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ionization of base
- most ionized: pKa > pH (H2O sol)
- least ionized: pKa < pH
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ionization of acid
- most ionized: pKa < pH (H2O sol)
- least ionized: pKa > pH
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- how long does it take to reach steady state concentration without a loading dose
- 4 t1/2 (4 half lives)
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lipid diffusion
- - most common way drugs cross cell membrance
- -
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aqueous diffusion
- restricted to solutes with MW < 100
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percentage of nonionized or ionized drug as a function of the difference between pKa and pH
- 0= 50%
- 0.5= 76%
- 1= 90%
- 2= 99%
- 3= 99.9%
- >3= >99.9%
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ion trpping
- - process by which [drug] can climb very high compared to the [drug] outside the cell. This can be the result of change in pH and b/t ionized and non-ionized forms once it reached the inside of the cell
- - ie ASA mostly lipid solube(non ionized) in the gut lumen (low pH) and then mostly H2O soluble in the cells (pH=7), this results in the ions being trapped within the cell
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acidic drugs
- mostly ionized/H2O soluble when pKa<pH
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drugs that cross cell membranes via endo/exocytosis
- 2000-100,000 MW
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Drugs that travel via bulk flow/filtration/convective transfer
- - up to 40,000 MW
- - passive
- - non selective
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first order kinetics
- a contant fraction (or percentage) of a drug is absorbed, distributed or eliminated per unit time
-
zero order kinetics
- - a constant amount of the drug is absorbed, distributed or eliminated per unit time
- - accounts for very few drugs
-
bioavailabilty (F) based on AUC
- F= AUCx/AUCiv
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gas administration
- - most rapid
- - acheive systemic effects
- - absorption is directly proportional to the Px of the gas in the alveoli
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aerosol administration
- - absorption is usually slow and very limited
- - acheive local effects
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SC and IM administration
- - absorption occurs mainly via bulk-flow transfer thru intercellular pores of endothelium of b/v
- - SM (10-30 min)
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volume of distibution (Vd)
- Vd = D x F/ Cp0 (independent of dose)
- D = dose, F = bioavailability, Cp0 = [drug]pl at zero time
- Vd~3L: distribution restricted to vascular compartment
- Vd~13L: distibution thruout EC fluid, cant penetrate cells
- Vd~42L: distribution is in total body water
- Vd>42L: drug extensively stored w/in specific cells/tissue
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initial dose calculation
- - D = (Vd x C0)/F
- - desired [drug]pl must be known
-
drug binding
- - albumin if acidic
- - alpha1-acid glycoprotein if basic
- - binding is a constant percentage (independent of dose)
- - saturable
- -**competition can occur**(very relevant if binding is >90-95%, because a competitor can cause a large increase in [drug]pl
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circumventricular organs (cerebral regions outside the BBB)
- - posterior pituitary
- - median eminence of the HT
- - Supraoptic crest
- - Subfornical organ
- - area postrema
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placental drug transfer
- - <1000 MW
- - greater with lipophilic drugs
- - highly ionized drugs 200MW or higher cross slowly andpoorly
- - greater with un-protein bound drugs
- - easier in 3rd trimester
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main monooxygenases
- NAPDH- cytochrome P450 reductase and ctyochrome P450
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UDP- glucuronosyltransferase
- microsomal enzyme in the liver responsible for glucuronidation, the most common conjugation reaction of xenobiotics
-
microsomal enzymes
- - SER of the liver cyt P450
- - very low substrate specificity
- - only works with lipid soluble xenobiotics
- - mainly oxidations and glucuronidations
- - inhibited by cimetidine, amiodarone and SSRI's
- - induced by barbituates and rifampin
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non microsomal drug metabolizing enzymes
- - catalyze mainly conjugations, hydrolysis and redox
- - synthesis is under genetic control
- - can be inhibited, but NOT induced
- - products usually more H2O sol
- -variable substrate specificity
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renal clearance of a drug
- CL = (F x Ud)/ Pd
- F= urine flow rate
- Ud= [drug]urine
- Pd= [drug]pl
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renal drug elimination
- CL= 100-150 ml/min: glomerular filtration
- CL>150 ml/min: tubular secretion
- CL<100 ml/min: reabsorption (or protein binding)
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half life
- t1/2 = 0.7 (Vd/CL)
- **a drug is considered to be essentially eliminated from teh body after four half-lives**
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Steady state [drug]
- Css = (F x D)/ (Cl x T)
- F= bioavailability D= dose
- Cl= total clearance T= infusion time
- **TIME to reach Css is determined by elimination half-life only
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Css simple
- = 4t1/2
- - 94% plasma concentration is reached after 4 half lives
- - Css = 2 x [drug]pl after 1 half life
- *if dosing interval is <4t1/2, than accumulation will occur*
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Css long equation
Css = (F x D x t1/2)/ (T x 0.7 x Vd)
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Loading dose
Loading dose= (Vd x Cp)/F
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Maintenance dose
Maitenance dose/T = (Cl x Css)/F
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rate of infusion=rate of elimination
D/T = Css x CL
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drugs that follow zero order kinetics
- EtOH, salicylic acid and phenytion
-
dosing rate
DR = Css x total CL
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Theraputic index
- - TD1/ED99 **margin of safety**
- -TD50/ED50
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immunogenic molecules
have a MW or 6000 or higher or can function as a hapten (covalently bond to a protein forming an immunogenic compound)
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teratogen effects on embryo stage
- blastogenesis= death of embryo or total recovery
- organogenesis= most sensitive to morphological effects
- histogenesis= most sensitive to metabolic/fuctional effects (often appear only after many years)
- **TOXIC effects are most frequent in last months of prego*
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teratogen
- - dosage dependent
- - prego stage very important
- - category D and X drugs should be avoided
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carcinogens
- - dose dependent, additive and irreversible
- - many are also mutagenic (malformation that can be passed on in gametes)
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