APEX Pharmacodynamics

Pharmacodynamics is the study of

effect site concentration and clinical effect

"what the drug dose to the body"

Pharmacokinetics

describes the relationship between drug dose & plasma concentration (the dose you give and the plasma conc over time)

"what the body does to the drug"

Pharmacobiophasics

unites PK & PD by examining the r/s between plasma concentration & effect site concentration

The biophase is otherwise known as what

the effect-site; the specific area of the body where the drug engages its receptor

Pharmacokinetics is affected by what 4 things

Absorption

Distribution

Metabolism

Elimination

"ADME"

The drug conc in the ___ determines its clinical effect

biophase (not the plasma)

Plasma concentration of a drug does or does not parallel clinical effect?

Does NOT

Pharmacokinetic examples

Volume of distribution (Vd)

1/2 lives

Metabolism

Enzyme induction/inhibition

Clearance

Steady state

Context sensitive half time

degree of ionization

Protein binding

Ion trapping

Pharmacobiophasics examples

Rate constant b/w plasma & effect site

Pharmacodynamic examples

Potency

Efficacy

Dose response curve slope

Agonist

Antagonist

Partial agonist

Inverse agonist

ED50

TD50

TI

Stereochemistry

Relates Cp to effect site concentration

Pharmacobiophasics

Relates effect site concentration to clinical effect

Pharmacodynamics

Relates drug dose to Cp

Pharmacokinetics

What does the dose- response curve illustrate?

The relationship between drug dose and its clinical effects; tells us about potency, efficacy and slope

On the dose-response curve, the x-axis correlated with

potency

_____ is the dose required to achieve a given clinical effect

Potency

_____ is the intrinsic ability of a drug to elicit a given clinical effect

Efficacy

On the dose-response curve, the y-axis correlated with

Efficacy

The _____ of the dose response curve tells us how many receptors must be occupied to elicit a clinical effect

slope

When we compare the dose response curves from multiple pts we learn about the ____ of each pt

individual variability

The drug response curve illustrates the relationship between the drug ____ and its ______

dose; clinical effects

What 3 things does the drug response curve tell us

Potency

Efficacy

Slope

The ___ & ____ are. a measure of potency

ED50 & ED90

What are the ED50 & ED90

the dose required to achieve a given effect in 50% and 90% of the population

Once a drug reaches maximum efficacy, additional administration of the drug increases the risk of

toxicity

Individual variability is defined as

difference b/w pharmacokinetics & pharmacodynamics between patients; need dose-response curves from multiple patients to get an accurate representation of individual variability

Potency is affected by what 5 things

Absorption

Distribution

Metabolism

Elimination

Receptor affinity

Left shifted dose response curve illustrates

increased affinity for receptor --> higher potency --> lower dose required

Right shifted dose response curve illustrates

decreased affinity for receptor --> lower potency --> higher dose required

the height of the plateau on the y-axis represents

efficacy

a higher plateau represents a greater efficacy & vice versa

Once the plateau phase is reached, additional drug dose

does NOT produce additional clinical effect; only increases risk of toxicity

A steep slope on the curve implies that

most receptors must be occupied before we see a clinical response

Ex. NMB and volatile anesthetics have a steep slope

once the effect is observed, small increases in the dose can have ____

profound clinical effect

Which 2 anesthetics have a STEEP slope

NMB & VA

What binds to a receptor and activates a specific cellular response

Agonist

What binds to a receptor, but its only capable of eliciting a partial cellular response

Partial agonist

What binds to a receptor but does not elicit a clinical response

Antagonist

What binds to a receptor and causes the opposite effect of a full agonist; has negative efficacy

Inverse agonist

A full agonist instructs the receptor to produce its maximal response; what are examples?

NE

Dopamine

Propofol

Alfentanil

A partial agonist is only capable of partially activating a cellular response; give example

Nalbuphine

An antagonist binds to a receptor and prevents an agonist from binding to it, it doesnt tell the cell to do anything. what two kinds are there?

Competitive and non competitive antagonist

Competetive antagonism is _____?

REVERSIBLE

ex: atropine & NDMB

Noncompetitive antagonism is?

NOT reversible;

permanently bind to receptors, and their effects cannot be overcome by increasing the concentration of the agonist. This shifts the dose-response curve for the agonist downward, so that it resembles that of a partial agonist.

The effect of noncompetitive antagonist can only be reversed by producing new receptors

ex: ASA & phenoxybenzamine

Example of inverse agonist

Propranolol

synergism

1 + 1 = 3

effect of 2 drugs given at the same time is greater than the sum of their individual effects

ex: Propofol + Versed

Levodopa + carbidopa

Addition

1 + 1 = 2

the effect of 2 drugs given at the same time are added to each other

ex: morphine + hydromorphone

aspirin + ibuprofen

Potentiation

1 + 0 = 3

Effect of 1 drug is enhances by a drug that has no effect on its own

ex: PCN + probenecid

Antagonism

1 + 1 = 0

simultaneous admin of 1 drug negates the effect of a 2nd drug

ex: versed + flumazenil

fentanyl + narcan

A drug that binds to a receptor follows the law of

mass action

theres a rate constant for drug binding & for dissociation from receptor

law of mass action

[Drug] + [Receptor] <---> [Drug-receptor complex]

• Drug can be classified according to the degree of efficacy. Remember, efficanacy is measured by the height of y-axis of the dose response curve

Full agonist

binds to a receptor and turns on a specific cellular response

mimics an endogenous ligand

Instructs receptor to produce maximal response

different drugs may produce same clinical effect, but each may require a diff dose to do so (difference in potency)

Continuous adminsitration of an agonist may cause down-regulaton of the target receptors

Ex. Levo, dopamine, propofol, alfentanil

continuous administration of an agonist may cause _____ of the target receptors

down regulation

A partial agonist is also called an

agonist-antagonist

By definition an antagonist does not have

efficacy

Continuous administration of an antagonist may cause _____ of the target receptors

up-regulation

If a pt received a competative antagonist, the dose response curve for the agonist shifts to the

right

Non-competitive antagonist permanently bind to a receptor through what type of bond?

covalent

their effects cant be overcome by increasing conc of the agonist

a non competitive antagonist shifts the dose response curve for the agonist ____, so that it resembles a ____

down; partial agonist

the effects of a noncompetitive antagonist can only be reversed by

producing new receptors

therapeutic index is a measure of

drug safety;

calculated by ratio of TD50 to ED 50

TI calculation

LD50/ED50 to determine drug safety

The ED50 is the dose that

produces the Expected clinical response in 50% of the population

a measure of potency

A drug with a narrow TI has a narrow

margin of safety

ex: VA & chemotherapy

Chirality is a division of

stereochemistry; deals with 3-dimensional asymmetry

Chirality has a center of 3 dimensional

asymmetry

What kind of bonding is in a chiral molecule?

tetrahedral bonding of carbon, where carbon binds to 4 different atoms

A molecule with 2 chiral carbon will exists as 2

enantiomers

A ________ contains 2 enantiomers in equal amounts

racemic mixture

ex: epinephrine

Stereochemistry is the study of

3 dimensional structure of molecules

Enantiomers are

chiral molecules that are non superimposable mirror images of one another

Receptors that are ____ may respond differently to different enantiomers

stereospecific

R & S enantiomers are mirror images of one another; what are some examples?

Ketamine

Isoflurane

Morphine

By changing the ratio of R & S enantiomers in a mixture, we can manipulate certain ______

side effects

Enantiomers in a solution are distinguished from each other by the direction they can ?

rotate plane-polarized light

Dextrorotatory enantiomer (D, +) rotates ______

clockwise

its positive

The levorotatory enantiomer (L, -) rotates ___

counterclockwise

its negative

The R & S designations describe the 3-D orientation of atoms around a chiral center

R= ? S= ?

R= right hand

S= left hand

About _____ of the drugs we give are enantiomers and just about all of these are prepared as racemic mictures

1/3

exceptions are: Levobupivacaine & ropivacaine which are prepared as single enantiomers

Examples of racemic mixtures

Ephedrine

Ketamine

Thiopental

Methohexital

Isoflurane

Desflurane

Mepivacaine

Prilocaine

Bupivacaine

Morphine

Methadone

Ibuprofen

Ketorolac

Enantiomers often function as 2 different drugs- with different ___ for the target receptor and different _____

affinities; side effects

S-bupivacine (levobupivacaine) is ____ than R-bupivacaine of the racemic mixture

less cardiotoxic

Compared to the R enantiomer of ketamine, the S enantiomer (esketamine) is more ___ and less likely to cause ______

potent; emergence delerium

How many enantiomers exist in a molecule with one chiral carbon?

2

The physiologic effect of giving PCN with probenecid is best described as?

A. antagonism

B. potentiation

C. addition

D. syngergism

B. potentiation

effect of 1 drug is enhances by a drug that has no effect on its own (1+0=3)

probenecid doesn't have antibiotic effect, but it improves PCNs drug levels and drug effect

What concept describes the intrinsic ability of a drug to elicit a given clinical effect?

A. Efficacy

B. Potency

C. Affinity

D. Enantiomerism

A. Efficacy

Match each drug with its pharmacological action

Nalbuphine

ASA

Mivacurium

Nalbuphine - Partial agonist

ASA- Non competitive antagonist

Mivacurium- competitive antagonist

Drug A on the drug dose response curve is shifted left compared to Drug B and both of their plateaus are the same, what description best described drug A?

A. Greater efficacy

B. Narrow TI

C. Less individual variability

D. Higher potency

Higher potency

Potency represented on x-axis. Its the dose requires to achieve a given clinical effect

Left shifted curve= increased affinity for receptor, higher potency, and lower dose required

right shifted curve= decreased affinity for receptor, lower potency, and higher dose required

An experimental anesthetic agent has a TD50 of 500mg and a therapeutic index of 20. Calculate the ED for this drug.

25mg

TI = TD50/ED50

20= 500mg / X

X= 500/20

X (ED50) = 25mg

All of the following enantiomeric drugs are supplied as racemic mixtures EXCEPT?

A. Ephedrine

B. Desflurane

C. Ropivacaine

D. Ketamine

C. Ropivacaine

In entaniomers, the chemical formula is the same, but the difference is how they _______

rotate plane polarized light

Which route of administration is associated with the LOWEST bioavailabilty?

A. Rectal

B. SL

C. IV

D. Intrathecal

D. Intrathecal

The route of administration determines how much of a drug will enter the systemic circulation and ultimately reach its _______

effect site

IV administration produces

100% bioavailability

The lowest amount of bioavailability occurs with

intrathecal administration

but not a problem bc we are delivering the drug directly to its effect site (we don't need blood to take it there)

What is a partial agonist?

Less efficacious than a full agonist

AKA agonist- antagonist

Blocks the effects of agonist by competing for binding sites. Ex. giving a partial opioid agonist to an opioid addicted patient can precipitate withdrawal

TD 50

The dose that will produce toxicity in 50% of the population

LD 50

Lethal dose 50 is a dose that produces death, not toxicity, in 50% of the population