Pharmacology - principles

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  1. Enzyme kinetics
    • Michaelis-Menten kinetics
    • [S] = concentration of substrate
    • V = velocity
    • Km is inversely related to the affinity of the enzyme for its substrate
    • Vmax is directly proportional to the enzyme concentration
    • Most enzymes follow a hyperbolic curve (Michaelis-Menten kinetics); some follow cooperative kinetics (i.e., hemoglobin) have a sigmoid curve
  2. Lineweaver-Burk plot
    • ↑ y-intercept, ↓ Vmax
    • The further to the right the x-intercept, the greater the Km and the lower the affinity
  3. Enzyme inhibition
    • Competitive inhibitors cross each other competitively, whereas noncompetitive inhibitors do not
  4. Competitive  inhibitors
    • Resemble substrate
    • Overcome by ↑ [S]
    • Bind active site
    • No effect on Vmax
    • Increase Km
    • Decreases potency (pharmacodynamics)
  5. Noncompetitive inhibitors
    • Does not resemble substrate
    • Not overcome by ↑ [S]
    • Does not bind active site
    • Decreases Vmax
    • No change on Km
    • Decreases efficacy (pharmacodynamics)
  6. Pharmacokinetics
    factors that influence...
    • Bioavailability (F)
    • Volume of distribution (Vd)
    • Half-life (t1/2)
    • Clearance (CL)
  7. Bioavailability (F)
    • Fraction of administered drug that reaches synstemic circulation unchanged
    • For IV dose, F = 100%
    • Orally: F typically <100% to incomplete absorption and first-pass metabolism
  8. Volume of distribution (Vd)
    • Theoretical fluid volume required to maintain the total absorbed drug amount at the plasma concentration
    • Vd of plasma protein-bound drug can be altered by liver and kidney disaese (↓ protein binding, ↑ Vd)
    • Vd = (amount of drug in the body)/(plasma drug concentration)
  9. Vd
    blood, ECF, all tissue
    • Blood: Vd low (4-8L)
    • -Drugs: large/charged molecules; plasma protein bound

    • ECF: Vd medium
    • -Drugs: small hydrophilic molecules

    • All tissues: Vd high
    • -Drugs: small lipophilic molecules, especially if bound to tissue protein
  10. Half-life (t1/2)
    • The time required to change the amount of drug in the body by 1/2 during elimination (or constant infusion)
    • Property of first-order elimination
    • Drug infused at a constant rate takes 4-5 half-lives to reach steady state
  11. Clearance (CL)
    • Relates the rate of elimination to the plasma concentration
    • Clearance may be impaired with defects in cardiac, hepatic, or renal function
    • CL = (rate of elimination of drug)/(plasma drug concentration)
    •  (elimination constant)
  12. Dosage calculation
    • Loading dose = Cp × Vd/F
    • Maintenance dose = Cp × CL/F
    • -In renal or liver disease, maintenance dose ↓ and loading dose is unchanged
    • Cp = target plasma concentration
    • -Time to steady state depends primarily on t1/2 and is independent of dosing frequency or size
  13. Zero-order elimination
    • -Rate of elimination is constant regardless of Cp
    • -Capacity-limited elimination: constant amount of drug eliminated per unit time
    • -Cp ↓ linearly with time

    • ExamplesPhenytoin, Ethanol, and Aspirin (at high or toxic concentrations)
    • *PEA (a pea is round, shaped like a "0" in "zero-order"
  14. First-order elimination
    • -Rate of elimination is directly proportional to the drug concentration
    • -Flow dependent elimination: constant fraction of drug eliminated per unit time
    • -Cp ↓ exponentially with time
  15. Urine pH and drug elimination
    • Ionized species are trapped in urine and cleared quickly
    • Neutral forms can be reabosrbed
  16. Weak acids
    • Examples: phenobarbital, methotrexate, aspirin
    • Trapped in basic environment
    • Treat overdose with bicarbonate
    • RCOOH ⇌ RCOO- + H+
    • (lipid soluble) ⇌ (lipid soluble)
  17. Weak bases
    • Examples: amphetamines
    • Trapped in acidic environments
    • Treat overdose with ammonium chloride
    • RNH3+ ⇌ RNH2 + H+
    • (trapped) ⇌ (lipid soluble)
  18. Drug metabolism
    Phase I, phase II
    • Phase I:
    • -Reduction, oxidation, hydrolysis with cytochrome P-450 usually yield slightly polar, water-soluble metabolites (often still active)
    • -Geriatric patients lose phase I first

    • Phase II:
    • -Conjugation (Glucuronidation, Acetylation, Sulfation) usually yields very polar, inactive metabolites (renally excreted)
    • *Geriatric patients have GAS (phase II)
    • -Patients who are slow acetylators have greater side effects from certain drugs because of ↓ rate of metabolism
  19. Efficacy
    • Maximal effect a drug can produce
    • High-efficacy drug classes: analgesics, antibiotics, antihistamines, decongestants
    • Partial agonists have less efficacy than full agonists
  20. Potency
    • Amount of drug needed for a given effect
    • ↑ potency, ↑ affinity for receptor
    • High potent drug classes: chemotherapeutics, antihypertensives, antilipid drugs
  21. Competitive antagonist
    • ↓ potency (shifts curve to right)
    • no change in efficacy
    • Can be overcome by increasing the concentration of agonist substrate
    • example: diazepam + flumazenil on GABA receptor
  22. Noncompetitive antagonist
    • ↓ efficacy
    • Cannot be overcome by increasing agonist substrate concentration
    • Example: NE + phenoxybenzamine on α-receptors
  23. Partial agonist
    • Acts at same site as  full agonist, but with reduced maximal effect → ↓ efficacy
    • Potency is a different variable and can be ↑ or ↓
    • Examples: Morphine (full agonist) and buprenorphine (partial agonist) at opioid μ-receptor
  24. Therapeutic index
    • Measurement of drug safety
    • LD50/ED50 = median lethal dose/median effective dose
    • TILETherapeutic IndexLD50/ED50
    • Safer drugs have higher TI values
    • Low TI value: digoxin, lithium, theophylline, warfarin
  25. Therapeutic window
    • Measure of clinical drug safety
    • Range of minimum effective dose to minimum toxic dose

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Pharmacology - principles
2013-03-31 21:05:33

Pharmacology principles
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