Pharm 1

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Pharm 1
2013-02-07 00:01:56

exam 1
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  1. Pharmacokinetics
    what the body does to the drug: ADME
  2. Pharmacodynamics
    • what the drug does to the body
    • -interactios, pt's functional state, placebo effects
  3. ways to cross a membrane
    • channels/pores: passive
    • direct diffusion
    • transport systems: active, energy dependent, ie P glycoprotein
  4. absorption
    movement from site of administration to bloodstream
  5. factors affecting absorption
    • molecular weight
    • lipid solubility
    • ionization
    • blood flow
  6. effect of pH on absorption
    • non ionized drugs pass through membranes easier
    • -weak acids in acidic environment get absorbed, then ionize in neutral blood and stay there
    • -make urine basic to excrete acids
  7. pKa
    pH at which drug will be in equilibrium b/w ionized and non-ionized
  8. IV administration
    bypass barriers to absorption, introduced directly to systemc circulation
  9. IM administration
    avoid 1st pass metabolism, but still subject to blood flow to site, oils can prolong absorption
  10. PR administration
    • good to use if can't take PO (vomitting), but inconsistent absorption. 
    • 50% bypasses liver, but some still has 1st pass
  11. transdermal
    • requires highly lipophilic drug
    • slow delivery to site of action
    • no 1st pass
    • no harsh GI environment
  12. distribution
    high blood flow areas (heart, liver, kidneys, brain) get drug 1st; bones/fat/skin are 2nd

    lipid solubility and size still apply for exiting bloodstream to tissue/cells
  13. protein binding
    • drugs that are highly protein bound (albumin) stay in vasculature
    • - ie warfarin, NSAIDs, dilantin, benadryl
    • only free drug can interact with receptors to enter cells

    pts with decreased albumin may have larger response to these meds r/t higher free drug
  14. blood brain barrier
    hard for drugs to get into CNS r/t tight junctions of cells lining capillaries 
  15. metabolism phases in liver
    1) oxidation/reduction: done by enzymes, ie CYP

    2) conjugation/hydrolysis: hydrolyze a drug to a large polar molecule to inactivate it or enhance excretion (make it water soluble)
  16. CYP 450
    • -changes fat soluble item to water soluble
    • -comprised of multiple proteins
    • -present in almost all body tissues, but liver and gut have the most

    CYP3A is most common (50%)
  17. CYP450 competition
    drug with higher affinity gets metabolized, so the other one will build up
  18. CYP450 indcution
    expression and activity of CYP in increased --> more rapid metabolism of substrates --> lower concentrations and effects
  19. CYP450 inhibition
    • drugs and dietary substances increase concentration of substrates
    • -ie grapefruit
  20. sites of elimination
    urine, bile, sweat, saliva, breast milk, lungs, and KIDNEYS
  21. glomerular filtration
    • move drugs from blood to urine
    • depends on size of drug, GFR, and protein binding (protein bound stay in blood)
  22. tubular reabsorption
    • passive
    • most drugs here
    • lipid soluble stay in blood, water soluble and ionized get excreted
  23. clinical pharmacokinetics
    • relationship b/w pharmacologic effect of the drug and the concentration of the drug in the body
    • -clearance, volume of distribution, bioavailability, elimination half life
  24. volume of distribution
    • comparing [x] in blood to rest of body/site of action. 
    • large VD means well distributed (very little remains in blood), small VD means held in blood stream
  25. clearance
    • *theoretical* volume of blood that is completely cleared of a drug in a given period of time
    • -vol per unit time
    • NOT an indicator of how much drug is removed
  26. bioavailability
    • fraction of the administered dose that reaches systemic circulation
    • -mostly for oral. IV would be 100%
  27. half life
    • time required for serum plasma [x] to decrease by 1/2
    • usually 5 half lives until drug reaches steady level
  28. drug receptor theory
    • receptors used by drugs are normal point of control of physiologic processes
    • - normally regulated by molecules supplied by the body
    • -drug doesn't give body new function, just mimic or block action of body's own regulatory molecules
  29. drug-receptor activity
    usually temporary/irreversible, but there are some irreversible
  30. competitive antagonist 
  31. non-competitive antagonist
  32. dose-response relationship
    • PD of a drug can be quantified by the relationship b/w the [x] of the drug and the pt's response.
    • -generally inc. dose --> inc response
    • -only up to a maximum effect; further drug will not cause more response b/c receptor is saturated
    • -can still --> more SE though
  33. therapeutic index
    • lethal dose of a drug from 50% of population divided by minimum effective dose for 50% of pop.
    • -wider index is safer
    • -need to get serum levels of drugs w/ narrow index (warfarin, dilantin, digoxin)
  34. pharmacogenomics
    influence of genetic variation on drug response by correlating gene expression or single nucleotide polymorphisms with a drugs efficacy/toxicity 
  35. CYP450 phenotypes
    • PM: poor metabolizer
    • IM: intermediate metabolizer
    • EM: extensive metabolizer
    • UM: ultrametabolizer
  36. federal food and drug act
    1906: prohibited manufacture of adulterated/misbranded/poisonous food,drugs, meds, liquor
  37. food drug cosmetic act
    • 1938: created FDA
    • apprroval of drugs based on safety
    • which drugs need an rx
  38. kefauver-harris amendments
    1962: required safety and efficacy of drugs before approval
  39. what is the FDA responsible for?
    • human and animal drugs, biomedical devices, food, cosmetics, radiation products
    • NOT herbals
  40. controlled substances act
    • 1970: manufacturers, distributors, and dispensers of controlled substances need to register with DEA annualy
    • 5 classes
  41. alexander flemming
    discovered penicillin in 1928 by staph growing in halo on mold
  42. NCE
    • new chemical entities
    • may lead to drug discovery
  43. NDA
    • new drug application
    • -safety
    • -efficacy
    • -benefits>risks
    • -labeling
    • -manufacturing adequate to preserve strength/quality/purity
  44. ABNA
    abbreviated new drug application
  45. IND
    investigational new drug
  46. drug development
    pre clinical
    in vivo (lab) or in vitro (animals)
  47. drug development phase 0
    • exploratory and IND
    • apply to FDA to see if clinical trials should proceed
  48. drug development phase 1
    • fisrt human testing, small groups of healthy volunteers (20-100) 
    • assess PK, PD, safety, tolerability
  49. drug development phase 2
    • larger groups of actual patients (300-3000)
    • see how well drug works
  50. drug development phase 3
    • randomized, multicenter
    • definitive assessment of efficacy of drug
    • compared to current DOC, then apply for NDA
  51. drug development phase 4
    post-marketing surveillance, safety, ADRs
  52. fast track status
    accelerated development and approval for serious and life threatening diseases
  53. orphan drug
    • disease that affects <200,000 ppl in US
    • exclusive approval for this indication for 7 yrs post approval
  54. schedule 1
    • high abuse potential- no accepted medical use or lack of safety for use
    • heroin, MDMA, psilocybin, LSD, pot?
  55. schedule 2
    • high potential for abuse, have accepted medical use
    • -cocaine, opium, methadone, oxycodone, PCP, hydromorphone 
  56. schedule 3
    • less abuse potential than 1/2
    • anabolic steroids, ketamine, marinol
  57. schedule 4
    • low potential for abuse
    • benzos, ambien, phenobarb
  58. schedule 5
    • low abuse potential
    • cough suppressant with low codeine, lyrica
    • may be available OTC in some states
  59. med error categories
    • A: capacity to cause error
    • B: error occured, didn't reach pt
    • C: reached pt, no harm
    • D: reached pt, required monitoring to ensure no harm
    • E: likely caused temporary harm, needing intervention
    • F: required hospitalization
    • G: likely caused permanent harm
    • H: required intervention to sustain life
    • I: likely contributed to pt death
  60. pregnancy category A
    • adequate studies showed no harm
    • -folic acid/B6/synthroid
  61. pregnancy category B
    • no adequate human studies (animal studies showed no harm) OR animal studies showed adverse effect, but human studies haven't shown any risk
    • tylenol, prednisone, insulin, amox, zyrtec, claritin
  62. pregnancy category c
    • animal studies showed adverse effect and no studies in humans OR no animal or human studies
    • antidepressants, diflucan, cipro, compazine
  63. pregnancy category D
    • adequate human studies showed risk to fetus
    • benefits of therapy may outweigh risks if needed and no safer alternative
    • lithium, dilantin, valproic acid, ACEi, chemo, tetracyclines, caramazepine
  64. pregnancy category x
    • adequate studies showed fetal anomalies or risks
    • cytotec, accutane
  65. NSAIDs in pregnancy
    category c- dont use late in pregnancy r/t premature closure of DA
  66. sustiva in pregnancy
    • category D- high risk in 1st tri
    • long half life
    • should avoid pregnancy for 12 wks after d/c
  67. bactrim in pregnancy
    • category c
    • no well controlled studies in humans, but --> cleft palates in rats.
    • interferses w/ folic acid metabolism
  68. autonomic NS
    • involuntary function: cardiac muscle, smooth muscle, secretory glands
    • 2 neuron linkage: pre and post ganglionic, second one is outside CNS
  69. sympathetic
    • fight/flight
    • neurons in thoracolumbar
  70. parasympathetic
    • rest/digest
    • craniosacro neurons
  71. preganglionic neurotransmitter
    acetylcholine (ACh)for sym and parasym
  72. postganglionic neurotransmitter
    • ACh for para
    • Norepi or ACh for sym (epi secreted from adrenal medulla also part of sympathetic)
  73. cholinergic receptors
    • stimulated by ACh
    • Nicotinic and Muscarinic
  74. adrenergic receptors
    • sympathetic
    • stimulated by epi or norepi
    • Alpha1 Alpha 2 Beta1 Beta2 dopamine
  75. nicotinic receptors
    NN: nicotinic neuronal- stimulate postganglionic neurons of PSNS and SNS, stimulate adrenal medula to --> Epi/norepi

    NM: nicotinic muscular: at neuromuscular junction --> contraction of skeletal muscle
  76. muscarinic receptors
    • end organs of PSNS
    • sweat glands innervated by SNS
  77. alpha1 receptors
    • vasoconstrict
    • ejaculation
    • contract bladder neck/prostate
    • sensitive to: epi, norepi, dopamine
  78. alpha 2 receptors
    • presynaptic junction: broader effect
    • minimal clinical significance
    • sensitive to: epi, norepi
  79. Beta 1 receptors
    • heart: increases heart rate, force of contraction, velocity of AV conduction
    • kidneys: renin release
    • sensitive to: epi, norepi, dopamine
  80. beta 2 receptors
    • bronchial dilation
    • uterine relaxation
    • vasodilation
    • glycogenolysis
    • liver, pancreas
    • sensistive to: epi only
  81. dopamine receptors
    • dilate renal blood vessels
    • sensitive to: dopamine only
  82. what receptors do epi activate?
    alpha1/2 beta1/2
  83. what receptors do norepi activate?
    alpha1/2, beta1
  84. what receptors does dopamine activate?
    alpha1, beta1, dopamine
  85. sympathetic preganglionic fibers
    secrete? receptor?
    • secrete: Ach
    • receptor: nicotinic (cholinergic)
  86. sympathetic postganglionic fibers
    secrete? receptor?
    • secrete: norepi
    • receptor: adrenergic (alpha,beta, dopa)
  87. parasympathetic preganglionic fibers
    secrete? receptor?
    • secrete: ACh
    • receptor: cholinergic (N and M)
  88. parasympathetic postganglionic fibers
    secrete? receptor?
    • secrete: ACh
    • receptor: cholinergic (N and M)
  89. pathophys of asthma
    • antigen binds to IgE mast cell --> mediators (histamines/leukotrienes) 
    • inflammation
    • bronchoconstriction
    • airway edema
    • airway hyperresponsiveness: exaggerated bronchoconstrictor response to stimuli
    • airway remodeling: inflammation, mucus hypersecretion, subepithelial fibrosis, smooth muscle hypertrophy, angiogenesis
  90. COPD
    • airway obstruction that is NOT reversible
    • dyspnea that is progressive. 
    • usually worse w/ exercise
    • persistent
    • DONT respond to anti-inflammatories : b/c main mediator is neutrophil which is steroid resistant --> steroids manage acute symptoms but not disease progression (bronchodilate but don't help w/ inflammation)
  91. sympathomimetics/B2 agonists
    • most effective bronchodilators
    • MOA: B2 selective increase cAMP --> dilate bronchioles
    • use: in ACUTE bronchospasm, should not use regularly
    • caution: CV disease r/t vasodilation, pregnancy, lactation, digoxin
    • SE: hypokalemia, tachycardia, vasodilation, hyperglcemia, tremors
    • administration: inhalers --> direct administration lung, usually stays there
  92. long acting B2 agonists
    • salmeterol, fomoterol
    • onset 10-15 min
    • duration 12 hr
    • shouldn't be used as monotherapy: can cause B receptor downregulation r/t desensitizing, use w/ ICS which up regulates B receptors
    • use: BID dosing, not for acute symptoms
    • black box: can inc. asthma related deaths, only used for additional therapy for pts not controlled on other meds
  93. short acting B2 agonists
    • albuterol, levalbuterol (may have fewer SE)
    • onset 5-15 min
    • duration 4-6 hr
  94. xanthine derivatives
    • theophylline, caffeine- not used much now
    • MOA: bonchodilation through inhibition of phsphodiesterase --> inc cAMP
    • -inhibit pulmonary edema, decrease vascular permeability, enhance mucus clearance, improve diaphragmatic contractility
    • SE: Gi, CNS, CV; narrow therapeutic window, OD can cause seizure or arryhthmias
    • interactions: 90% liver CYP450 metabolism
  95. anticholinergics
    • ipatropium bromide(short acting), tiotropium(long acting), combivent (ipatropium +albuterol)
    • MOA: blocks muscarinic receptors by anatagonizing ACh --> bronchodilation
    • use: only approved for COPD, used in asthma too. NOT for acute
    • CI: soy/peanut allergy 
    • caution: urinary retention, bladder obstruction, BPH
  96. anticholinergic side effects
    • SLUD: salivation, lacrimation, urination, defecation
    • hot hare
    • mad hatter
    • red beet
    • dry bone
    • blind bat
  97. Inhaled corticosteroids
    • budesonide, fluticasone (pulmicort/flovent)
    • MOA: beta receptor upregulation --> bronchodilation, dec. mucus, prevent/reverse airway remodeling, dec. capillary permeability, inhibit leukotriene
    • *improve asthma more effectively than any other long term med*
    • max effect: 4-8 wks
    • use: not for acute, use intranasal for allergic rhinitis
    • ADR: generally not systemic- hoarse, altered taste, thrush, throat irritation, impaired growth in peds (early in tx, dose related, not progressive)
    • if give iv/po --> fluid retention, muscle weakness, ulcers, malaise, impaired wound healing, N/V, HA, osteoporosis, cataracts, glaucoma, hyperglycemia
  98. cromolyn
    • mast cell stabilizer
    • MOA: inhibits histamine release
    • inhaled from capsule- peak effect in 1wk
    • use: if not tolerating other meds for asthma, allergic rhinitis. NOT for acute
    • caution: seafood allergy
    • AE: swollen eyes, HA, dry mucosa, bitter taste, bronchospasm (can preadminister Bagonist), cough, throat irritation
  99. zileuton/zyflo
    • antileukotriene/lipoxygenase inhibitor
    • blocks the enzyme that --> leukotrienes
  100. antileukotrienes
    • *newer* 
    • zarfirlukast, mentelukast (singulair/accolate)
    • leukotrienes --> mucus, bronchoconstriction, edema, and eosinophils
    • MOA: improve lung fn, decrease need of short acting, preven exacerbations
    • use: long term use in asthma, esp. peds
    • modest efficacy in allergic rhinitis
    • AE: elevated hepatic enzymes, drug interactions, HA, GI upset, churg-strauss syndome (vasculitis)
    • caution: liver failure
  101. omalizumab
    • recombinant DNA monoclonal antibody
    • MOA: binds to IgE to dec binding to mast cells and basophils --> no inflammation
    • use: mod-persistent asthma resistant to other tx b/c $$$ 
    • AE: HA, injection site rxn, URI
    • black box: anaphylaxis
  102. asthma steps
    • intermittent
    • 1: SABA
    • persistent
    • 2: lose dose ICS
    • 3: lose doseICS + LABA
    • 4: med dose ICS+ LABA
    • 5: high dose ICS + LABA, maybe omalizumab
    • 6: High dose ICS + laba + oral steroid maybe omalizumab
  103. antihistamine
    • uses: allergic rhinitis, conjuctivitis, acute hypersensitivity, urticaria, angioedema, sleep aid, motion sickness
    • MOA: inverse agonists: bind and stabilize inactive receptor so stays inactive (when histamine binds, receptor becomes active)
    • can be receptor selective ($$) or not (SE).
    • *can decrease milk production, paradoxical CNS stimulation can occur in PEDS
    • CI: narrow angle glaucoma, lower resp s/s, BPH, bladder obstruction
    • caution: urinary retention, increased IOP, hyperthyroid, CV diease, HTN
    • AE: CNS, GI, nausea, anticholinergic
    • half life can be up to 28 hrs
  104. histamine receptors
    • mediate effects on smooth muscle leading to vasodilation, increased vascular permeability, contraction of nonvascular smooth muscle
    • location: endothelium, brain, smooth muscle
  105. histamine receptors
    • mediate histamine stimulation of parietal cells of gastric acid secretion, maybe cardia stimulation
    • location: mass and cells, gastric mucosa, cardia muscle, brain
  106. histamine receptors
    • feedback inhibitors in CNS, GI tract, lungs, heart
    • location: brain, mesenteric plexus
  107. 1st gen antihistamines
    • non-selective
    • benadryl
    • lipophilic, small molecule --> cross BBB --> sedation
    • affinity for muscarinic receptors --> anticholinergic effects
  108. 2nd gen antihistamines
    • peripheral H1 selective
    • loratidine, fexofenadine, desloratadine
    • large, lipophobic --> no sedation, no anticholinergic effects
  109. inhaled antihistamine
    • azelastine
    • intranasal H1 blocker
    • use: seasonal allergic rhinitis, vasomotor rhinitis
    • AE: bitter taste, somnolence, HA, weight gain, myalgia, local irritation
  110. decongestants
    • MOA: vasoconstrict by stimulate alpha receptors in respiratory mucosa
    • pseudoephedrine, phenylephrine 3-5 days
    • oxymetazoline (afrin) 3 days only to prevent rebound congestion
    • AE: tachycardia, HTN, anxiety, HA, lightheaded, drowsy, tremor, insomnia
    • CI: severe HTN, severe CAD, MAOI use-mimic meth
  111. antitussives
    • MOA: elevate threshold for coughing, anesthetize stretch receptors in resp passages, 
    • use: control non productive cough
    • dextromethorphan, codeine sulfate, tessalon perles (more peripheral)
    • AE: drowsiness, dizzy, nausea, GI, HA, pruritus, constipation
    • abused by teens: PCP effect in high doses
  112. expectorants
    • MOA: increase output of respiratory tract by decreasing adhesiveness and surface tension- promotes ciliary action
    • --> productive cough
    • guaifenesin
    • AE: GI, n/v, drowsy, diarrhea, rash, HA
  113. intrinsic pathway
    contact activation of the damaged surface with coagulation factors in the blood
  114. extrinsic pathway
    damaged tissue reveals tissue factor
  115. common pathway
    • where intrinsic and extrinsic meet, bottleneck --> clot
    • prothrombin (II) --> thrombin (IIa), also X-Xa: this is what antithrombin works agains
    • Protein C works against V-Va and 8-8a

    natural endogenous anticoagulants usually regulate clotting cascade
  116. warfarin
    • coumarin derivative
    • works on clotting factos: 2, 7, 9, 10 (vit K dependent)
    • quick absorption (1-2 hr), but effect is dependent on depletion of factors, and 2 has long half life (72hr)
    • 2 enantemers- both metabolized by CYP450 --> many drug rxn
    • amiodarone --> much higher INR, hold next dose of coumadin and reduce by 50%
    • antibiotics (cephalosporins, bactrim, avelox, flagyl) --> less activated clotting factor b/c kill flora and alter vit K absorption
    • pregnancy: category X
    • stop 3-5 days before procedure and bridge with LMWH
  117. warfarin and vit K
    • clotting factors require vit K for enzymatic process to convert to active form. 
    • Warfarin interrupts the enzyme (epoxide reductase) from reducing vit K
    • foods w/ vitK antagonize warfarin, need consistent diet
  118. warfarin dosing
    • narrow therapeutic range, but dose varies by pt from 0.5-30 mg/day
    • generally start 5mg/day >65 start 2.5
    • need INR to tell effective dose
  119. INR
    • not on warfarin: 0.8-1.2
    • DVT/AFib/PE: 2-3
    • mechanical valve: 2.5-3.5
  120. warfarin reversal
    • elevated INR <6: hold 1-2 dose
    • higher INR or bleeding: vitamin K, generally PO but can use IV for pts with absorption issues. SQ/IM not recommended 
  121. coumadin colors
    • red, purple, green, tan, blue, orange, turquoise,  yellow, white
    • (1,2,2.5,3,4,5,6,7,10)
  122. heparin/LMWH
    • MOA:activate antithrombin III 
    • LMWH is smaller --> greater affinity, need less, but have longer duration
    • not absorbable in GI
    • antiXa: monitors toxicity (target 0.4-0.7)
    • ADR: bleeding, HIT, osteoporosis
    • reversible w/ protamine sulfate
  123. heparin dosing
    • prophylaxis: 5000units TID
    • treatment: varies by weight
  124. Heparin induced thrombocytopenia
    • low platelets
    • interleukins see heparin as foreign body
    • much lower risk with lovenox, no risk with fondaparinux
  125. fondaparinux
    • smaller than lovenox, heparin, with more affinity for antithrombin
    • very long acting (3x lovenox)
    • in system 3-5 days --> only used outpt
    • no reversal!
    • C/I: severe renal impairement (CrCl<30), weight <50 for pts with joint replacement surgery
    • caution: elderly
  126. fondaparinux dosing
    • prophylaxis: 2.5mg daily
    • treatment: based on weight
    • <50: 5mg/day
    • 50-100: 7.5 mg/day
    • >100: 10mg/day
  127. factor Xa inhibitors
    • Rivaroxaban (Xarelto)/Apixaban (eliquis)
    • marketed for prophylaxis in joint replacement, also approved for afib
    • directly inhibits Xa
    • no reversal
  128. direct thrombin inhibitors
    • argatroban(Refludan)/ bilvarudin(angiomax)/ lepirudin (prodaxa)
    • competitive inhibitors of thrombin
    • monitor aPTT
    • weight based dosing
  129. argatroban
    • direct thrombin inhibitor
    • also approved for treatment of HIT
    • falsely elevates INR 2-3pt, so if transitioning to coumadin, need target INR >4 before d/cing
    • IV only
  130. dabigatran
    • direct thrombin inhibitor
    • approved for afib and hip surgery
    • 150mg PO BID
    • fixed dose, so no lab testing, but very $$
    • -do need dose adjustments in renal impairement
    • no reversal- many fatal bleeds
    • opening capsule increases bioavailability
  131. antiplatelets
    • not for pts w severe hepatic disease or GI ulcers
    • main se is bleeding, otherwise well tolerated
  132. COX pathway
    • arachidonic pathway uses COX to produce TXA2 and PGI2 
    • TXA2: vasoconstriction, platelet degranulation
    • PGI2: vasodilation, inhibit platelet degranulation
    • opposites in balance, but net effect is platelet aggregation
  133. COX1
    • produced by platelets- induce aggregation and vasoconstriction
    • platelets have no nuclei, once inhibited, cant make more
  134. COX2
    • produced by vascular endothelial cells-inhibit platelet aggregation and promote vasodilation
    • endothelial cells have nuclei, can replace inhibited enzyme
  135. Aspirin
    • rapid onset, 15 min half life, peak level in 30min, platelet inhibition within hr
    • but effect last lifetime of platelet 7-10 days
    • low dose: irreversibly inhibit cox 1
    • med dose: inhibit cox1 and cox 2, block prostoglandin production
    • high dose: anti inflammatory, rarely used b/c of toxicity (tinnitus and GI intolerance)
  136. Thienopyridines
    • class including clopidogrel, ticlopidine, pasugrel- but different metabolism pathways
    • inhibit ADP induced platelet aggregation
    • prodrugs: converted to active metabolite in-vivo
    • MOA: irreversible inhibition of P2Y12 receptor on platelet so ADP cant bind
    • Blocks stimulated adenylyl-cyclase activity
  137. ticlopidine
    • 1st gen thienopyridine
    • rapid absorption, peak plasma 1-3 hr.
    • halflife: 24-46 hrs, but increases with consisten use X 14 days to 96 hrs
    • delayed antithrombotic effect: no protection for 2 wks (use for prevention, not acute)
    • C/I: severe hepatic impairment (no renal adjustment needed)
    • black box: neutropenia, TTP, aplastic anemia
    • pregnancy: B
  138. clopidogrel
    • 2nd gen thienopyridine
    • rapid oral absorption, and permanent inhibition of P2Y12 receptor for life of platelet
    • once daily dosing
    • pts that are CYP2C19: won't metabolize --> never get active form "fail therapy:
    • caution: renal impairment
    • use: ACS/MI, recent MI, recent CVA, PAD
    • ADR: rash, diarrhea, bleeding, TTP (1st 2 wks), thrombocytopenia, no neutropenia!
    • plavix+aspirin: additive effects, good for PCI pts
    • Pregnancy: B
  139. pasugrel
    • 3rd gen thienopyridine
    • load 60mg then 10 mg/day, 5 if <50kg
    • caution: hepatic injury, no renal adjustment needed
    • better efficacy than plavix, but more bleeding
    • black box: bleed risk in elderly
    • use: thrombotic CV event
    • not for: hx of CVA/TIA, >75yr, <60kg
  140. dipyridamole
    • vasodilator/antiplatelet with unclear MOA, probably similar to plavix (not used much)
    • half life: 10 hr, need BID 
    • use: reduce risk of ischemic stroke when combined w/ ASA; no intrinsic antiplatelet activity alone
    • ADR: HA, hypotension, bronchospasm, MI, arrhythmias, nausea, dizzy, rash, flishing, paresthesias
  141. Abciximab (reporo), Tirofiban (agggrestat), Eptifibatide (Integrilin)
    • MOA: block glycoprotein IIb/IIIa to prevent platelets from attaching to each other 
    • most potent antiplatelet activity b/c don't inactivate, prevent sticking together irrelevant of activation
  142. fibrinolytic system
    • dissolves intravascular clots
    • tPA released from endothelial cells in response to venous stasis (and other stimuli) to convert plasminogen --> plasmin (active form)
    • plasmin is non specific- digests any clot whether protective or thrombotic
    • fibrinolytic drugs are also non specific --> high potential for hemorrhage; newer agents are fibrin specific --> less systemic complications
  143. tisse plasminogen activator
    tPA released from endothelial cells in response to venous stasis (and other stimuli) to convert plasminogen --> plasmin

    • tPA normally cleared from blood stream rapidly to prevent systemic effects
    • also limited by circulating inhibitors (plasminogen activator inhibitor 1,2)
  144. fibrynoliytic therapy
    fibrinolytic drugs are also non specific --> high potential for hemorrhage; newer agents are fibrin specific --> less systemic complications

    indications: STEMI, PE, thrombosed IV access, catheter directed thrombolysis (LE DVT)
  145. streptokinase
    • 1st gen fibrinolytic
    • MOA: forms stable complex with plasminogen --> conformational change to allow conversion to plasmin
    • no intrinsic enzyme activity
    • not fibrin specific
    • similar structure to streptococci so can have antibodies against it from prior infection- risk for allergic rxn
  146. alteplase/tPA
    • 2nd gen fibrinolytic
    • fibrin specific, only converts fibrin bound plasminogen to plasmin
    • improved efficacy for ACS
    • more $ than streptokinase
    • shortest half life of all fibrynolytics 3-8 min
  147. urokinase
    • 2nd gen fibrinolytic
    • expensive as alteplase with the SE of streptokinase --> limited use
  148. reteplase
    • 3rd gen fibrinolytic
    • deletion mutant of tPA, less fibrin specific, but increased efficacy and similar $, similar risks
    • only fibrinolytic with renal metabolism, so best choice in hepatic probs
  149. tenecteplase
    • 3rd gen fibrinolytic
    • recombinant version of tPA, more $, similar efficacy. also fibrin specific
  150. exogenous serum lipoprotein formation
    • fat and cholesterol absorbed after a meal --> TG and cholesterol in intestinal cell, packed into chylomicrons
    • CMs enter lymph and circulation --> TG hydrolyzed to FFA and glycerol
    • removed from circulation by adipose and muscle tissue
  151. endogenous serum lipoprotein formation
    • VLDL processed and secreted by liver
    • in circulation, hydrolyzed by lipase --> FFA and glycerol
    • 50% absorbed by fat/muscle, rest transformed in IDL then LDL, circulate 2-3 days
  152. atherosclerosis
    build up of cholesterol on arterial wall- mainly LDL, some HDL
  153. low atherosclerosis risk
    • 0-1 risk factors
    • goal <160 LDL
  154. moderate atherosclerosis risk
    • 2+ risk factors
    • <130 LDL goal
    • * most people
  155. high atherosclerosis risk
    • CHD
    • <100 LDL goal
  156. statins
    • MOA: inhibit HMG-CoA reductase- rate limiting enzyme in biosynthesis of cholesterol in liver
    • inhibit endogenous cholesterol
    • food decreases absorption for most statins, but increases for lovastatin
    • monitor liver f'n 1-2 months monitor CK b/c --> aches r/t muscle breakdown
    • ADR: HA, GI, rhabdomyolysis, myalgia
    • take before bed
    • given after MI
    • each agent has different SE
  157. potency of statins
    • each has different reduction in LDL, cholesterol, TG and increase in HDL
    • Atorvastatin and rotuvastatin are most potent
  158. nicotinic acid
    • Niacin: reduces hepatic synthesis of VLDL by decreasing release of FFA --> less LDL/TG
    • also decrease HDL breakdown --> increased levels
    • MOA: unsure
    • caution: contains yellow dye 5
    • ADR: flushing- need to gradually increase dose, take ASA prior to use, avoid hot fluids and take w/ meals
  159. bile acid sequestrants
    • colestipol, cholestyramine
    • MOA: promote increased excretion of bile acid --> liver converts more cholesterol into bile acid --> more uptake of LDL from plasma
    • dose: one packet mixed w/ liquid 30 min before during or 30 min after meal
    • increase dose gradually
    • ADR: severe constipation, flatulence, N/v- need stool softener. reduced folate levels with long term use
    • not used much, sometimes adjunct to statin
  160. fibrates
    • gemfibrozil/fenfofibrate (lopid/tricor)
    • increase lipolysis of TG, also dec LDL and inc HDL
    • *use low dose of fenfo in renal impairment
    • ADR: rhabdo (not used w/ statin), minimal GI but do not use w/ gallstone hx
  161. ezetimibe/zetia
    • MOA: inhibits cholesterol absorption across gut border (exogenous)
    • combined with statins (vytorin=combo product)
    • well tolerated but --> fatty stool
  162. Renin-Angiotensin- Aldosterone system
    • release of renin from kidney cells in response to  dec renal blood flow/dec. BP/B1 activation
    • renin: angioteninogen-->angI (weak vasconstrictor)
    • ACE: angI-->ang II (potent vasoconstrictor) AngII: also promotes aldos secretion --> retain Na and H20, but lose K 
  163. nitric oxide
  164. bradykinin
  165. prostacyclin
  166. autonomic NS and BP
    • baroreceptors in aortic arch/carotid sinus sense BP- if down, brainstem sends sympathetic impulse to B1 receptors (inc HR) and A1 (vasoconstriction)
    • *diuresing pt wont help with this
  167. Kidneys and BP
    kidney senses dec BP --> dec GFR --> retain water and Na --> inc BV--> inc CO --> inc BP

    also activation of RAAS
  168. diuretics in HTN
    • Thiazide are first line, in combo w/ other antihypertensives
    • loop and K sparing are not often used for soley treating HTN
    • drug interactions: NSAIDs block PG --> block renal blood flow; Lithium (follows ion [x], can end up w/ too much or little); bile acid sequestrants
  169. long term use of diuretics
    decrease in systemic vascular resistance- unknown mechanism
  170. Thiazide diuretics
    • HCTZ
    • MOA: inhibit Na reabsorption in distal tubule
    • ADR: hypoK, hypovol, hyperuricemia/glycemia/cholesterolemia (bc dec nephron perfusion)
    • don't take at night to avoid nocturia
    • ineffective CrCl<30 (already not working, can't make it work harder)
    • once daily
    • mod-low potency
  171. loop diuretics
    • lasix!
    • MOA: inhibit Na reabsorption in ascending loop
    • ADR: HypoK, ototoxic in high doses
    • most potent of commonly used
    • cross sensitivity w/ sulfa allergy
    • dont use w/ aminoglycosides r/t ototoxic
  172. k sparing diuretic
    • sprinolactone/aldactone
    • MOA: antagonize aldosterone secretion in distal tubule, inhibit Na channels on aldosterone sensitive Na pump
    • ADR: HyperK, gynecomastia (steroid like structure)
    • mild action
    • avoid in CrCl<30
    • avoid use w/ ACE inhibitors
  173. ACE inhibitors MOA
    • MOA: prevent conversion of angI to ang II
    • CV effects: dec BP, improve heart O2, downregulate sympathetic adrenergic activity, dec. inappropriate remodeling after MI
    • also prevent bradykinin breakdown (a vasodilator)
  174. ACE use
    • ex: ___PRIL (captopril)
    • precaution: impaired renal f'n
    • CI: renal artery stenosis, angioedema(r/t vasodilation), pregnancy
    • ADR:dry cough (bradykinin buildup), angioedema, hyperK (no aldos-->no K loss)
    • af am don't respond well; can use w/ diuretic to improve efficacy
    • drug interactions: lithium, iron, NSAIDs (rt vasoconstriction from blocked PG --> dec renal blood flow)
    • renal protective: good for DM, HF, CKD so often use even if no HTN
  175. angII receptor blocker MOA
    • ex: ___sartan (valsartan/diovan)
    • only blocks angII type 1, so still get benefits of type2 (vasodilation, tissue repair, inhibition of cell growth)
    • CV effects: dilate arteries, dec pre/afterload, down regulate sympathetic andrenergic activity/norepi reuptake (vasoconstriction), promote renal Na/H20 excretion, inhibit remodeling
  176. angII receptor blocker use
    • ADR: hyperK, orthostatic hypoten- but overall low SE 
    • precaution: impaired renal fcn, renal artery stenosis, angioedema (but NOT contraindicated), drugs that raise K
    • CI: pregnancy
    • often used in combo with w/ thiazide diuretic
  177. Aliskiren/tekturna
    • renin inhibitor
    • MOA: prevents angiotensinogen to angI
    • precautions: angioedema, severe renal impairment
    • ADR: hyperK, diarrhea
  178. Beta receptor blockers MOA
    • CV effects: dec contractility, HR, conduction velocity
    • Renal effects: dec renin release --> less vasoconstriction
    • vascular effects: block B2 mediated vasodilation, but eventually --> reduced sympathetic outflow and TPR
    • hepatic metabolism
  179. atenolol (tenormin)/metoprolol (lopressor)
    • B1 selective blocker: safer for asthma, COPD, PAD
    • b/c B2 blocking --> vaso/broncho constriction. 
    • lose selectivity in high doses
  180. B receptor blockers use
    • precautions: resp conditions, hyperlipidemia, DM (can block signs of hyper/hypoglycemia)
    • CI: AV block b/c alters conduction velocity
    • ADR: brady, dizzy, dry mouth, dec libido, masked hypoglycemia
    • drug interactions: clonidine, OTC cold meds (inc BP/HR, vasconstrict), other antihypertensives
    • use in combo w/ diuretic
    • nonselective= propranolol
  181. combined B/A antagonist
    • carvedilol(coreg)/labetalol
    • blocks A1, B1/2
    • precaution: bronchospasms, hepatic impairment
    • ADR: brady, dizzy, dry mouth, dec libido, masked hypoglycemia
  182. A1 antagonists
    • cardua, minipress, flomax(tamulosin)
    • MOA: block A1 receptors in vasculature--> dec a/v vasoconstriction, dec PVR
    • precaution: volume depletion, HF
    • ADR: orthostatic (esp 1st dose postural), impotence
    • drug of choice for BPH
  183. central A2 agonists
    • clonidine (catapres), guanfasine
    • MOA: stimulate A2 receptors in brain --> dec HR/CO/PR, dec renin activity, dec baroreceptor reflexes
    • ADR: anticholinergic, nightmares/insomia (clonidine), Na/H20 retention
    • interactions: B blocers, CNS depression
    • withdraw gradually to avoid rebound HTN
    • give w/ diuretic to avoid too much H20 retention
  184. methyldopa (aldomet)
    Central A2 agonist- 1st line for HTN in pregnancy
  185. Dihydropyridines
    • norvasc (amlodipine), nifedipene (procardia)
    • peripheral Ca Chanel blocker --> preripheral vasodilator, no AV conduction effects
    • ADR: flushing, HA, HTN, edema, reflex tachy, gingival hyperplasia
  186. non-Dihydropyridines
    • verapamil, cardizem (dilatizem)
    • cardiac ca channel blocker--> dec HR, slow AV node conduction, dec contractility
    • ADR: brady, anorexia, nausea, edema, constipation
    • CYP metabolism
    • short acting and SR forms
    • avoid in CHF (b/c dec contractility)
  187. Ca channel blockers
    • short acting and SR forms
    • more ADR with short acting
  188. hydralizine/minoxidil
    • peripheral vasodilators:only relax arterioles (no venous)
    • both well absorbed orally, minoxidil has higher bioavailability since not protein bound, and lasts longer b/c has active metabolite (also more severe SE)
    • interactions: NSAID (r/t PG vasoconstriction)
    • ADR:activates baroreceptor reflex, Na/H20 retention, lupus like syndrome (hydralazine), hair growth (minoxidil---rogaine!)
    • can use Beta blocker and thiazide diuretic to dec ADR
  189. drug choice in HTN
    • Initial Drug Choice:Thiazide diuretic, ACE-I, ARB, CCB
    • Compelling indications: Usually Beta-blocker, ACE-I or ARB
    • Combination Therapy: Diuretic + ACE-I, BB, ARB, CCB
    • Difficult to Treat HTN: Utilize alternate agents- alpha2 agonists, peripheral vasodilators
  190. anti HTN for HF
    • diuretic + ACE inhibitor
    • b blocker
    • ARB, aldosterone antagonist
  191. anti HTN post MI
    • B Blocker + ACE inhibitor
    • aldosterone antagonist
  192. anti HTN coronary disease risk
    • B Blocker
    • ACE inhibitor, CCB, diuretic
  193. anti HTN DM
    • ACE inhibitor OR ARB
    • diuretic
    • B Blocker, CCB
  194. anti HTN CKD
    ace inhibitor or ARB
  195. anti HTN prevent recurrent stroke
    diuretic + ACE inhibitor
  196. chronic HTN in pregnancy
    • methyldopa is traditional drug of choice
    • labetolol: increasingly preferred (low SE)
    • clonidine: limited date, use in 3rd tri
    • BBlocker --> IUGR
    • CCB: limited data
    • diuretics: safe in low doses if stated before conception
    • ACE/ARB/renin inhibitors: CONTRAINDICATED
  197. digoxin MOA
    • cardiac glycoside: positive inotrope --> increase force of ventricular contraction
    • MOA: inhibits Na/K pump --> Ca buildup in cell --> inc contractility but dec automaticity/conduction velocity of AV node *stronger but slower
  198. digoxin use
    • HF: dec sympathetic tone, inc urine, dec renin release
    • precautions: renal impairment, lyte imbalances (hypoK hyperCa can --> arrythmias)
    • CI: AV block, arrythmias
    • ADR: anorexia, n/v, diarrhea, yellow vision, halo effect, brady, gynecomastia
    • monitor drug levels until normalized, then not as much
    • also monitor lytes, CrCl
  199. digoxin drug interactions
    • drugs that --> hypoK: inc dig levels (diuretics)
    • drugs that --> hyperK: dec dig levels (ACE-I/ARB)
    • verapamil (ccb): dec dig effects by dec contractility
  200. Isosorbide (imdur/isordil)
    • oral nitrates (similar to nitro)
    • MOA: vaso dilate, reduce pre/after load, dec O2 demand b/c heart relaxes
    • sig. 1st pass for oral
    • precautions: volume depletion (makes heart want to work harder)
    • CI: head trauma, cerebral hemorrhage (dont want to dilate more)
    • interactions: anti HTN, ASA (increase nitrate [x]), may dec effect of heparin
    • bidil:combo with hydralazine, shows more improvement
    • *need 10-12 hr nitrate free interval
    • treat HA w/ tylenol
  201. parasympathetic vs sympathetic control of heart
    • sym: rate of nodal discharge, rate of conduction and excitability, force of contraction
    • para: rate rhythmic contraction, release ACh
  202. ions and action potentials
    • fast:
    • Na in--> depol
    • Ca in --> contraction
    • K out --> repol

    • slow:
    • slower depol mediatied by Ca influx
  203. anti arrhythmic classes
    • I: NA channel blocker
    • quinidine: dec CV, inc RP, dec A
    • lidocaine: 0/dec CV, dec RP, dec A
    • flecanide: big dec CV, 0 R, dec A
    • II: beta blockers-  dec CV, inc RP, dec A
    • III: K channel blockers- o CV, big inc RP, 0A
    • IV: Ca channel blockers- dec CV, inc RP, dec A

    • CV- conduction velocity
    • RP- refractory period
    • A- automaticity
  204. quinidine
    • Na channel blocker
    • slow impulse conduction, delay repol (by blockin K channels), anticholinergic action
    • use: long term arrythmia suppression
    • ADR: prolonged QT, diarrhea, ringing ears, HA, n/v, vsion disturbance
    • metabolized and inhibited by different CYP
  205. lidocaine
    • Na channel blocker
    • slows conduction, reduces automaticity, accelerates repol (short action potential)
    • *no anticholinergic
    • *no ECG change
    • use: short term ventricular arrythmia
    • ADR: brady, asystole, dizzy, seizures, confusion
  206. Flecanide
    • Na channel blocker
    • last line agent: very potent, use w/ discretion
    • markedly dec rate of depol --> delay repol
    • ADR: prolonged PR, QRS; sinus node dysfunction, reduced conduction velocity, conduction block
    • interactions: amiodarone/dig increase serum levels- should dec felc dose by 50% and monitor dig levels
  207. BBlockers (antiarrhtymic)
    • propanolol, esmolol, acebutolol
    • MOA: dec adrenergic activity --> dec automaticity of SA node, dec AV conduction velocity, dec contractility
    • ADR: bronchospasm, AV block
    • CI: 2nd/3rd def block
  208. K channel blockers
    • delay repol of fast potential (prolong refractory period)
    • dec automaticity of ventricles
    • prolong QT
  209. amiodarone
    • K channel blocker
    • but also has class I, II, IV activity; inhibiting Ca ---> node depression
    • use: broad spectrum arrhythmias
    • extensive liver/CYP metabolism: inhibits its own metabolism --> long half life --> toxic effects can last weeks-months; also many drug interaction
    • ADR: lung damage, vision disturbance, hepatotoxicity, CNS rxn
    • need baseline PFT
    • interactions: can increase levels of dig, dilantin, warfarin, statins
  210. CCB as anti arrhythmic
    • slow SA automaticity, delay AV conduction, reduce contractility- same effects as BBlockers
    • use: SVT
    • precautions: high fat/carb meals inc toxicity of cadizem; antihistamines (H2) increase CCB level, BBlocker supplement activity, CCB increase Dig levels
    • highly protein bound
  211. digoxin as antiarrhythmics
    • use: SVT
    • MOA: potent and selective Na channel inhibitor --> significant inc Ca in cell --> inc contractility, dec automaticity, dec AV conduction velocity
    • suppresses s/s, but doesn't treat, not 1st line agent
    • inc extracellular K reverses toxic effects (b/c pushes Na into cell)
    • non CYP but extensive hepatic metabolism
    • CI: av block, vfib, hypoK, severe brady, severe renal impairment
    • ADR: t wave inversion/depression, prolonged PR, proarrythmic, brady, gynecomastia, encephalopathy
    • antidote: digtoxin
  212. dronedarone
    • novel therapy for arrhythmias
    • resembles amiodarone, but fewer toxicity and shorter half life
    • reduces rate and stimulation of heart
    • QT prolongation
    • inhibits Na channels, esp SA node
    • inc repolarization phase, dec HR, antiadrenergic