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Pharm Basics High Yield
Greg Gayer
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Pharmacokinetic
Key Concepts
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Pharmacokinetics: Key concepts
Bioavailability (F)
Drug  absorbed  distribute to
(carrier protein for lipophilic
drugs) Barrier Target Oral (F=depends on
absorption and 1st
pass)
Free Drug--Permeate across
barriers
transporters
(facilitated/active)
passive diffusion
acid:base
distributed
IV (F=1)
Liver
metabolism
(1st pass)
Absorbed
(lipid solubility, charge, size, structure)
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Pharmacokinetics:
Permeation (high yield)
• Most drugs are weak acid and bases
Log P/unP = Pka-pH
Weak acid
H+ + A- = HA
•Unprotonated
•charged
•Hydrophilic
•excreted
O
-
H3C
+ H+
O
Weak base
Note: opposite
•Protonated
•uncharged (neutral)
•Lipophilic (crosses
membranes absorbed or
reabsorbed)
OH
=
H3C
B + H+ = BH+
•Unprotonated
•Uncharged
•lipophilic (crosses
membranes absorbed or
reabsorbed)
NH2
O
N
CH3
CH3
Ibuprofen (Advil, etc.)
CH3
(C)CH
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+
H+
=
•Protonated
•charged
•Hydrophilic
•excreted
+
NH3
N
Tacrine (Cognex)
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Renal Drug Excretion
High pH
(making urine more basic
accelerates excretion of weak acid)
Low pH
(acidifying urine accelerates
excretion of a weak base)
Urine
pH X
Urine
pH X
H+
+
A-
H+ + A- = HA
= HA
↓[H+]
↑[H+]
B + H+ = BH+
B + H+ = BH+
Excretion
accelerated
Weak acid:
protonated,
uncharged, lipid
soluble, reabsorbed
Weak base:
protonated,
charged, lipid
insoluble, excreted
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Excretion
accelerated
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Volume of distribution (Vd)
Cp X Vd
Loading dose 
F
Cp X Vd
t1 / 2 
F
Used to
calculate
Loading
dose and
t1/2
Amount of drug in body
Vd 
Cplasma
(Units=volume)
Water soluble drugs
A A
A A A
A
A
A
A
Vd = 10/10 =1L
A
Small Vd
B
B
B
B
B
B
B
B
B
B
Fat soluble drugs
Vd = 10/1 =10L
Large Vd
apparent volume: “the volume needed to contain the
amount of drug at the concentration found in the blood”
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Clearance (CL)
Rate of eliminatio n
CL 
C
in
(Units = volume per unit time)
(L/h/70kg)
out
Dosing rate = Cl (Css)
•Used to calculate maintenance dose (steady
state level)
•Used to calculate drug half life
•Varies with age
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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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Zero-Order Elimination Rate
•Other names: capacity-limited,
saturable, dose- or concentrationdependent, Michaelis-Menten
elimination etc.
•Rate of elimination = Vmax x C
Km + C
•At high concentration (relative to
KM) elimination becomes
independent of C
•Drugs: Ethanol, Phenytoin, and
Aspirin
Zero
order
=
Vmax x
Km +
C
C
= Vmax
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Zero-Order Elimination Rate
1000 Molecules
100 Molecules
500
• 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).
Unit of Drug
– E.g. 1000 v 500 units ingested
• Metabolize 100 units per hour
100
250
– It would take 5 hours and 2.5 to
reduce 1000 units and 500 in
half, respectively
100
TIME
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First-Order Elimination Rate
• Most drugs
• A constant fraction of the
drug is eliminated per unit
time.
Fraction
• Non-saturable
metabolized
– Note: blood flow can be
limiting factor
• t1/2 is a constant
dependent on
Vmax and Km
of metabolic
enzymes
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3 different drug concentrations
First order
A vast excess of enzymes per drug ratio =
first order kinetics. Metabolic capacity
cannot be saturated at therapeutic
concentrations
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First-Order Elimination Rate
e.g 90% eliminated
1000 molecules
Constant fraction cleared
more drug = more elimination
Unit of Drug
900 molecules
Clearance CL = Rate of elimination
Plasma Concentration (Cp)
100
Rate of elimination = Cl X Cp
90
Cl = k X Vd
10
9
TIME
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Half-Life (1st order elimination)
• After 4 half lives 93.75% of the drug is removed
from the body
4
12.5
6.25
0
3
25
2
50
1 t1/2
Amount in body
100
time
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Bioavailability (F)
F = AUCPO
AUCIV
By definition IV admin F=1
Metabolism by
liver (1st pass)
Plasma [drug]
Fraction of a dose
that reaches the
systemic circulation
AUCIV
Absorption
through gut
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AUCPO
Time
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Bioequivalence
Preparations of drug have the same bioavailability
FDA: Trade v Generic should be 80-120% similar AUC
Plasma [drug]
AUCPO
AUCPO
Minimum effective
concentration
Minimum effective
concentration
Yes
No
Duration of action
Duration of action
Time
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Time
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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
Cl X Cp
Maintence Dose 
F
toxicity
Plasma levels (ug/ml)
8
Dose X dosing rate
Steady state
4
(In = out)
2
Minimum effectiveness
clearance
1
1
2
3
4
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6
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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
Dose 1
2
3
4
5
In this diagram several
doses of the same
drug are administered
50
25
3
2
1 t1/2
0
4
Plasma levels (ug/ml)
100
1
2
3
time
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4
5
6
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TIME to steady state
Plasma levels (ug/ml)
Run 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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Css
time
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Shape of curve reflects Drug t1/2
and Time to Steady state
Steady State Levels
Unit of Drug
100
Multiple doses are not shown
50
Drug B
Elimination rate
Drug A
TIME
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STEADY STATE RULE
Plasma levels (ug/ml)
If all of this PPT fails to help MEMORIZE the Rule below
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14
12
8
93.75%
87.5%
Css
75%
•
Quick rule of thumb
–
–
–
–
50%
t 1/2
t 1/2
t 1/2
1
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50% of steady state = 1 ½ life
75% = 2
87.5% = 3
93.75 = 4 or 90% =3.3
t 1/2
3
time
4
5
e.g. Drug A half life of 1
20
hour
Why is biotransformation necessary?
• Lipophilic molecules (xenobiotics, foreign molecules)
must be charged to be excreted without reabsorption.
reabsorption
Lipophilic
molecule
Biotransformation+
Excretion =
termination of
drug effect
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Phase I & II biotransformation
• Phase I
• Phase II
– 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)
– 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
acetaminophen
isoniazid
2E1 (induced by ethanol)
INH (isoniazid) (TB med)
Treats neurons and hepatocytes poorly
Antidote: N-acetylcysteine
regenerate glutathione
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Figure 4.4, Katzung
permission
23
Human liver P450 family
CYP
isotype
Substrate
Example
Inducers (gene expression ↑ Inhibitors (inhibit activity of
# enzymes = less drug effect)
existing enzymes = more drug
toxicity)
1A2
12%
drugs
Theophylline
Acetaminophen
Aromatic
Hydrocarbons (smoke)
Cruciferous vegetables,
omeprazole
Cimetidine, quinolones,
grapefruit juce,
macrolides, isoniazid,
zileuton
2C9
4%
of drugs
Phenytoin
Warfarin
General inducers (see
next slide)
Amiodarone, cimetidine,
isoniazid, metronidazole,
SSRIs, zafirlucast
2D6
28% of drugs
Many
CV & CNS drugs
St. John’s wort
rifampin
Amiodarone, paroxetine
Quinidine
2E1
Acetaminophen, gas
anesthetics,
Ethanol, isoniazid
disulfiram
3A4
50% of drugs
General inducers (see
next slide)
General
Inhibitors (see following
24
slide) Grapefruit juice
in PDR
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Board Mnemonics
General inducers: Drug-drug interaction: More enzymes
=  metabolism =  effect
• Barbiturates, Phenytoin, Rifampin, Griseofulvin,
Carbamazepine (Barb takes Phen-phen & Refuses
• Rifampin’s 4 R’s:
Greasy Carbs)
•RNA polymerase inhibitor
•Revs up microsomal P-450s
•Red/orange body fluids
•Rapid resistance
General Inhibitors: Drug-drug interaction: inactive
enzymes =  metabolism = effect or toxicity
• Isoniazid, Sulfonamides, Cimetidine, Ketoconazole,
Erthromycin, Grapefruit juice. Inhibitors Stop CyberKids from Eating Grapefruit.
25
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Development & Regulation of Drugs
In vitro studies
Animal Testing
Human Clinical Trials
Screening
Testing Lead drug:
Mechanism
Efficacy
Selectivity
Toxicity (minimum
and median lethal
dose, terato-,
carcino-, mutagenicity
Pharmacokinetics
0
Phase 1
Non-blind small # (25-50) study in
healthy volunteers
comparing animals to humans: testing
safe dose, pharmacokinetics,
4
8-9
IND
NDA
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Development & Regulation of Drugs
In vitro studies
Animal Testing
Human Clinical Trials
Screening
Testing Lead drug:
Mechanism
Efficacy
Selectivity
Toxicity (minimum
and median lethal
dose, terato-,
carcino-, mutagenicity
Pharmacokinetics
0
Phase 1
Phase 2
single-blind small # (100-200) study in
patients with target disease. Efficacy in
patients
4
8-9
IND
NDA
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Development & Regulation of Drugs
In vitro studies
Animal Testing
Human Clinical Trials
Screening
Testing Lead drug:
Mechanism
Efficacy
Selectivity
Toxicity (minimum
and median lethal
dose, terato-,
carcino-, mutagenicity
Pharmacokinetics
0
double-blind large multi-center study in
Phase 1with target disease. Efficacy in
patients
patients without placebo effect
Phase 2
Phase 3
4
8-9
IND
NDA
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Development & Regulation of Drugs
In vitro studies
Animal Testing
Human Clinical Trials
Screening
Testing Lead drug:
Mechanism
Efficacy
Selectivity
Toxicity (minimum
and median lethal
dose, terato-,
carcino-, mutagenicity
Pharmacokinetics
0
Phase 1
Post marketing
surveillance
Phase 2
Phase 3
Phase 4
4
8-9
IND
NDA
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Patent
expired29
Pharmacodynamic
Key Concepts
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Quantitation of Drug-Receptor Interactions and
Elicited Response
Drug (C) + receptor (R)
k1
k2
CR
effect
Reflects Efficacy
Emax
Maximal intracellular response
produce when all receptors are
occupied
R
Reflects Affinity or potency
KD = [free drug] at which half-maximal binding
R
is observed or the [drug] in which half the
receptors are filled . KD = EC50 (no spare
receptors). KD >EC50 (+ spare receptors).
EC50
log[Agonist]
R
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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
Potency
100
Drug C
Drug A
Drug B
50
EC50
log[Agonist]
EC50
32
Partial Agonist
•Partial agonist: produce a lower
response than full agonist when all
receptors are bound
100
•This effect has nothing to do with
affinity of the drug for the receptor
Full Agonist
Full Agonist
50
Partial
Agonist
log[Full Agonist or Partial
Agonist]
Partial
Agonist
log[Agonist]
33
Partial agonist can act as antagonist
Pharmacologic Response
Net response
E.g pindolol use in
hypertension
Partial agonist
contribution
Full agonist
contribution
Log (partial agonist)
See Fig. 2-6C Katzung
34
Competitive & Irreversible Antagonist
Intracellular cascade (biologic
response)
agonist
outside
No conformational change in
receptor
antagonist
inside
outside
inside
Antagonist have no
intracellular effects when
given alone
Antagonist work by blocking function of agonist
Full agonist or partial agonist will produce a
biologic response (intracellular cascade)
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Competitive Antagonist
Low [ ]
compared to [ ]
Agonist
High [ ]
compared to [ ]
Antagonist
Agonist =
Antagonist =
100
Bind to receptor
without activating
them. Binding can be
competed for by
increasing agonist
amount
50
EC50 (agonist
alone)
log[Agonist]
EC50 (+competitive antagonist)
36
Irreversible Antagonist
Covalent linkage
100
Agonist alone
50
+ antagonist
log[Agonist]
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)
37
Signal Transduction
Autonomic Receptor Mnemonic
HAVe 1 M&M
H1, 1, V1, M1, M3
R
Gq
PIP2
DAG
• “Qiss (kiss) and qiq (kick) till you’re siq
receptor G-protein class
(sick) of sqs (sex)”
[Ca]in
IP3
PLC
Autonomic Receptor mnemonic
Or X1 = Gq
but betas (all Gs
coupled) and the
dumb Ds
PKC
1, 2, D1, H2, V2
R
Gs
AC
cAMP
MAD 2s
M2, 2, D2
R
Gi
AC
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•
•
•
•
PKA
cAMP
PKA
1st Aide USMLE 17
X2 = Gi coupled
but betas and V2




MI
M2
M3
D1
D2
H1
H2
V1
V2
q
i
s
s
q
i
q
s
i
q
s
q
s
Kiss
kick
sick
sex
1st Aide USMLE
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
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Quantal
Dose
Response
Curves
Potential Variability Between Individuals
100
Number of persons responding
80
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.
60
40
20
o
Drug Concentration
39
Quantal Dose Response Curves
Measure of the
safety or
therapeutic
window of a drug.
Goodman & Gilman’s The
pharmacological basis of
therapeutics, 9th edition, Fig 3-3
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% death
40
Therapeutic index = LD50/ED50: A rough measure of drug safety margin.