UVMCOM A&D Pharmacology I

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Block I pharmacology equations and key facts

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

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