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80 terms

UVMCOM A&D Pharmacology I

Block I pharmacology equations and key facts
STUDY
PLAY
Form of drug with highest lipid solubility
uncharged
F of IV
100
F of Transdermal
80 - ≤100
F of IM
75 - ≤100
F of SQ
75 - ≤100
F of Rectal (PR)
30 - <100
F of Oral
5 - <100
F of Inhalation
5 - <100
Pharmacodynamics
Drug effect on body
Pharmacokinetics
Body effect on drugs
ADME
Affinity
Strength/durability of drug/receptor interaction
Efficacy
Max effect that drug can produce
Increased = higher relative response
Equal curve heights = work on same receptor
Potency
Amount of drug needed to produce a given effect (EC50, ED50)
Increased = lower [Drug]
Agonist + competitive antagonist
Affects POTENCY (not efficacy)
Agonist + non-competitive antagonist
Affects EFFICACY (not potency)
Agonist + partial agonist
Partial agonist acts as antagonist against full agonist
Low efficacy partial agonist
Act clinically as antagonists
Moderate efficacy partial agonist
Act as agonists with low & moderate sympathomimetic activity (moderate heart failure)

Act as antagonists with high sympathomimetic activity (severe heart failure)
High efficacy partial agonist
Act clinically as agonists
Except after full agonist XS dose
Graded dose-response curve
Relates dose to intensity of effect
Quantal dose-response curve
Relates dose to frequency of effect (ie % responding)
Therapeutic index eqn
TD_50/ED_50
Safety factor eqn
TD_1/ED_99
Synergism
A = 1 B = 1 A+B = 3
Potentiation
A = 0 B = 1 A+B = 3
Additive
A = 1 B = 1 A+B = 2
Antagonism
A = 0 B = 1 A+B = 0
Absorption parameter
F
Distribution parameter
Vd
Metabolism/Excretion parameter
λ
Metabolism/Excretion parameter
CL
Bioavailability definition
Fraction of administered drug that reaches the systemic circulation
Key in determining onset of drug action
Bioavailability equation
F = AUC_po / AUC_iv
AUC = area under curve ([ ] vs time)
Henderson-Hasselbalch Eqn
pH = pKa + log([HA]/[A-])
Factors affecting absorption (PO)
pH
Surface area
Distribution definition
Passage of drugs from blood to tissues
Volume of distribution definition
Apparent volume of body fluid that drug appears to distribute into to produce a drug [ ] equal to that in blood
Vd =
Q/C_0
Total body fluid =
60% of body weight
IC fluid =
2/3 TBF
XC fluid =
1/3 TBF
Plasma (blood fluid) =
1/4 EC fluid
Interstitial fluid =
3/4 XC fluid
RBC volume =
[ Hct / (1-Hct) ] * plasma
Evan's blue distribution
IV space (plasma vol) = 3.5L
Inulin distribution
IV + interstitial = XC fluid = 14L
Ethanol distribution
TBF = 42L
Quinacrine distribution
>3000L
Sequesterd inside cells (C_0 << Q)
Acidic drugs bind
Albumin
Basic drugs bind
α1 acid glycoprotein
Acid==Albumin and Base==α1 acid Gp
Reversible
Binding sites of albumin/α1 acid Gp non-selective
Drugs can displace each other
Bound drug activity
Inactive
Type of drugs that are most affected by changes in protein binding
Highly bound (>90%)
Small Vd
eg warfarin
Vd ≤ vascular volume characterization
Very large or binds to plasma proteins
Vd > TBF characterization
Sequestered in tissues
Order of highest perfusion tissues (rapid drug distribution)
Brain/liver/kidney < sk m < adipose
Drug redistribution effects
Changes drug action via redistribution to low-perfusion tissues (sk m, fat)
LD =
Vd * Cp
Vd * Css / F
Significant routes of elimination
Renal (GFR dep on size <40kDa, charge, protein binding - drugs not bound cleared at creatine rate)
Hepatic (via bile), exhalation
Increase excretion of acidic drugs in urine
Raise pH (H2CO3)
Increase excretion of basic drugs in urine
Lower pH (NH4Cl)
Zero order kinetics
Fixed AMOUNT of drug metab/unit time
First order kinetics
Fixed FRACTION of drug metab/unit time
Most drugs, amount metabolized proportional to drug [ ]
λ's to clear/accumulate >99% of drug
7
λ's to achieve steady state
4-5
CL = (Kel)
Kel / Cp
λ =
ln(2) / k
CL = (k)
k * Vd
D / T =
Css * CL / F
Dosing rate adjustment
Dependent on D/T = const
Helps increase compliance
Phase I
Functionalization reactions that introduce or expose a functional group on parent compound (eg oxidation)
NON-SYNTHETIC
Phase II
Covalent conjugation of parent/endogenous compounds (eg sulfation)
SYNTHETIC
CYP reactions result
Generally convert smaller molecules to more polar compounds
CYP reactions
Aliphatic/aromatic hydroxylation
Dealkylation (N-, O-, S-)
N-oxidation, S-oxidation
Deamination
Dehalogenation
P450 inducers
Phenobarbital
St Johns Wort
Polycyclic aromatic hydrocarbons (PAHs)
P450 inhibitors
Grapefruit juice
Ketoconazole, omeprazole
Cimetidine
Probenecid
Macrolides
Non-CYP drug biotransformations
Phase I: ox/red, hydrolyses
Phase II: conjugation
Conjugation reactions
Glucuronidation (high capacity)
Sulfation (low capacity)
Acetylation (variable capacity)
MD (Maintenance Dose) =
(Css CL / F ) T