Drug actions

PharmacologyPharmacologyPharmacologyPharmacology

Pharmacokinetics

Pharmacodynamics

Pharmacokinetics

Pharmacodynamics

PharmacokineticsPharmacokineticsPharmacokineticsPharmacokinetics

• Time course of drug absorption, distribution, metabolism, excretion

• Time course of drug absorption, distribution, metabolism, excretion

How the drugHow the drugcomes and goes.comes and goes.How the drugHow the drug

comes and goes.comes and goes.

“LADME” is key

Pharmacokinetic ProcessesPharmacokinetic ProcessesPharmacokinetic ProcessesPharmacokinetic Processes

LiberationLiberationLiberationLiberation

AbsorptionAbsorptionAbsorptionAbsorption

DistributionDistributionDistributionDistribution

MetabolismMetabolismMetabolismMetabolism

ExcretionExcretionExcretionExcretion

LiberationLiberationLiberationLiberation

• Applies to drugs given orally

• Components– Release of drug from pill, tablet, capsule– Dissolving of active drug in GI fluids

• Applies to drugs given orally

• Components– Release of drug from pill, tablet, capsule– Dissolving of active drug in GI fluids

Ex: Enteric coated Ex: Enteric coated aspirin slows absorption in aspirin slows absorption in

stomach vs non-coatedstomach vs non-coated

Ex: Enteric coated Ex: Enteric coated aspirin slows absorption in aspirin slows absorption in

stomach vs non-coatedstomach vs non-coated

AbsorptionAbsorptionAbsorptionAbsorption

• Movement from administration site into circulation

• Movement from administration site into circulation

Factors Affecting Liberation/AbsorptionFactors Affecting Liberation/AbsorptionFactors Affecting Liberation/AbsorptionFactors Affecting Liberation/Absorption

• Formulation factors– Tablet disintegration

– Inert ingredient / solvent effects

– Solubility

– Drug pH

– Concentration

• Formulation factors– Tablet disintegration

– Inert ingredient / solvent effects

– Solubility

– Drug pH

– Concentration

• Patient factors– Absorbing surface

– Blood flow

– Environmental pH

– Disease states

– Interactions with food, other drugs

• Patient factors– Absorbing surface

– Blood flow

– Environmental pH

– Disease states

– Interactions with food, other drugs

Lipid Bilayer

Small, uncharged

Large, uncharged

Small charged ions

H2O, urea, CO2, O2, N2

Glucose Sucrose

H+, Na+, K+, Ca2+, Cl-, HCO3

-

DENIED!

DENIED!

Swoosh!

Hydrophobic Tails

Hydrophobic Tails

Hydrophilic Heads

Hydrophilic Heads

Membranes and AbsorptionMembranes and AbsorptionMembranes and AbsorptionMembranes and Absorption

LaChatlier’s PrincipleLaChatlier’s PrincipleLaChatlier’s PrincipleLaChatlier’s Principle

a.k.a. Mass Actiona.k.a. Mass Action A reaction at equilibriumresponds to stress in away to best return to

equilibrium

A reaction at equilibriumresponds to stress in away to best return to

equilibrium

4 Na+ 4 Cl_ 4 NaCl+

Systemat

Equilibrium

Systemat

Equilibrium

4 4 Cl- 4 NaCl+ 12 NaCl

1. System at equilibrium1. System at equilibrium

by 8

2. Stress applied to system2. Stress applied to system3. System responds to stress3. System responds to stress

System not atSystem not atequilibrium!equilibrium!

System not atSystem not atequilibrium!equilibrium!

4 Na+

by 4 by 4

8 Na+ 8 Cl- 8 NaCl

4. System returns to equilibrium!4. System returns to equilibrium!

4 NaCl dissociate

An example ofAn example ofLaChatlier’s LaChatlier’s

PrinciplePrinciple

IonizationIonizationIonizationIonization

AcidsAcids Release/Donate H+Release/Donate H+

HA H+ + A-

BasesBases Bind/Accept H+Bind/Accept H+

H+ + B- HB

Ionizedform

Ionizedform

Non-ionizedform

Non-ionizedform

If we put an acidic drug in an environment with a lot of H+ (low pH) what will this equilibrium do?

If we put an acidic drug in an environment with a lot of H+ (low pH) what will this equilibrium do?

Environmental pH and Environmental pH and IonizationIonizationEnvironmental pH and Environmental pH and IonizationIonization

HA H+ + A-

System at EquilibriumSystem at Equilibrium H+ from acid environment H+ from acid environment

HAHAHAHA

Non-ionized form predominates!Non-ionized form predominates!

Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form?

Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form?

NON-IONIZED

A real live, actual clinical A real live, actual clinical question...question...A real live, actual clinical A real live, actual clinical question...question...

Why?Why?

Lipid Bilayer

How will this affect aspirin How will this affect aspirin absorption?absorption?How will this affect aspirin How will this affect aspirin absorption?absorption?

Ionized form (charged)

Ionized form (charged) A-

Ionized form (uncharged)

Ionized form (uncharged) HA HA

Moral of the story...Moral of the story...Moral of the story...Moral of the story...

Acidic drugs are best absorbed from acidic environments

Acidic drugs are best absorbed from acidic environments

Basic drugs are best absorbed from

basic environments

Basic drugs are best absorbed from

basic environments

So...So...So...So...

To absorption of an acidic drug…

acidify the environment


acidify the environment


alkalanize the environment...


alkalanize the environment...

DistributionDistributionDistributionDistribution

• Rate of perfusion

• Plasma protein (albumin) binding

• Accumulation in tissues

• Ability to cross membranes– Blood-brain barrier– Placental barrier

• Rate of perfusion

• Plasma protein (albumin) binding

• Accumulation in tissues

• Ability to cross membranes– Blood-brain barrier– Placental barrier

warfarin (Coumadin) is highly protein warfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same bound (99%). Aspirin binds to the same site on serum proteins as does site on serum proteins as does Coumadin. If a patient on Coumadin Coumadin. If a patient on Coumadin also takes aspirin, what will happen?also takes aspirin, what will happen?

warfarin (Coumadin) is highly protein warfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same bound (99%). Aspirin binds to the same site on serum proteins as does site on serum proteins as does Coumadin. If a patient on Coumadin Coumadin. If a patient on Coumadin also takes aspirin, what will happen?also takes aspirin, what will happen?

The available Coumadin will increase.

Plasma Protein BindingPlasma Protein BindingPlasma Protein BindingPlasma Protein Binding

1) Why?2) Why do we care?

1) Why?2) Why do we care?

The blood brain barrier consists of The blood brain barrier consists of cell tightly packed around the cell tightly packed around the capillaries of the CNS. What capillaries of the CNS. What characteristics must a drug possess characteristics must a drug possess to easily cross this barrier?to easily cross this barrier?

The blood brain barrier consists of The blood brain barrier consists of cell tightly packed around the cell tightly packed around the capillaries of the CNS. What capillaries of the CNS. What characteristics must a drug possess characteristics must a drug possess to easily cross this barrier?to easily cross this barrier?

Non-protein bound, non-ionized, and highly lipid

soluble

Blood-Brain BarrierBlood-Brain BarrierBlood-Brain BarrierBlood-Brain Barrier

Metabolism Metabolism (Biotransformation)(Biotransformation)Metabolism Metabolism (Biotransformation)(Biotransformation)• Two effects

– Transformation to less active metabolite– Enhancement of solubility

• Liver = primary site

• Liver disease– Slows metabolism– Prolongs effects

• Two effects– Transformation to less active metabolite– Enhancement of solubility

• Liver = primary site

• Liver disease– Slows metabolism– Prolongs effects

Hepatic ‘First-Pass’ Hepatic ‘First-Pass’ MetabolismMetabolismHepatic ‘First-Pass’ Hepatic ‘First-Pass’ MetabolismMetabolism• Affects orally administered drugs

• Metabolism of drug by liver before drug reaches systemic circulation

• Drug absorbed into portal circulation, must pass through liver to reach systemic circulation

• May reduce availability of drug

• Affects orally administered drugs

• Metabolism of drug by liver before drug reaches systemic circulation

• Drug absorbed into portal circulation, must pass through liver to reach systemic circulation

• May reduce availability of drug

EliminationEliminationEliminationElimination

• Kidneys = primary site– Mechanisms dependent upon:

• Passive glomerular filtration

• Active tubular transport

– Partial reabsorption– Hemodialysis

• Renal disease– Slows excretion– Prolongs effects

• Kidneys = primary site– Mechanisms dependent upon:

• Passive glomerular filtration

• Active tubular transport

– Partial reabsorption– Hemodialysis

• Renal disease– Slows excretion– Prolongs effects

Active Tubular TransportActive Tubular TransportActive Tubular TransportActive Tubular Transport

Probenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy?

Probenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy?

It competes with the antibiotic at the pump

and slows its excretion.

A patient has overdosed on A patient has overdosed on phenobartital. Phenobarbital is an acid. phenobartital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the bicarbonate what will happen to the phenobarbital molecules as they are phenobarbital molecules as they are filtered through the renal tubules?filtered through the renal tubules?

A patient has overdosed on A patient has overdosed on phenobartital. Phenobarbital is an acid. phenobartital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the bicarbonate what will happen to the phenobarbital molecules as they are phenobarbital molecules as they are filtered through the renal tubules?filtered through the renal tubules?

They will ionize...

Urine pH and EliminationUrine pH and EliminationUrine pH and EliminationUrine pH and Elimination

Non-ionized

HA H+ + A-

How will this affect phenobarbital How will this affect phenobarbital reabsorption by the kidney?reabsorption by the kidney?How will this affect phenobarbital How will this affect phenobarbital reabsorption by the kidney?reabsorption by the kidney?

Decreased reabsorptionDecreased reabsorption

Increased eliminationIncreased elimination

Ionized


• Other sources– Feces– Exhaled air– Breast milk– Sweat

• Other sources– Feces– Exhaled air– Breast milk– Sweat

Biological Half-life (t Biological Half-life (t 1/21/2))Biological Half-life (t Biological Half-life (t 1/21/2))

• Amount of time to eliminate 1/2 of total drug amount

• Shorter t 1/2 may need more frequent doses

• Hepatic disease may increase t1/2

• Amount of time to eliminate 1/2 of total drug amount

• Shorter t 1/2 may need more frequent doses

• Hepatic disease may increase t1/2

A drug has a half life of 10 seconds. You A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 give a patient a dose of 6mg. After 30 seconds how much of the drug remains?seconds how much of the drug remains?

A drug has a half life of 10 seconds. You A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 give a patient a dose of 6mg. After 30 seconds how much of the drug remains?seconds how much of the drug remains?

TimeTime AmountAmount

0 sec0 sec 6 mg6 mg

10 sec10 sec 3 mg3 mg

20 sec20 sec 1.5 mg1.5 mg

30 sec30 sec 0.75 mg0.75 mg

Administration RoutesAdministration RoutesAdministration RoutesAdministration Routes

• Intravenous– Fastest, Most dangerous

• Endotracheal– Lidocaine, atropine, narcan, epinephrine

• Inhalation– Bronchodilators via nebulizers

• Transmucosal– Rectal or sublingual

• Intravenous– Fastest, Most dangerous

• Endotracheal– Lidocaine, atropine, narcan, epinephrine

• Inhalation– Bronchodilators via nebulizers

• Transmucosal– Rectal or sublingual

Administration RoutesAdministration RoutesAdministration RoutesAdministration Routes

• Intramuscular– Depends on perfusion quality

• Subcutaneous– Depends on perfusion quality

• Oral– Slow, unpredictable – Little prehospital use

• Intramuscular– Depends on perfusion quality

• Subcutaneous– Depends on perfusion quality

• Oral– Slow, unpredictable – Little prehospital use

PharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamics

• The biochemical and physiologic mechanisms of drug action

• The biochemical and physiologic mechanisms of drug action

What the drugWhat the drugdoes when it gets there.does when it gets there.

What the drugWhat the drugdoes when it gets there.does when it gets there.

Drug MechanismsDrug MechanismsDrug MechanismsDrug Mechanisms

• Receptor interactions

• Non-receptor mechanisms

• Receptor interactions

• Non-receptor mechanisms

Receptor InteractionsReceptor InteractionsReceptor InteractionsReceptor Interactions

Agonist Receptor

Agonist-Receptor

Interaction

Lock and key mechanism


Receptor

Perfect Fit!

Induced Fit


Antagonist Receptor

Antagonist-Receptor

ComplexDENIED!

CompetitiveInhibition

Agonist Receptor

Antagonist

‘Inhibited’-ReceptorDENIED!


Non-competitive Inhibition

Non-receptor MechanismsNon-receptor MechanismsNon-receptor MechanismsNon-receptor Mechanisms

• Actions on Enzymes– Enzymes = Biological catalysts

• Speed chemical reactions

• Are not changed themselves

– Drugs altering enzyme activity alter processes catalyzed by the enzymes

– Examples• Cholinesterase inhibitors

• Monoamine oxidase inhibitors

• Actions on Enzymes– Enzymes = Biological catalysts

• Speed chemical reactions

• Are not changed themselves

– Drugs altering enzyme activity alter processes catalyzed by the enzymes

– Examples• Cholinesterase inhibitors

• Monoamine oxidase inhibitors


• Changing Physical Properties– Mannitol– Changes osmotic balance across membranes– Causes urine production (osmotic diuresis)

• Changing Physical Properties– Mannitol– Changes osmotic balance across membranes– Causes urine production (osmotic diuresis)


• Changing Cell Membrane Permeability– Lidocaine

• Blocks sodium channels

– Verapamil, nefedipine• Block calcium channels

– Bretylium• Blocks potassium channels

– Adenosine• Opens potassium channels

• Changing Cell Membrane Permeability– Lidocaine

• Blocks sodium channels

– Verapamil, nefedipine• Block calcium channels

– Bretylium• Blocks potassium channels

– Adenosine• Opens potassium channels


• Combining With Other Chemicals– Antacids– Antiseptic effects of alcohol, phenol– Chelation of heavy metals

• Combining With Other Chemicals– Antacids– Antiseptic effects of alcohol, phenol– Chelation of heavy metals


• Anti-metabolites– Enter biochemical reactions in place of normal

substrate “competitors”– Result in biologically inactive product– Examples

• Some anti-neoplastics

• Some anti-infectives

• Anti-metabolites– Enter biochemical reactions in place of normal

substrate “competitors”– Result in biologically inactive product– Examples

• Some anti-neoplastics

• Some anti-infectives

Drug Response RelationshipsDrug Response RelationshipsDrug Response RelationshipsDrug Response Relationships

• Time Response

• Dose Response

• Time Response

• Dose Response

Latency Duration of Response

Maximal (Peak) Effect

Effect/

Response

Time

Time Response RelationshipsTime Response RelationshipsTime Response RelationshipsTime Response Relationships

Effect/

Response

Time

IVSC

IM

Time Response RelationshipsTime Response RelationshipsTime Response RelationshipsTime Response Relationships

Dose Response RelationshipsDose Response RelationshipsDose Response RelationshipsDose Response Relationships

• Potency– Absolute amount of drug required to produce

an effect– More potent drug is the one that requires lower

dose to cause same effect

• Potency– Absolute amount of drug required to produce

an effect– More potent drug is the one that requires lower

dose to cause same effect

PotencyPotencyPotencyPotency

Effect

Dose

A B

Which drug is more potent?

A!A!Why?Why?

TherapeuticEffect


• Threshold (minimal) dose– Least amount needed to produce desired effects

• Maximum effect– Greatest response produced regardless of dose

used

• Threshold (minimal) dose– Least amount needed to produce desired effects

• Maximum effect– Greatest response produced regardless of dose

used

Dose Response RelationshipsDose Response Relationships

Which drug has the lower threshold dose?

Effect

Dose

A

B

Which has the greater maximum effect?

AA

BB

TherapeuticEffect


• Loading dose– Bolus of drug given initially to rapidly reach

therapeutic levels

• Maintenance dose– Lower dose of drug given continuously or at

regular intervals to maintain therapeutic levels

• Loading dose– Bolus of drug given initially to rapidly reach

therapeutic levels

• Maintenance dose– Lower dose of drug given continuously or at

regular intervals to maintain therapeutic levels

Therapeutic IndexTherapeutic IndexTherapeutic IndexTherapeutic Index

• Drug’s safety margin

• Must be >1 for drug to be usable

• Digitalis has a TI of 2

• Penicillin has TI of >100

• Drug’s safety margin

• Must be >1 for drug to be usable

• Digitalis has a TI of 2

• Penicillin has TI of >100

50

50

ED

LDTI

50

50

ED

LDTI

Therapeutic IndexTherapeutic IndexTherapeutic IndexTherapeutic Index

Why don’t we use adrug with a TI <1?

Why don’t we use adrug with a TI <1?

ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!

Factors Altering Drug Factors Altering Drug ResponsesResponsesFactors Altering Drug Factors Altering Drug ResponsesResponses• Age

– Pediatric or geriatric– Immature or decreased hepatic, renal function

• Weight– Big patients “spread” drug over larger volume

• Gender– Difference in sizes– Difference in fat/water distribution

• Age– Pediatric or geriatric– Immature or decreased hepatic, renal function

• Weight– Big patients “spread” drug over larger volume

• Gender– Difference in sizes– Difference in fat/water distribution

Factors Altering Drug Factors Altering Drug ResponsesResponsesFactors Altering Drug Factors Altering Drug ResponsesResponses• Environment

– Heat or cold– Presence or real or perceived threats

• Fever

• Shock

• Environment– Heat or cold– Presence or real or perceived threats

• Fever

• Shock

Factors Altering Drug Factors Altering Drug ResponsesResponsesFactors Altering Drug Factors Altering Drug ResponsesResponses• Pathology

– Drug may aggravate underlying pathology– Hepatic disease may slow drug metabolism– Renal disease may slow drug elimination– Acid/base abnormalities may change drug

absorption or elimination

• Pathology– Drug may aggravate underlying pathology– Hepatic disease may slow drug metabolism– Renal disease may slow drug elimination– Acid/base abnormalities may change drug

absorption or elimination

Influencing factorsInfluencing factorsInfluencing factorsInfluencing factors

• Genetic effects– Lack of specific enzymes– Lower metabolic rate

• Psychological factors– Placebo effect

• Genetic effects– Lack of specific enzymes– Lower metabolic rate

• Psychological factors– Placebo effect

Pediatric PatientsPediatric PatientsPediatric PatientsPediatric Patients

• Higher proportion of water

• Lower plasma protein levels– More available drug

• Immature liver/kidneys– Liver often metabolizes more slowly– Kidneys may excrete more slowly

• Higher proportion of water

• Lower plasma protein levels– More available drug

• Immature liver/kidneys– Liver often metabolizes more slowly– Kidneys may excrete more slowly

Geriatric PatientsGeriatric PatientsGeriatric PatientsGeriatric Patients

• Chronic disease states• Decreased plasma

protein binding• Slower metabolism• Slower excretion

• Chronic disease states• Decreased plasma

protein binding• Slower metabolism• Slower excretion

• Dietary deficiencies• Use of multiple

medications• Lack of compliance

• Dietary deficiencies• Use of multiple

medications• Lack of compliance

Site of ActionDosage Effects

PlasmaConcen.

Pharmacokinetics Pharmacodynamics

www.freelivedoctor.com

Dose

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0 1 2 3 4 5 6 7 8 90

2

4

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8

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12

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC


DISPOSITION OF DRUGS

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).


Bound Free Free Bound

LOCUS OF ACTION

“RECEPTORS”TISSUE RESERVOIRS

SYSTEMIC CIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATIONwww.freelivedoctor.com

Plasma concentration vs. time profile of a single dose of a drug ingested orally

0

2

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TIME (hours)

Pla

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Dose

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TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC



LOCUS OF ACTION



Free Drug

Bound Drug



Bioavailability

Definition: the fraction of the administered dose reaching the systemic circulation

for i.v.: 100%for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism

First Pass Effect


BioavailabilityBioavailabilityBioavailabilityBioavailability

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation


PRINCIPLEPRINCIPLE

For drugs taken by routes other than the i.v. route, the extent of absorption and the bioavailability must be understood in order to determine what dose will induce the desired therapeutic effect. It will also explain why the same dose may cause a therapeutic effect by one route but a toxic or no effect by another.


Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution (Vd).

Vd = Amount of drug in body ÷ Concentration in Plasma

PRINCIPLEPRINCIPLE

(Apparent) Volume of Distribution:Volume into which a drug appears to distribute with a concentration equal to its plasma concentration



Drug L/Kg L/70 kg

Sulfisoxazole 0.16 11.2

Phenytoin 0.63 44.1

Phenobarbital 0.55 38.5

Diazepam 2.4 168

Digoxin 7 490

Examples of apparent Vd’s for Examples of apparent Vd’s for some drugssome drugsExamples of apparent Vd’s for Examples of apparent Vd’s for some drugssome drugs


K IDNEYf iltra tion

secre tion( rea bsorp tion )

LIVERm etabo lism

secre tion

LU NGSexha lation

O THERSm othe r's m ilk

sw ea t, sa liva e tc.

Eliminationof drugs from the body

MAJOR

MINOR


Elimination by the KidneyElimination by the KidneyElimination by the KidneyElimination by the Kidney

• Excretion - major1) glomerular filtrationglomerular structure, size constraints,

protein binding

2) tubular reabsorption/secretion- acidification/alkalinization,- active transport, competitive/saturable,

organic acids/bases - protein binding

• Metabolism - minor

• Excretion - major1) glomerular filtrationglomerular structure, size constraints,

protein binding

2) tubular reabsorption/secretion- acidification/alkalinization,- active transport, competitive/saturable,

organic acids/bases - protein binding

• Metabolism - minor


Elimination by the LiverElimination by the LiverElimination by the LiverElimination by the Liver

• Metabolism - major1) Phase I and II reactions

2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney

3) Possibility of active metabolites with same or different properties as parent molecule

• Biliary Secretion – active transport, 4 categories

• Metabolism - major1) Phase I and II reactions

2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney

3) Possibility of active metabolites with same or different properties as parent molecule

• Biliary Secretion – active transport, 4 categories


The enterohepatic shuntThe enterohepatic shuntThe enterohepatic shuntThe enterohepatic shunt

Portal circulation

Liver

gall bladder

Gut

Bile

duct

Drug

Biotransformation;glucuronide produced

Bile formation

Hydrolysis bybeta glucuronidase


Dose

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TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC


0

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TIME (hours)

Pla

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Influence of Variations in Relative Rates of Absorption and Elimination on Plasma Concentration of an Orally Administered Drug

Ka/Ke=10

Ka/Ke=0.1

Ka/Ke=0.01

Ka/Ke=1



• Zero order: constant rate of elimination irrespective of plasma concentration.

• First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.

Rate of elimination ∝ AmountRate of elimination = K x Amount

• Zero order: constant rate of elimination irrespective of plasma concentration.

• First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time.

Rate of elimination ∝ AmountRate of elimination = K x Amount


Zero Order EliminationZero Order Elimination Pharmacokinetics of EthanolPharmacokinetics of Ethanol

Zero Order EliminationZero Order Elimination Pharmacokinetics of EthanolPharmacokinetics of Ethanol

• Ethanol is distributed in total body water.• Mild intoxication at 1 mg/ml in plasma.• How much should be ingested to reach it?

Answer: 42 g or 56 ml of pure ethanol (VdxC)Or 120 ml of a strong alcoholic drink like whiskey

• Ethanol has a constant elimination rate = 10 ml/h• To maintain mild intoxication, at what rate must ethanol be taken

now? at 10 ml/h of pure ethanol, or 20 ml/h of drink.

• Ethanol is distributed in total body water.• Mild intoxication at 1 mg/ml in plasma.• How much should be ingested to reach it?

Answer: 42 g or 56 ml of pure ethanol (VdxC)Or 120 ml of a strong alcoholic drink like whiskey

• Ethanol has a constant elimination rate = 10 ml/h• To maintain mild intoxication, at what rate must ethanol be taken

now? at 10 ml/h of pure ethanol, or 20 ml/h of drink.

Rarely Done DRUNKENNESS Coma Death


0

2

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TIME (hours)

Pla

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ion Ct = C0 . e – Kel •t

lnCt = lnC0 – Kel • t

logCt = logC0 – Kel •t 2.3

DC/dt = – k•C

y = b – a.x

First Order EliminationFirst Order EliminationFirst Order EliminationFirst Order Elimination

dA/dt A∝ DA/dt = – k•A


Time

Pla

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100

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10000

First Order Elimination

logCt = logC0 - Kel . t 2.303


Time

Pla

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1

10

100

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10000

C0

Distribution equilibrium

Elimination only

Distribution and Elimination

Plasma Concentration Profile after Plasma Concentration Profile after a Single I.V. Injectiona Single I.V. InjectionPlasma Concentration Profile after Plasma Concentration Profile after a Single I.V. Injectiona Single I.V. Injection


lnCt = lnCo – Kel.t

When t = 0, C = C0, i.e., the concentration at time zero when distribution is complete and elimination has not started yet. Use this value and the dose to calculate Vd.

Vd = Dose/C0


lnCt = lnC0 – Kel.t

When Ct = ½ C0, then Kel.t = 0.693. This is the time for the plasma concentration to reach half the original, i.e., the half-life of elimination.

t1/2 = 0.693/Kel


PRINCIPLEPRINCIPLEPRINCIPLEPRINCIPLE

Elimination of drugs from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).

Elimination of drugs from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).


First Order EliminationFirst Order EliminationFirst Order EliminationFirst Order Elimination

• Clearance: volume of plasma cleared of drug per unit time.Clearance = Rate of elimination ÷ plasma conc.

• Half-life of elimination: time for plasma conc. to decrease by half.

Useful in estimating: - time to reach steady state concentration. - time for plasma concentration to fall after dosing

is stopped.

• Clearance: volume of plasma cleared of drug per unit time.Clearance = Rate of elimination ÷ plasma conc.

• Half-life of elimination: time for plasma conc. to decrease by half.

Useful in estimating: - time to reach steady state concentration. - time for plasma concentration to fall after dosing

is stopped.


Rate of elimination = Kel x Amount in bodyRate of elimination = CL x Plasma Concentration

Therefore,Kel x Amount = CL x Concentration

Kel = CL/Vd

0.693/t1/2 = CL/Vd

t1/2 = 0.693 x Vd/CLwww.freelivedoctor.com


The half-life of elimination of a drug (and

its residence in the body) depends on its

clearance and its volume of distribution

t1/2 is proportional to Vd

t1/2 is inversely proportional to CL

The half-life of elimination of a drug (and

its residence in the body) depends on its

clearance and its volume of distribution

t1/2 is proportional to Vd

t1/2 is inversely proportional to CL

t1/2 = 0.693 x Vd/CL


Multiple dosingMultiple dosingMultiple dosingMultiple dosing

• On continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where:

rate of administration = rate of elimination ie. steady state is reached.

• Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma conc.

OrIf you aim at a target plasma level and you know the

clearance, you can calculate the dose required.

• On continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where:

rate of administration = rate of elimination ie. steady state is reached.

• Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma conc.

OrIf you aim at a target plasma level and you know the

clearance, you can calculate the dose required.


Constant Rate of Administration (i.v.)zz


0

1

2

3

4

5

6

7

0 5 10 15 20 25 30

Time

Pla

sma

Co

nce

ntr

atio

n

Repeated doses –Maintenance dose

Therapeutic level

Single dose – Loading dose


Concentration due to a single dose

Concentration due to repeated doses

The time to reach steady state is ~4 t1/2’s


Pharmacokinetic parametersPharmacokinetic parametersPharmacokinetic parametersPharmacokinetic parameters

• Volume of distribution Vd = DOSE / C0

• Plasma clearance Cl = Kel .Vd

• plasma half-life t1/2 = 0.693 / Kel

• Bioavailability (AUC)x / (AUC)iv

• Volume of distribution Vd = DOSE / C0

• Plasma clearance Cl = Kel .Vd

• plasma half-life t1/2 = 0.693 / Kel

• Bioavailability (AUC)x / (AUC)iv

Get equation of regression line; from it get Kel, C0 , and AUC


But C x dt = small area under the curve. For total amount eliminated (which is the total given, or the dose, if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC

dC/dt = CL x C

dC = CL x C x dt


0

10

20

30

40

50

60

70

0 2 4 6 8 10

Pla

sma

con

cen

trat

ion

Time (hours)

Bioavailability (AUC)o

(AUC)iv

=

i.v. route

oral route


Daily Dose (mg/kg)

Pla

sma

Dru

gC

on

cen

trat

ion

(m

g/L

)

0 5 10 150

10

20

30

40

50

60

Variability in PharmacokineticsVariability in PharmacokineticsVariability in PharmacokineticsVariability in Pharmacokinetics



The absorption, distribution and elimination of a drug are qualitatively similar in all

individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually

and doses adjusted accordingly.

The absorption, distribution and elimination of a drug are qualitatively similar in all

individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually

and doses adjusted accordingly.


Site of ActionDosage Effects

PlasmaConcen.

Pharmacokinetics Pharmacodynamics



LOCUS OF ACTION



Free Drug

Bound Drug



WHY BE CONCERNED ABOUT HOW DRUGS WORK?

• FDA Approved and Unapproved Uses

• Interactions with Other Drugs

• Adverse Effects and Contraindications

AIDS MEMORIZATION OF:



• Better assessment of new modalities for using drugs

• Better assessment of new indications for drugs

• Better assessment of new concerns regarding risk-benefit

AIDS EVALUATION OF MEDICAL LITERATURE:



The patient has more respect for and trust in a therapist whocan convey to the patient how the drug is affecting the patient’s body.

AIDS PATIENT-DOCTOR RELATIONSHIP:

A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease.



Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

PEACE OF MIND!


HOW DO DRUGS WORK?

• Some antagonize, block or inhibit endogenous proteins

• Some activate endogenous proteins

• A few have unconventional mechanisms of action

Most work by interacting withendogenous proteins:


HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

•Inhibitors of Signal Transduction Proteins


A macromolecular component of the organism that binds the drug and initiates its effect.

Definition of RECEPTOR:

Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate.


A receptor that is embedded in the cell membrane and functionsto receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment.

Definition of CELL SURFACE RECEPTOR:


HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? KEY CONCEPTS:

• Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell.

• Some compounds bind to cell surface receptors, yet do not activate the receptors to trigger a response.

• When cell surface receptors bind the molecule,the endogenous chemical cannot bind to the receptor and cannot trigger a response.

• The compound is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.


Footnote:

Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. If binding is reversible - Competitive antagonistsIf binding is irreversible - Noncompetitive antagonists However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor. (Noncompetitive antagonists)

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?


ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORSCLINICALLY USEFUL?

• Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency(losartan [Cozaar®]; valsartan [Diovan®])

Some important examples:

• Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood pressure, performance anxiety(propranolol [Inderal®]; atenolol [Tenormin®])


ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORSCLINICALLY USEFUL?

• Mineralocorticoid Receptor Antagonists for edema due toliver cirrhosis and for heart failure(spironolactone [Aldactone®])


• Estrogen Receptor Antagonists for the prevention and treatment

of breast cancer (tamoxifen [Nolvadex®])










HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Inactive Enzyme

Substrate

Bound Enzyme Inhibitor (Drug)


HOW DO DRUGS WORK BY INHIBITING ENZYMES?KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from substrates.

• Some drugs bind to enzymes and inhibit enzymatic activity.

• Loss of product due to enzyme inhibition mediates theeffects of enzyme inhibitors.


ARE DRUGS THAT INHIBIT ENZYMESCLINICALLY USEFUL?

• Cyclooxygenase Inhibitors for pain relief,particularly due to arthritis (aspirin; ibuprofen [Motrin®])


• Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and chronic renal insufficiency(captopril [Capoten®]; ramipril [Altace®])

• HMG-CoA Reductase Inhibitors for hypercholesterolemia(atorvastatin [Lipitor®]; pravastatin [Pravachol®])










ARE DRUGS THAT BLOCK ION CHANNELSCLINICALLY USEFUL?

• Calcium Channel Blockers (CCBs) for angina and high blood pressure(amlodipine [Norvasc®]; diltiazem [Cardizem®])


• Sodium Channel Blockers to suppress cardiac arrhythmias(lidocaine [Xylocaine®]; amiodarone [Cordarone®])


ARE DRUGS THAT INHIBIT TRANSPORTERSCLINICALLY USEFUL?

• Selective Serotonin Reuptake Inhibitors (SSRIs) for thetreatment of depression (fluoxetine [Prozac®]; fluvoxamine [Luvox®])


• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) inrenal epithelial cells to increase urine and sodium output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])


• Tyrosine Kinase Inhibitors for chronic myelocytic leukemia(imatinib [Gleevec®])


• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction(sildenafil [Viagra®])

• This is a major focus of drug development

ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINSCLINICALLY USEFUL?


HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?

• Agonists of Cell Surface Receptors(e.g. alpha-agonists, morphine agonists)

• Agonists of Nuclear Receptors(e.g. HRT for menopause, steroids for inflammation)

• Enzyme Activatorse.g. nitroglycerine (guanylyl cyclase), pralidoxime

• Ion Channel Openerse.g. minoxidil (K) and alprazolam (Cl)


HOW DO CHEMICALS WORK BY ACTIVATING CELL SURFACE RECEPTORS?KEY CONCEPTS:

• Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell.

• Some chemicals bind to cell surface receptors and trigger a response.

• Chemicals in this group are called receptor agonists.

• Some agonists are actually the endogenous chemical signal,whereas other agonists mimic endogenous chemical signals.


HOW DO CHEMICALS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION?

• Disrupting of Structural Proteins e.g. vinca alkaloids for cancer, colchicine for gout

• Being Enzymes

e.g. streptokinase for thrombolysis

• Covalently Linking to Macromoleculese.g. cyclophosphamide for cancer

• Reacting Chemically with Small Moleculese.g. antacids for increased acidity

• Binding Free Molecules or Atomse.g. drugs for heavy metal poisoning, infliximab (anti-TNF)


HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)?

• Being Nutrientse.g. vitamins, minerals

• Exerting Actions Due to Physical Propertiese.g. mannitol (osmotic diuretic), laxatives

• Working Via an Antisense Actione.g. fomivirsen for CMV retininitis in AIDS

• Being Antigens e.g. vaccines

•Having Unknown Mechanisms of Actione.g. general anesthetics


Characteristics of Drug-Receptor InteractionsCharacteristics of Drug-Receptor InteractionsCharacteristics of Drug-Receptor InteractionsCharacteristics of Drug-Receptor Interactions

• Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent.

• Saturable• Competitive• Specific and Selective • Structure-activity relationships• Transduction mechanisms

• Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent.

• Saturable• Competitive• Specific and Selective • Structure-activity relationships• Transduction mechanisms



NH4+-CH2(n)-NH4

+


Receptor Transduction MechanismsReceptor Transduction MechanismsReceptor Transduction MechanismsReceptor Transduction Mechanisms

• Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-)

• Second messenger generation, adenylate cyclase stimulation or inhibition - cAMP,guanylate cyclase - cGMP,phospholipase C - IP3, DAG• Some receptors are themselves protein kinases• Intracellular receptors (e.g. corticosteroids, thyroid

hormone)

• Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-)

• Second messenger generation, adenylate cyclase stimulation or inhibition - cAMP,guanylate cyclase - cGMP,phospholipase C - IP3, DAG• Some receptors are themselves protein kinases• Intracellular receptors (e.g. corticosteroids, thyroid

hormone)


k1

D + R <=> DR k2

By Law of Mass Action: [D]•[R]•K1= [DR]•K2

Therefore K2 /K1= Kd = [D]•[R]/[DR]

If RT = total # of receptors, thenRT = [R] + [DR]

Replace [R] by (RT-[DR]) and rearrange: [DR] [D]

RT Kd + [D]=

OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS

EFFECT

effectMax. effect=



Receptor Binding %

Bou

nd

Concentration of Ligand

Kd


[D] (concentration units)

[DR

]/R

T

0.01 0.10 1.00 10.00 100.000.00

0.25

0.50

0.75

1.00

Kd=1kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Receptor


Competitive Noncompetitive

Types of Receptor Antagonistswww.freelivedoctor.com


[D] (concentration units)

% M

axim

al E

ffec

t

0.01 0.10 1.00 10.00 100.00 1000.000.0

0.2

0.4

0.6

0.8

1.0

Partial agonist

Full Agonist

Partial agonist

PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ.



Drug (D)

Ri

DRi DRa

Ra

CONFORMATIONAL SELECTION

HOW TO EXPLAIN EFFICACY?

The relative affinityOf the drug to either conformation will determine the effect of the drug


R

R1*

R2*

R3*

R R

R1*

R1*

R2*

R2*

R3*

R3*


Spare Receptors


Receptor RegulationReceptor RegulationReceptor RegulationReceptor Regulation

• Sensitization or Up-regulation1. Prolonged/continuous use of receptor blocker2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation

• Desensitization or Down-regulation1. Prolonged/continuous use of agonist2. Inhibition of degradation or uptake of agonist

Homologous vs. HeterologousUncoupling vs. Decreased Numbers

• Sensitization or Up-regulation1. Prolonged/continuous use of receptor blocker2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation

• Desensitization or Down-regulation1. Prolonged/continuous use of agonist2. Inhibition of degradation or uptake of agonist

Homologous vs. HeterologousUncoupling vs. Decreased Numbers





GRADED DOSE-RESPONSE CURVE

ED50

ED50


QUANTAL DOSE-RESPONSE CURVE

Frequency Distribution

CumulativeFrequency Distribution



Morphine

Aspirin


THERAPEUTIC INDEX – AN INDEX OF SAFETY

Hypnosis Death


Margin of Safety = LD1

ED99

ED50AED99A

LD1A


Causes of Variability in Drug ResponseCauses of Variability in Drug ResponseCauses of Variability in Drug ResponseCauses of Variability in Drug Response

Those related to the biological system

1. Body weight and size

2. Age and Sex

3. Genetics - pharmacogenetics

4. Condition of health

5. Placebo effect

Those related to the biological system

1. Body weight and size

2. Age and Sex

3. Genetics - pharmacogenetics

4. Condition of health

5. Placebo effect


Causes of Variability in Drug ResponseCauses of Variability in Drug ResponseCauses of Variability in Drug ResponseCauses of Variability in Drug Response

• Those related to the conditions of administration1. Dose, formulation, route of administration.2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy

3. Drug interactions:chemical or physical; GI absorption; protein binding/distribution; metabolism (stimulation/inhibition); excretion (ph/transport processes); receptor (potentiation/antagonism); changes in pH or electrolytes.

• Those related to the conditions of administration1. Dose, formulation, route of administration.2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy

3. Drug interactions:chemical or physical; GI absorption; protein binding/distribution; metabolism (stimulation/inhibition); excretion (ph/transport processes); receptor (potentiation/antagonism); changes in pH or electrolytes.


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Drug actions