Pharm Basics High Yield Greg Gayer 1 (C) Greg Gayer Do Not Distribute without permission

(C) Greg Gayer Do Not Distribute without permission

1

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)


• 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


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)

plasmaC

bodyin 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

F

Vd 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

C

neliminatio of RateCL

(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


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

(C) Greg Gayer Do Not Distribute without permission 16

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

F

Cp X ClDose Maintence


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


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

20(C) Greg Gayer Do Not Distribute without permission

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


Phase I & II biotransformation


isoniazid

INH (isoniazid) (TB med)Treats neurons and hepatocytes poorly

Figure 4.4, Katzung

acetaminophen

Antidote: N-acetylcysteine regenerate glutathione

2E1 (induced by ethanol)


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


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,



0 4

IND




8-9

NDA

Phase 2

single-blind small # (100-200) study in patients with target disease. Efficacy in patients

Phase 1



0 4

IND




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



0 4

IND




8-9

NDA

Phase 2

Phase 1

Phase 3

Phase 4

Post marketing surveillance

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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

ffect

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

axim

a l E

ffect

log[Agonist]

100

50

EC50

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

ffect

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

axim

al E

ffect

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

axim

a l E

ffect

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

(C) Greg Gayer 1/2008 17

Autonomic Receptor MnemonicHAVe 1 M&M

H1, 1, V1, M1, M3

RGq

PLC

PIP2

DAG

IP3 [Ca]in

PKC1, 2, D1, H2, V2

RGs

AC cAMP PKA

M2, 2, D2

RGi

AC 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.

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Pharm Basics High Yield Greg Gayer 1 (C) Greg Gayer Do Not Distribute without permission