-Don't combine biologics with one another
-Decrease ability to combat infections: Don't start if have active infection or chronic infections
MOA of Etanercept (Enbrel)
-Mimics TNF receptor; consists of 2 soluble TNF p75 Receptors linked to the Fc portion of human IgG1; binds 2 TNF alpha (and beta) molecules
Etanercept
-Administration
-Given via subcutaneous injection
-Given twice weekly
-Improvement may occur in a week
Etanercept
-Adverse effects
-Injection site reactions common
-Increases risks of serious infections
-Antibodies against Etanercept develop, but do not effect drug efficacy
-Do not give to people with multiple sclerosis and demyelinating diseases
Etanercept
-Clinical uses
-Rheumatoid arthritis; can be given with methotrexate, and the combo is more potent than methotrexate alone
-Psoriatic arthritis
-Ankylosing spondylitis
MOA of Infliximab (Remicade)
-Part human, part mouse monoclonal antibody against TNF alpha
Pharmacokinetics of Infliximab
-Given IV only, at 0,2,6 weeks, and then every 4 to 8 weeks
-Can be used alone or in combo with methotrexate
Adverse effects of Infliximab
-Upper respiratory infections
-Allergic reactions
-Antibodies form against infliximab, but do not effect drug efficacy and are reduced by methotrexate
-Can aggravate heart failure; do not use in patients with CHF
-Do not use during pregnancy
-Increased incidence of TB
Clinical use of Infliximab
-Used for rheumatoid arthritis, +/- methotrexate
-Also used from Crohn's disease, ulcerating colitis, and ankylosing spondylitis
MOA of Adalimumab (Humira)
-Fully human anti-TNFalpha antibody; blocks TNF alpha binding to p75 and p55 TNF receptors
Pharmacokinetics of Adalimumab
-Given subcutaneously, every other week
-Can be used alone or with methotrexate; combo more effective than methorexate alone
Adverse effects of Adalimumab
-Ijection site reactions
-Increased incidence of TB, invasive fungal infections and other opportunistic infections
Clinical uses of Adalimumab
-Alone or in combo with methotrexate for rheumatoid arthritis
MOA of Anakinra (kineret)
-Recombinant human IL-1 receptor antagonist; binds to IL-1 instead of IL-1 receptor, reducing cartilage degredation and bone resorption
Pharmacokinetics of Anakinra
Given as subcutaneous injection, given daily
Adverse reactions of Anakinra
-Injection site reactions common
-Increases risk of serious infections
-May cause lymphoma
Clnical use of Anakinra
-In patients over 18 who have failed one or more Disease Modifying Antirhumatic Drugs (DMARDs; methotrexate, chloroquin, sulfasalazine)
-Cannot be used in combo with anti-TNF alpha drugs
MOA of Leflunomide
-Inhibits dihydroorotate dehydrogenase, decreasing UMP (lymphocytes need much more pyrimidine synthesis form proliferation than purine synthesis)
-Arrests cells in G1
-Mostly decreases B cells, but also effects T cells
Pharmacokinetics fo Leflunomide
-Prodrug; converted to active form my intestinal mucosa and liver
-Has plasma half life of 15 days, which is long due to plasam protein binding and enterohepatic recirculation
-Cholestyramine increases rate of elimination by decreasing enterohepatic circulation
Adverse effects of Leflunomide
-Diarrhea
-Reversible allopecia
-Elecvation of liver enzymes
-contraindicated in pregnancy
-Inhibits a p450, causing increased levels of ibuprofen and other NSAIDs
Clinical uses of Leflunomide
-Rheumatoid arthritis +/- methotrexate
-Wegener's Granulomatosis
-SLE
-Myasthenia gravis
MOA of Abatacept
-Recombinant CTLA-4 that binds to CD80 and CD85 on APCS, preventing their bidning with CD28 on T lymphocytes and inhibiting costimulation
Pharmacokinetics of Abatacept
-Given IV every 2 weeks
Adverse reaction of Abatacept
-Increase in infections
-Headache
-Nasopharyngitis
-Nausea
-Exacerbates COPD
Clinical uses of Abatacept
-Used in Rheumatoid arthritis if all other drugs fail
MOA of Rituximab
-Monoclonal antibody that binds to CD20 on B cells, preventing their activation and causing their lysis
Pharmacokinetics of Rituximab
-IV injection
-Given on days 1 and day 15
-Half life is 19 days
Adverse reactions of Rituximab
-Chills
-Fever
-Headache
-Nausea
-Myelosuppression in long term
Clinical uses of Rituximab
-Rheumatoid arthritis when other drugs fail
What does it mean for a drug to have anticholinergic properties?
Xerostomia, blurred vision from mydriasis and cyclopegia, Anhidrosis leading to cutaneous vasodilation (hot, flushed skin), constipation, difficulty urinating; tachycardia; CNS effects of confusion, sedation, and delirium
What does it mean for a drug to have alpha blockade side effects?
-Impotence, edema, hypotension, reflex tachycardia
What are adverse effects of first generation H1 blockers?
-Sedation
-anticholinergic
-alpha blockade
First generations H1 blockers:
-administration
-duration
-uses
-Given PO
-Last 2-6 hours
-Used for allergic reactions, pruritis, motion sickness (H1)
Second generation H1 blockers
-adverse effects
-No anticholinergic, no alpha blockade, no sedation effects
-Can cause headache and tremor
Second generation H1 blockers
-Administration
-Duration
-Uses
-Given PO
-Last 12 hours
-Used for allergies
Cimetidine (Tagamet)
-MOA
-H2 blocker, ihibits gastric acid and pepsin secretion
Cimetidine
-Administration
-Uses
-Given PO and IV
-#1 for acute peptic ulcers in hospital
Why is Cimetidine not used to treat peptic ulcers and heart burn chronically?
-Metabolized by p450, and is a universal inhibitor of the p450 system; increases the levels of many drugs if used for more than 2 weeks
-Decreases testosterone levels in males, cuasing penis shrinkage, testicle shrinkage, and gynecomastia (good for transvestites)
-Can cause psychosis
-Increases risk of CHF; do not give to heart failure patients
Rantidine (Zantac)
-MOA
-H2 blocker, inhibits gastric acid and pepsin secretion
Rantidine
-Administration
-Given PO
Rantidine
-Adverse effects
-No effects of p450, testosterone, and psychosis like cimetidine
-Can cause some sedation and tremor
-Does have small increased risk of CHF
Rantidine
-Uses
-peptic ulcers
-heart burn
-other secretory syndromes and GI tract problems
Diphenhydramine (Benadryl)
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blocker
-has strong anticholinergic properties
-has strong sedative properties
-Used for motion sickness and allergies
Dimenhydrinate (Dramamine)
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blocker
-Has strong anticholinergic properties
-Has strong sedation properties
-used for motion sickness
Tripelenamine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blocker
-slight anticholinergic properties
-intermediate sedative properties
-used for allergies
Hydroxyzine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blocker
-no anticholinergic properties
-intermediate sedation
-used for allergies and puritis in hospitals, also sedation
Meclizine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blocker
-no anticholinergic properties
-mild sedation
-used for motion sickness, anti-vertigo, anti-dizziness
Chlorpheniramine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-1st generation H1 blcoker
-mild anticholinergic properties
-mild sedation
-used for allergies
Terfenadine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-2nd generation H1 blocker
-No anticholinergic properties
-Mild sedation
-Used for allergies
Loratidine
-Class
-Anticholinergic properties
-Sedation properties
-Uses
-2nd generation H1 blocker
-No anticholindergic properties
-No sedation
-Used for allergies
Who expresses 5-Lipoxygenase and makes Leukotrienes?
-Inflammatory cells: Polys, macrophages, and mast cells
Actions of 12-HETE (leukotriene)
-chemottractant for smooth muscle, causing myointimal proliferation after injury
Actions of LTC4
1. Decrease myocardial contractility
2. Decrease coronary blood flow
3. Bronchoconstriction
4. Increase vascular permeability and exudation
5. Increase airway mucus secretion
6. Chemoattraction and activation of eosinophils
Actions of LTD4
1. Decrease myocardial contractility
2. Decrease coronary blood flow
3. Bronchoconstriction
4. Increase vascular permability and exudation
5. Increase airway mucus secretion
6. Chemoattraction and activation of eosinophils
Actions of LTB4
1. Produced by colonic cells to increase neutrophil chemotaxis
2. Chemoattraction and activation of neutrophils
Actions of thromboxanes
1. Smooth muscle mitogen
2. Vasoconstriction
3. Contraction of respiratory smooth muscle and bronchoconstriction
4. Potent platelet aggregator
5. Renal vasoconstriction, but only if renal inflammatory process occuring
Action of prostacyclins
1. Vasodilation
2. Bronchodilation/relaxation of respiratory smooth muscle
3. Inhibits platelet aggregation
4. Increases renin release
5. Vasodilation of afferent arteriole and increases GFR
6. Increase Na and H20 excretion (diuresis) because prevents ADH from increasing intracellular AC activity
7. Induces hyperalgesic response
Actions of Prostaglandins
1. Vasodilation
2. Stimulates mucus production, increases blood flow, and inhibits acid secretion in the GI tract
3. Contraction of ciruclar and longitudinal smooth muscle in GI tract, producing colicky cramps
4. PGE2 causes bronchodilation (PGF causes bronchoconstriction)
5. Inhibit platelet aggregation
6. Increase renin release
7. Vasodilate afferent arteriole and increase GFR
8. Increase Na and H20 excretion (diuresis)
9. PGE and PGF2a soften the cervix, induce labor, and cause uterine contractions
10. PGD2 induces natural sleep
11. PGE and PGE2 increase body temperature set point
12. Increase GH, PRL, TSH, ACTH, FSH, and LH levels
13. Increase bone turnover and increase bone formation
14. Decrease intraocular pressure and increase outflow of aqueous humor
15. Hyperanalgesic response
PGE2 binds to which receptors?
-EP1 (G, increases Ca2+, contractile)
-EP2 (Gs, increases cAMP, relaxant)
-EP3 (Gi, decrease cAMP, inhibitory)
-EP4 (Gs, increase cAMP, relaxant)
PGD2 binds to which receptors?
-DP1 (Gs, Increase cAMP, relaxant)
-DP2
PGF2 binds to which receptors?
-FP (Gq, increases Ca, contractile)
PGI2 binds to which receptors?
IP (Gs, increases cAMP, relaxant)
TXA2 binds to which receptors?
TP (Gq, increase Ca, contractile)
LTB4 binds to which receptors?
-B-LT1 (Gi, decreases cAMP, involved in chemotaxis)
-B-LT2 (Gq, increases Ca, involved in neutrophil secretion activation)
LTC4 and LTD4 bind to which receptors?
-CysLT1
-CysLT2
Which eicosanoid receptors are relaxant receptors (Gs, increase cAMP?)
-IP
-DP1
-EP2, EP4
Which eicosanoid receptors are contractile receptors (Gq, increase Ca?)
-EP1
-FP
-TP
Which eicosanoid receptors are inhibitory receptors (Gi, decrease cAMP)
-EP3
Montelukast
-MOA
-Uses
-CysLT1 receptor antagonist (blocks LTC4 and LTD4)
-Used for asthma
Montelukast
-Adverse effects
Most frequent:
-Abnormal hepatic function tests
-Headache disorder
Less Frequent:
-Increased respiratory, GI, and skin infections
-Fever
Abdominal pain
-etc.
Zileuton
-MOA
-Uses
-5-Lipoxygenase inhibitor (inhibits leukotriene formation)
-Used for asthma
Zileuton
-Adverse effects
Most frequent:
-Dyspepsia
-Nausea
Less Frequent:
-Abdominal pain with cramps
-Generalized weakness
Zileuton
-Drug interactions
-NEVER use with Pimozide (antipsychotic)
-Severely increases the effects of Astemizole and Terfenadine (anti-histamines)
-Severly increases the effect of Tizanidine (muscle relaxant)
-Moderately increase the effect of Propanolol
-Moderate adverse reaction with theophylline
Zafirlukast
-MOA
-Uses
-CysLT1 receptor antagonist (blocks effects of LTC4 and LTD4)
-used for asthma
Adverse effects of Zafirlukast
-Headache disorder
-Nausea
Drug interactions with Zafirlukast
-Zafirlukast increases the effects of selected anti-coagulants
Dinoprostone
-MOA
-Uses
-Synthetic PGE2
-Used for the induction labor and pregnancy termination
Dinoprostone
-Adverse effects
-V/D
-fever
-Bronchoconstriction
-Fetal cardiac rhythm abnormalities
Misoprostol
-MOA
-Uses
-Synthetic PGE1
-Usesd for ulcer treatment, but not recommended in the US because of side effects
Misoprostol
-adverse effects
-Abdominal pain/cramps
-Diarrhea
Latanoprost
-MOA
-uses
-PGF2a derivative
-used for glaucoma
Adverse effects of Latanoprost
-Blurred vision
-Conjunctival hyperemia
-Iris hyperpigmentation
etc.
Epoprostenol
-MOA
-Uses
-Prostacyclin
-Used for primary pulmonary hypertension (because dilates respiratory vessels and is naturetic)
Carboprost
-MOA
-Uses
-PGF2a analogue
-Used for abortion in the second trimester
-Used for post partum hemorrhage
How are amide local anesthetics metabolized?
-Amides are metabolized by P450 system
How are ester local anesthetics metabolized?
-Esters are metabolized by plasma pseudocholinesterase
What is the MOA of local anesthetics?
-Increases stability of inactive state of neuronal sodium channels
-Therefore decreases size of action potentials, decreases firing rate of neuron, and increases refractory period
How does local pH effect the efficacy of local anesthetics?
-Local anesthetics are weak bases that blocks Na channels in the ionized form intracellularly
-But needs to be unionized to cross the cell membrane
-Therefore, alkaline conditions are better
What does it mean for a local anesthetic to be "use dependent?"
-If a nerve is stimulated at a high frequency (i.e. during pain), more Na channels will be in the inactivated state because they will have less time to recover before the next action potential
-Therefore, local anesthetics have a greater affinity for more actively stimulated neurons
How does the size of the nerve fiber effect the efficacy of local anesthetics?
-The smaller the nerve fiber, the more susceptible to local anesthetics
-Smallest: Type C pain fibers, most susceptible
-Medium: Type B Autonomic Fibers, some effect
-Large: Type A Motor Fibers, little if any effect by only a few long-duration amides
How does the position of a nerve fiber within a nerve bundle effect the action of local anesthetics?
-Nerves innervating proximal sites in nerve bundles are located on the outside of nerve bundles and are effected first (because the anesthetic has to diffuse through the rest of the bundle)
-Also, larger motor fibers are located to some degree on the outside of the bundle, causing a small decrement in motor control preceding the pain block
How can local anesthetics be injected?
1. Topical/surface: skin and mucosa
2. Infiltration: direct injection (i.e. knee)
3. Peripheral nerve block: Injected close to nerve trunks (i.e. brachial)
4. Spinal: injected into subarachnoid space near spinal cord
5. Epidural: Injection just above the dura surrounding the spinal cord, near the nerve roots (less effect on spinal nerves as a spinal block, so can preserve more motor function)
Adverse effects of local anesthetics:
-CNS
1. Low dose: Tremors, oral numbness, dizziness, confusion, agitation (exception=cocaine)
2. Moderate dose: Muscle twitching, followed by convulsions (can prevent with anti-convulsant, like thiopental)
-High doses: possible respiratory depression
Adverse effects of local anesthetics:
-Cardiovascular
1. Vasodilation (exception=cocaine); can give with EPI to decrease washout and penetration into systemic circulation
2. Myocardial depression, possibly reducing cardiac output
3. Ventricular arrhythmias and cardiac arrest with unintentionally high levels (but can occur with normal IV doses of Bupivacaine)
Adverse effects of local anesthetics:
-Dermatologic
-May cause local dermatitis with some topicals; rare systemic allergic response with injected esters due to PABA metabolite
Drug interactions with local anesthetics
-Potentiate the action of non-depolarizing NMJ blockers
Lidocaine (Xylocaine)
-Type
-Kinetics
-Amide
-Rapid onset, medium acting (1-2 hours)
Lidocaine
-Uses
-issues
-Everything: topical, spinal, PNB, epidural, infiltration
-Potent and can cause Preventricular Contractions
Ropivacaine
-Type
-Kinetics
-Amide
-Long lasting (3-10 hours)
Ropivacaine
-Uses
-Issues
-Epidural, PNB, infiltration
-Less potent substitute for Bupivacaine
Tetracaine
-Type
-Kinetics
-Ester
-Onset slow
-Lasts long for an ester (3 hours): very hydrophobic, gets stuck in membranes, and is then slow released
Tetracaine
-Uses
-Issues
-Spinal, topical
-Highest risk of toxicity because of its slow clearance from membranes
Mepivicaine (Carbocaine)
-Type
-Kinetics
-Amide
-Medium to long lasting
Mepivicaine
-Uses
-Issues
-#1 for peripheral nerve block; also infiltration
-Causes less vasodilation, but is toxic to the fetus (don't use during delivery)
Etidocaine (discontinued from US)
-Type
-Kinetics
-Amide
-Long (5-10 hours)
Etidocaine (discontinued from US)
-Uses
-Issues
-Iniltration, PNB, epidural
-Preferentially causes motor block
Benzocaine
-Type
-Kinetics
-Ester
-Rapid onset, short duration
Benzocaine
-Uses
-Topical
-Also in spray form
Prilocaine
-Type
-Kinetics
-Amide (similar to lidocaine)
-Medium duration (1-2 hours)
Prilocaine
-Uses
-Issues
-Peripheral Nerve Block (dental), infiltration, topical (with Lidocaine)
-Less vasodilation
-Lower CNS toxicity
-Toxic to fetus, not for delivery
Cocaine
-Type
-Kinetics
-Ester
-Short
Cocaine
-Uses
-Issues
-Topical/nasomucosal
-Vasoconstrictor
-Potential for abuse
Dibucaine
-Type
-Kinetics
-Amide
-Long acting
Dibucaine
-Uses
-Issues
-Topical
-Very potent; too toxic for injection
Bupivacaine (Marcaine)
-Type
-Kinetics
-Amide
-Long lasting
Bupivacaine
-Uses
-Issues
-Topical
-Not for injection, too toxic
Procaine
-Type
-Kinetics
-Ester
-Short acting
Procaine
-Uses
-Limited because too shrot acting
2-Chloroprocaine
-Type
-Kinetics
-Ester
-Very short
2-Chloroprocaine
-Uses
-Issues
-Epidural
-OB: Just before delivery to control pain