pharm basics high yield
DESCRIPTION
Pharm Basics High Yield. Greg Gayer. Pharmacokinetic. Key Concepts. Pharmacokinetics: Key concepts. Bioavailability (F). Drug absorbed distribute to (carrier protein for lipophilic drugs) Barrier Target. Oral (F=depends on absorption and 1 st pass). IV (F=1). - PowerPoint PPT PresentationTRANSCRIPT
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Pharm Basics High Yield
Greg Gayer
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Pharmacokinetic
Key Concepts
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Pharmacokinetics: Key concepts
Drug absorbed distribute to (carrier protein for lipophilic drugs) Barrier Target
Absorbed(lipid solubility, charge, size, structure)
distributedFree Drug--Permeate across barrierstransporters (facilitated/active)passive diffusion
acid:base
Bioavailability (F)
Liver metabolism
(1st pass)
IV (F=1)Oral (F=depends on absorption and 1st pass)
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• Most drugs are weak acid and bases
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Weak acid Weak baseNote: oppositeH+ + A- = HA
•Unprotonated•charged•Hydrophilic•excreted
•Protonated•uncharged (neutral)•Lipophilic (crosses membranes absorbed or reabsorbed)
B + H+ = BH+
•Unprotonated•Uncharged•lipophilic (crosses membranes absorbed or reabsorbed)
•Protonated•charged•Hydrophilic•excreted
Pharmacokinetics: Permeation (high yield)
=Ibuprofen (Advil, etc.)
+ H+
=Tacrine (Cognex)
+ H+ OH
OCH3
CH3
CH3
O-
OCH3
CH3
CH3
N
NH2
N
NH3+
Log P/unP = Pka-pH
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Renal Drug Excretion
5Excretion accelerated
UrinepH X
H+ + A- = HA
B + H+ = BH+
↑[H+]
Low pH (acidifying urine accelerates
excretion of a weak base)
5Excretion accelerated
UrinepH X
H+ + A- = HA
B + H+ = BH+
↓[H+]
High pH (making urine more basic
accelerates excretion of weak acid)
Weak acid:protonated, uncharged, lipid soluble, reabsorbedWeak base:protonated, charged, lipid insoluble, excreted
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Volume of distribution (Vd)
plasmaCbodyin drug of AmountVd
(Units=volume)
A AA
AA
AA
A
BB
BB B
BB
BB
AA
B
Vd = 10/10 =1L
Vd = 10/1 =10L
apparent volume: “the volume needed to contain the amount of drug at the concentration found in the blood”
Fat soluble drugs
Water soluble drugs
Small Vd
Large Vd
FVd X p CdoseLoading Used to
calculate Loading dose and t1/2 F
Vd X p2/1t C
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Clearance (CL)
(Units = volume per unit time)
•Used to calculate maintenance dose (steady state level)•Used to calculate drug half life•Varies with age
Cneliminatio of Rate
CL(L/h/70kg)
in out
Dosing rate = Cl (Css)
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Two types of drug elimination
1) “Zero-order” : saturable• Ethanol, high dose (aspirin,
phenytoin)
2) “First-order” : non-saturable
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•Other names: capacity-limited, saturable, dose- or concentration-dependent, Michaelis-Menten elimination etc.•Rate of elimination = Vmax x C
•At high concentration (relative to KM) elimination becomes independent of C•Drugs: Ethanol, Phenytoin, and Aspirin
Zero-Order Elimination Rate
Km + C
Km + CVmax x C=
Vmax=
Zero order
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Zero-Order Elimination Rate
TIME
Uni
t of D
rug
• A constant amount of drug is eliminated per unit time.
• Drugs with zero-order elimination have no fixed half-life (t1/2 is a variable). – E.g. 1000 v 500 units ingested
• Metabolize 100 units per hour– It would take 5 hours and 2.5 to
reduce 1000 units and 500 in half, respectively
1000 Molecules
100 Molecules
500
100
250
100
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• Most drugs• A constant fraction of the
drug is eliminated per unit time.
• Non-saturable– Note: blood flow can be
limiting factor• t1/2 is a constant
First-Order Elimination Rate
Fraction metabolized dependent on Vmax and Km of metabolic enzymes
A vast excess of enzymes per drug ratio = first order kinetics. Metabolic capacity cannot be saturated at therapeutic concentrations
First order
3 different drug concentrations
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First-Order Elimination Rate
TIME
Uni
t of D
rug
more drug = more elimination
Clearance CL = Rate of eliminationPlasma Concentration (Cp)
Rate of elimination = Cl X Cp
Constant fraction cleared1000 molecules
e.g 90% eliminated
900 molecules
100
9010
9
Cl = k X Vd
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Half-Life (1st order elimination)• After 4 half lives 93.75% of the drug is removed
from the body
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100
50
0
25
time
Amou
nt in
bod
y
1 t1
/2
2
3 412.56.25
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Bioavailability (F)
Fraction of a dose that reaches the systemic circulation
F = AUCPO
AUCIV
Time
AUCIV
AUCPOPlas
ma
[dru
g]
Absorption through gut
Metabolism by liver (1st pass)
By definition IV admin F=1
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Bioequivalence
Time
AUCPO
Plas
ma
[dru
g] Minimum effective concentration
Duration of action
abso
rptio
n
Time
AUCPO
Minimum effective concentration
Duration of action
abso
rptio
n
Preparations of drug have the same bioavailabilityFDA: Trade v Generic should be 80-120% similar AUC
Yes No
Steady State Plasma levels• Target concentration (TC): serum level that produces desired effect. When the
curve is no longer rising steady state is reached. At this point the amount given matches the amount cleared (in = out) and is defined as steady state
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8
4
2
11 2 3 4 5 6
Plas
ma
leve
ls (u
g/m
l)
(In = out)
toxicity
Minimum effectiveness
Steady state
Dose X dosing rate
clearance
FCp X ClDose Maintence
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Plas
ma
leve
ls (u
g/m
l)
time1 2 3 4 5 6
Time to steady state and Maintenance dose• Time to steady state is dependent on drug ½ life only. Or, the shape of
the curve reflects half life of the drug
100
50
0
25
1 t1
/2
2
3 4
Dose 1 2 3 4 5
In this diagram several doses of the same drug are administered
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Plas
ma
leve
ls (u
g/m
l)
time
Css
TIME to steady stateRun this slide in PPT mode: Note: 1) How stacking the new dose on top of the amount remaining from the previous dose increases the plasma level. 2) When the amount of the first dose becomes negligible it no longer contributes to the overall plasma level. In general 4 half lives. 3) How the overall plasma level curve at the top mirrors the elimination curve. This the underlying basis for why t1/2 dictates time to steady state.
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Shape of curve reflects Drug t1/2 and Time to Steady state
TIME
Uni
t of D
rug
Drug ADrug B
100
50Multiple doses are not shown
Steady State Levels
Elimination rate
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STEADY STATE RULE
• Quick rule of thumb– 50% of steady state = 1 ½ life– 75% = 2 – 87.5% = 3– 93.75 = 4 or 90% =3.3
Plas
ma
leve
ls (u
g/m
l)
time1 2 3 4 5
e.g. Drug A half life of 1 hour
Css
8
16
12
14
t 1/2 t 1/2 t 1/2t 1/2
50%
75%
87.5%93.75%
If all of this PPT fails to help MEMORIZE the Rule below
Why is biotransformation necessary?• Lipophilic molecules (xenobiotics, foreign molecules) must
be charged to be excreted without reabsorption.
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Excretion = termination of drug effect
Lipophilic
molecule
reabsorption
Renal Tubule
-
+- -
Biotransformation
Renal Tubule
Phase I & II biotransformation• Phase I
– add or expose functional groups on parent molecules (-OH, -NH2, -SH)
– Elderly lose phase 1 – loss of pharmacologic activity
• sometimes increase activity, eg. prodrugs
– Located on smooth ER• Cytochrome P450 family (CYP)
– Drug interactions» Inhibited» Induction (gene
expression)
• Phase II– Biosynthetic reactions– covalent linkage
(conjugations) with various molecules
• glucuronic acid, sulfate, glutathione, amino acids, acetate
– Mostly cytosolic localization– May precede phase1
reactions with some drugs
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Phase I & II biotransformation
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isoniazid
INH (isoniazid) (TB med)Treats neurons and hepatocytes poorly
Figure 4.4, Katzung
acetaminophen
Antidote: N-acetylcysteine regenerate glutathione
2E1 (induced by ethanol)
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CYP isotype
SubstrateExample
Inducers (gene expression ↑ # enzymes = less drug effect)
Inhibitors (inhibit activity of existing enzymes = more drug toxicity)
1A2 12% drugsTheophyllineAcetaminophen
AromaticHydrocarbons (smoke)Cruciferous vegetables, omeprazole
Cimetidine, quinolones, grapefruit juce, macrolides, isoniazid, zileuton
2C9 4% of drugsPhenytoinWarfarin
General inducers (see next slide)
Amiodarone, cimetidine, isoniazid, metronidazole, SSRIs, zafirlucast
2D6 28% of drugsManyCV & CNS drugs
St. John’s wortrifampin
Amiodarone, paroxetineQuinidine
2E1 Acetaminophen, gas anesthetics,
Ethanol, isoniazid disulfiram
3A4 50% of drugsin PDR
General inducers (see next slide)
GeneralInhibitors (see following slide) Grapefruit juice
Human liver P450 family
Board Mnemonics
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General Inhibitors: Drug-drug interaction: inactive enzymes = metabolism = effect or toxicity
• Isoniazid, Sulfonamides, Cimetidine, Ketoconazole, Erthromycin, Grapefruit juice. Inhibitors Stop Cyber-Kids from Eating Grapefruit.
General inducers: Drug-drug interaction: More enzymes = metabolism = effect
• Barbiturates, Phenytoin, Rifampin, Griseofulvin, Carbamazepine (Barb takes Phen-phen & Refuses Greasy Carbs) • Rifampin’s 4 R’s:
• RNA polymerase inhibitor• Revs up microsomal P-450s• Red/orange body fluids• Rapid resistance
Development & Regulation of Drugs
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0 4
IND
In vitro studiesAnimal Testing
ScreeningTesting Lead drug:MechanismEfficacySelectivityToxicity (minimum and median lethal dose, terato-, carcino-, muta-genicityPharmacokinetics
Human Clinical Trials
8-9
NDA
Phase 1
Non-blind small # (25-50) study in healthy volunteerscomparing animals to humans: testing safe dose, pharmacokinetics,
Development & Regulation of Drugs
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0 4
IND
In vitro studiesAnimal Testing
ScreeningTesting Lead drug:MechanismEfficacySelectivityToxicity (minimum and median lethal dose, terato-, carcino-, muta-genicityPharmacokinetics
Human Clinical Trials
8-9
NDA
Phase 2
single-blind small # (100-200) study in patients with target disease. Efficacy in patients
Phase 1
Development & Regulation of Drugs
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0 4
IND
In vitro studiesAnimal Testing
ScreeningTesting Lead drug:MechanismEfficacySelectivityToxicity (minimum and median lethal dose, terato-, carcino-, muta-genicityPharmacokinetics
Human Clinical Trials
8-9
NDA
Phase 2
Phase 1
Phase 3
double-blind large multi-center study in patients with target disease. Efficacy in patients without placebo effect
Development & Regulation of Drugs
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0 4
IND
In vitro studiesAnimal Testing
ScreeningTesting Lead drug:MechanismEfficacySelectivityToxicity (minimum and median lethal dose, terato-, carcino-, muta-genicityPharmacokinetics
Human Clinical Trials
8-9
NDA
Phase 2
Phase 1
Phase 3
Phase 4
Post marketing surveillance
20
Patent expired
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Pharmacodynamic
Key Concepts
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Quantitation of Drug-Receptor Interactions and Elicited Response
Drug (C) + receptor (R) CR effectk1
k2
log[Agonist]
EC50
Emax
% M
axim
al E
ff ec t
R
R
Reflects Affinity or potencyKD = [free drug] at which half-maximal binding is observed or the [drug] in which half the receptors are filled . KD = EC50 (no spare receptors). KD >EC50 (+ spare receptors).
RReflects EfficacyMaximal intracellular response produce when all receptors are occupied
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Clinical Relevance• Potency: drug concentration (EC50) or dose (ED50) required to produce 50% of
drugs maximal effect.– Depends on affinity (KD) of drug-receptor binding– determines the dose necessary to administer to patient
• Efficacy: magnitude of response produced by drug– clinically more important than potency when selecting a drug
% M
a xim
al E
ff ec t
log[Agonist]
100
50EC50
Drug A Drug C
EC50
Drug B
Effica
cy
Potency
Partial Agonist
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•Partial agonist: produce a lower response than full agonist when all receptors are bound
•This effect has nothing to do with affinity of the drug for the receptor
% M
axim
al E
ff ec t
log[Full Agonist or Partial Agonist]
100
50
Full Agonist
Partial Agonist
log[Agonist]
Full Agonist
Partial Agonist
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Partial agonist can act as antagonistPh
arm
acol
ogic
Res
pons
e
Log (partial agonist)
Full agonist contribution
Partial agonist contribution
Net response
See Fig. 2-6C Katzung
E.g pindolol use in hypertension
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Competitive & Irreversible Antagonist
outsideinside
antagonist
outsideinside
agonist
Antagonist work by blocking function of agonistFull agonist or partial agonist will produce a biologic response (intracellular cascade)
Intracellular cascade (biologic response)
No conformational change in receptor
Antagonist have no intracellular effects when given alone
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Competitive Antagonist
Agonist =Antagonist =
% M
a xim
al E
ff ec t
log[Agonist]
100
50
EC50 (agonist alone)
EC50 (+competitive antagonist)
Agonist
Antagonist
Low [ ] compared to [ ] High [ ]
compared to [ ]
Bind to receptor without activating them. Binding can be competed for by increasing agonist amount
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Irreversible AntagonistCovalent linkage
% M
a xim
al E
ff ec t
log[Agonist]
100
50
Agonist alone
+ antagonist
Also know as noncompetitive antagonist: Antagonist bind with such tight affinity that they never come off no matter how much agonist is present. Usually covalent bonds (phenoxybenzamine is an example)
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Signal Transduction
• Ligand-gated ion channels: N-Ach (Na+/Ca++), GABAa (Cl-), NMDA (Na+/Ca++), • Intracellular receptors: steroids, thyroxine, • Tyrosine Kinase (transmembrane with TK intracellular domain): Insulin and some
growth factor receptors (PDGF, EFF)• Transmembrane receptors that activate intracellular cytoplasmic tyrosine kinases
then Jac/STAT transcription factors: cytokines, erythropoietin, and growth hormone receptors
Autonomic Receptor mnemonic• “Qiss (kiss) and qiq (kick) till you’re siq
(sick) of sqs (sex)” receptor G-protein class MIM2M3D1D2H1H2V1V2
qissqiqsiqsqs
Or X1 = Gqbut betas (all Gs coupled) and the dumb Ds
X2 = Gi coupled but betas and V2
Kiss
kick
sick
sex
1st Aide USMLE
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Autonomic Receptor MnemonicHAVe 1 M&M
H1, 1, V1, M1, M3
R GqPLC
PIP2
DAG
IP3 [Ca]in
PKC1, 2, D1, H2, V2
R GsAC cAMP PKA
M2, 2, D2
R GiAC cAMP PKA
MAD 2s
1st Aide USMLE
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Quantal Dose Response Curves
Quantal dose response curves represent large number of individual patients or experimental animals response to various drug concentrations while observing a single set data point--e.g. lower bp 10 mmHg, speed HR by 10 bpm, etc. It is useful in determining a drug concentration that 50% of the population will respond to in the expected therapeutic end point.
Potential Variability Between Individuals
Drug Concentration
Num
ber o
f per
sons
resp
ondi
ng
o
20
40
60
80
100
40
Quantal Dose Response Curves
ED50: median effective dose (dose at which 50% of individuals exhibit specific effect).TD50: dose required to produce a particular toxic effect in 50% of animals tested.LD50: 50% deathTherapeutic index = LD50/ED50: A rough measure of drug safety margin.
Goodman & Gilman’s The pharmacological basis of therapeutics, 9th edition, Fig 3-3
Measure of the safety or therapeutic window of a drug.