general concepts

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  1. pKa
    pH where acid is 50% ionized, 50% non-ionized
  2. weak acid better absorbed in acidic environ,
    better excreted in basic environ !
  3. To acidify urine
    • NH4Cl
    • vit C
    • cranberry juice

    • (ex) overdose on PCP, amphetamines
    • (ex) hepatic encephalopathy- give lactulose--> gut bacteria-->lactic acid--> NH4+--> eliminate ammonia this way
  4. alkalinze urine
    • NaHCO3
    • acetazolaminde

    (ex) Aspirin ovordose
  5. Bioavailability
    how much of the drug gets into the blood

    f= area under curve (PO)/ area under curve (IV)
  6. First pass effect
    w/ oral--> portal circ--> rapid hepaitc metabolism decrease bioavailability

    (ex) Lidocaine (IV vs PO)- huge first pass, no point of giving PO

    (ex) Nitroglycerin- give sublingual, bypass first pass, also fast onset
  7. Distribution (what affects it?)
    • - how much of drug gets from blood to target organs
    • -b/c high protein binding capacity, free fraction gen constant!
    • -only unbound drugs cross mem--> effect!!!

    • (ex) sulfonamide displace bilirubin from albumin--> jaundice
    • (ex) sulfonamide displace warfarin (98% protein bound)--> bleeding
  8. Traits of drug safe in pregnancy?
    • water soluble
    • large
    • highly protein bound
  9. approximate fluid compartment volumes (70kg)
    -plasma volume?
  10. approximate fluid compartment volumes (70kg)
    -blood volume?
  11. approximate fluid compartment volumes (70kg)
    -ECF volume?
    12-14 L

    • 1/3 of total body water
    • within ECF, plasma volume is 3L, rest is ICF
  12. approximate fluid compartment volumes (70kg)total body water?
    TBW= 40-42L
  13. Volume of distribution (Vd)
    -what is it?
    -what do low, high values mean?
    • volume of the compartment that drug gets into from plasma!
    • -where is the drug? blood or tissue? --> look at Vd

    • -Low Vd (4-8L)= distrubue in blood, high protein bound. High MW= protein bound, High charges (hydrophilic) = stay in plasma
    • -Medium Vd= distribute to extracellular space or body water (ex) high charge but small MW--> interstitial fluid outside plasma, intravascular. so Vd ~ ECF 14
    • -High Vd (>body wt)= go to tissues! highest Vd= small MW, lipophilic
  14. Volume of distribution (Vd) equation?
    Vd is needed to calc loading dose

    • Vd= Dose/C0
    • = amount of drug in body/ plasma drug conc at time zero (usu given for each drug)

    • -experimentally determined. So use it to calc dose
    • -changing Vd will affect half life!
    • -increase Vd-->increase half life
    • -increase Clearnce--> decrease half life
  15. Biotransformation: Phase I, PhaseII
    Phase I metabolism
    oxidation, reduction, hydrolysis

    -yield slightly more polar, water soluble metabolites

    • -Cyp P450- in smooth ER
    • -need O2, NADPH

    -Geriatric patients lose phase I first
  16. Cyp P450
    -which ones have genetic polymorphism?
    Cyp 2C9- Phenytoin, Warfarin

    • Cyp 2D6- many CV, CNS drugs
    • (inhibited by Haloperidol, Quinidine)

    No genetic polymorphism for Cyp 12A, 3A4

    Cyp 3A4- most active one
  17. pt w chronic bronchitis on bronchodilators, antibiotics
    (ex) theophylline, macrolides
    macrolide inhibit Cyp--> increase theophylline toxicity
  18. Non microsomal metabolism
    Hydrolysis- pseudocholinesterases genetic polymorphism

    • MOA- DA, NE, EPI, 5-HT
    • -exogenous compounds (ex) Tyramine

    Alcohol metabolism
  19. Phase II metabolism
    Acetylation, Glucuronidation, Sulfation

    • -yield very polar, inactive mtabolites
    • -Glucuronidation- inducible, reduced activity in neonates (ex) Chloramphenicol--> gray baby syndrome!

    • -Acetylation- fast vs. slow acetylators
    • (ex) drug induced SLE by slow acetylators w/ Hydralazine> Procainamide> Isoniazid

    -GLutathione conjugation- deplete GSH, acetominophen toxicity!
  20. Elimination

    definition of half life?
    elimination= termination of drug action. NOT same as excretion

    • half life= time to eliminate plasma level of drug by 50%
    • -property of 1st order kinetics
  21. Clearance
    • - volume of blood cleared of drug per unit time
    • -relate rate of elimination of drug to plasma concentration
    • -constant in 1st order kinetics
    • -same as GFR when no reabsorption/secretion, no plasma protein binding
    • -protein bound drug not clearde!

    CL= rate of elimination of drug/ plasma drug conc

    = Vd x Ke (Ke= elimination constant)

    =Free fraction x GFR
  22. Zero order elimination kinetics
    constant AMOUNT of drug eliminated per unit time, regardless of Cp.

    • -saturation kinetics (ex) drug metabolizing rxn has reached its Vmax.
    • -elimination is constant.
    • -half life is variable!
    • -Cp decreases linearly with time

    (ex) phenytoin, ethanol, aspirin (at high dose)
  23. 1st order elimination kinetics
    • Elimination rate is proportional to drug conc Cp!
    • -constant % (fraction) eliminated per unit time

    • -Cp decrease exponentially with time
    • -half life constant!
    • -clearance constant!
    • -elimination rate is variable! (depends on Cp)

    half life= 0.7x Vd/Cl
  24. half life equation?
    = 0.7 xVd/Cl

    = 0.7/ Ke (elimination constant)
  25. Renal elimination
    rate of elimination?
    = GFR + active secretion - reabsorption

    • Clearance= Free Fraction x GFR
    • = Vd x Ke

    GFR= inulin clearance
  26. Steady state
    -achieve and maintain steady state plasma level of drug that's above minimal effective conc, even at it's lowest Css

    rate in= rate out

    • -time to reach steady state depends ONLY on elimination half life!
    • -independent of dose or frequency of administration!
    • -takes about 4~5 half lives to reach steady stat
  27. Infusion rate and steady state?
    • Regardless of the rate of infusion, it will take the same amount of time to reach steady state!
    • -but Dose affects plasma conc Cp, so although it doesn't affect time to reach SS, it'll affect the DOSE AT steady state!

    -give more drug--> reach higher plasma steady state level, but won't get there any faster.eeee
  28. Infusion rate equation?
    Ko= Cl x Cp (at ss)
  29. Loading dose
    -what is it?
    use in situations when you can't wait 4~5 half lives to reach steady state (ex) Digoxin half life- 2 days (2x5= 10 days to reach SS!)

    • -give one time only loading dose + subsequent maintenance dose.
    • -loading dose- usu target plasma level at steady state!
  30. Loading dose equation
    LD= Cp x Vd/ bioavail

    Cp= target plasma level
  31. Maintenance dose equation
    MD= Cp x Cl/bioavail

    Cp=target plasma level
  32. in renal or liver disease, decrease maintenance dose!
    loading dose unchanged.
  33. Efficacy vs Potency
    Efficacy= max effect a drug can produce

    Potency= amount of drug needed for a given effect
  34. Competative antagonist
    • -shift curve to R--> decrease potency, no chnange in efficacy.
    • -same Vmax
    • -increase Km

    (ex) Diazepam + Flumazenil on GABA receptor
  35. Noncompetative antagonist
    • shift curve down--> decrease efficacy!
    • -decrease Vmax
    • -same Km

    (ex) NE + phenoxybenzamine on alpha-receptors
  36. Potentiator
    • shift curve to LEFT!
    • -increase potency!

    (ex) BZDs on GABA potency
  37. Partial agonist
    • agonist on its own,
    • antagonist w/ the endogenous agonist

    • -decrease efficacy
    • -potency variable

    (ex) Morphine + Buprenorphine
  38. Physiological antagonism
    substance that produces opposite physiologic effect of an agnist but does not act at the same receptor

    (ex) Phenylephrine + Nitroglycerin
  39. Therapeutic index
    measurement of drug safety

    LD50/ ED50

    want a drug with high TI, steep curve (low variability!)
  40. Gs--> cAMP--> PKA--> CREB

    ANS receptors?
    B1, B2, D1, H2, some 5-HT, Prostacyclin

    • also..
    • FSH, LH, ACTH, TSH, CRH, PTH, hCG,
    • ADH (V2), MSH, Calcitonin, GHRH, Glucagon
  41. Gi--> decrease cAMP

    ANS receptors?
    Alpha2, M2, D2, Opioid (mu), some 5HT
  42. Gq--> PLC--> IP3, DAG--> Ca, PKC

    ANS receptors?
    M1, M3, Alpha1

    • also..
    • -GnRH, Oxytosin, ADH (V1), TRH
  43. cGMP, NO signaling

    Nitrates, ANP, BK, His (some)
  44. Cytosol steroid receptor
    • Estrogen
    • Testosterone
    • Cortisol
    • vitD
  45. Nuclear receptor
  46. RTK--> Ras/MAP kinase path
    Insulin, IGF-1, FGF, PDGF
  47. Receptor associated tyr kinases--> JAK/STAT
    Prolactin, GH, Cytokines, EPO, Somatostatin
  48. alpha1--> Gq

    -smooth muscles, liver, kidney
    • vascular SM contract
    • pupillary dilator (mydriasis)
    • bladder sphincter contract
    • increase glycogenolysis (increase glucose)
    • decrease renin release
  49. alpha 2 --> Gi

    presynaptic, platelets, pancreas
    • decrease NE release
    • decrease insulin release
    • platelet aggreation
  50. B1--> Gs

    -heart, kidney, fat
    • increase HR
    • increase heart contractility
    • increase Renin release
    • increase Lipolysis
  51. B2--> Gs

    blood-->EPI--> all BV, broncial, uterine smooth muscle, heart, liver, pancreas
    • vasodilate
    • bronchodilate
    • increase heart rate
    • increase contractility
    • relax uterus
    • increase glycogenolysis (glucose in SKM--> tremor!
    • increase lipolysis!
    • also increase insuline release! (alpha2 decreases it)
    • (so tissues take up the released glucose)
  52. M1--> Gq--> Ca

    -CNS, GI
    • contract GI muscle
    • CNS effects
  53. M2--> Gi-->dec cAMP

    • decrease HR
    • decrease contractility
  54. M3--> Gq--> Ca

    smooth muscle (except vascular), glands
    (sweat, piloerector m. is SNS, but Ach-->M3)
    • -increase secretion! (sweat, salivate, lacrimate, GI)
    • -increase gut peristalsis
    • -increase bladder contract
    • -bronchoconstrict
    • -pupil constrict (miosis)
    • -ciliary muscle contract (accomodate)
  55. D1--> Gs

    kidney vascular, GI vascular, Coronary vascular
    relax kidney vascular smooth muscle!

    increase renal RBF, GFR, increase Na secretion!
  56. D2--> Gi

    presynaptic? CNS
    • modulate neurotransmitter release
    • esp. brain
  57. H1--> Gq
    • increase nasal, bronchial mucus production
    • contract bronchioles
    • pruritis
    • pain
  58. H2-->Gs
    Parietal cell gastric acid secretion!
  59. V1--> Gq

    -vascular smooth muscle
    ADH--> vasoconstrict
  60. V2--> Gs

    -collecting duct kidney
    ADH--> Vs-->cAMP--> aquaporin mobilize--> increase water permeability--> concentrate urine
  61. Drug tracings
    -nonselective beta agonist (ex) Isopreterenol
    • increase HR, decrease BP! increase PP
    • (increase CO--> increase sys BP, vasodilate--> decrease dias BP--> increase PP, decrease MAP)
  62. Drug tracing
    • alpha1--> increase BP
    • beta1--> increase HR, CO, PP
    • reflex bradycardia!

    • NO effect on B2
    • NE NEVER decrease BP!!
  63. Drug tracing
    -how to block reflex tachycardia, bradycardia?
    • Ganglionic blockade!
    • Hexamethonium
    • Mecamylamine
  64. Drug tracing
    low dose EPI
    • beta1--> increase HR, CO, PP
    • beta2--> decrease BP

    -looks like Isopreterenol!
  65. Drug tracing
    medium dose EPI
    • beta1--> increase HR, CO, PP
    • beta2--> decrease BP
    • alpha1--> increase BP

    antagonistic effect on BP cancle--> same MAP, just increase PP, HR!
  66. Drug tracing
    High dose EPI
    • alpha1> beta 1, 2
    • looks like NE!

    increase HR, PP, BP--> reflex tachycardia
  67. when you can't tell apart high dose EPI and NE,
    look for Beta2 specific signs!
    OR EPI reversal!
    • -bronchodilate
    • -glucose increase
    • -fat breakdown
    • -increase insulin

    • EPI reversal!- at high doses B1, alpha1 predominate, NE, EPI look same. Give alpha1 blocker-->
    • if pt on NE--> HR still high, but no increase in BP
    • if pt on EPI--> HR kept high, but BP drops! (unmask beta2)
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general concepts
general concepts
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