Dd- Pharmacodynamics And Drug Receptors

Front 1

Describe the drug-receptor concept and the types of bonds and receptor molecules involved in drug binding

Back 1

o Drug binds specific target receptor; the act of binding changes the conformation of the receptor in forming the drug-receptor; this conformation transduces and amplifies a biological response


SO in short

Front 2

Mechanisms of transduction/amplification

Back 2

• Ligand-gated ion channels
• G-protein-coupled receptors
• (serine/tyrosine) Kinase-linked receptors
• Nuclear (hormone) receptors

Front 3

speed of transduction / amplification

Back 3

fastest --> slowest

ligand-gated > Gpro > kinase linked /hormone nuclear receptors

Front 4

Re selectivity of a given drug

Back 4

weaker bond formation (ie H-bonds) is more important than covalent bond formation for selective drug-receptor binding. This is because the weaker bonds require a greater degree of conformational compatibility (which, in turn, is related to how specific a drug is to its target).

Front 5

Types of receptors

Back 5

• Proteins (can be highly specific to particular drugs thanks to 2o and 3o structure)
• Nucleic acids (generally low specificity)
• Membrane lipids (generally low specificity)
• Further broken down into specialized receptors and generalized receptors:
 Specialized receptors that are 'designed' to receive a particular signal and transduce a particular response.
• Hormone receptors
• Ion channel receptors
• Neurotransmitters
 Generalized receptors: essentially, any compounds that aren't specific receptors; any compound, doing any job in a cell, that can be targeted by a drug.
• Enzymes
• Transport proteins
• Structural proteins
 Note that it's easier to avoid widespread side effects with drugs targeting specialized receptors.

Front 6

Specialized receptors

Back 6

are 'designed' to receive a particular signal and transduce a particular response.
• Hormone receptors
• Ion channel receptors
• Neurotransmitters
easier to avoid widespread side effects

Front 7

Generalized receptors

Back 7

essentially, any compounds that aren't specific receptors; any compound, doing any job in a cell, that can be targeted by a drug.
• Enzymes
• Transport proteins
• Structural proteins

Front 8

Explain the theoretical aspects and therapeutic consequences of the hyperbolic shape of the dose-response curve.

Back 8

dose-response curve is asymptotic: it approaches a final degree of response (Emax), at first quickly but progressively more slowly.

• At low doses, the effect responds in a roughly linear fashion to dose.
 The region of the curve in which the dose and response are linearly related - where you get a proportional response for each dose of drug - is called the "therapeutic dosage range".
• At the high-concentration end of the curve, the response is more or less the same no matter what the dose is. This happens because all available receptors for that drug have complexed with drug molecules.
• Notice this means you have a kind of diminishing-returns scenario with all drugs-- the more you give, past a certain point, the less additional response you get out of it.

Front 9

Describe the advantages of the log dose-response curve versus the dose-response curve.

Back 9

o (So in a log-dose-response curve you've taken the base-10 logarithm of the dose of the drug (still on the x-axis) and plotted the response on the y-axis as its function.)
o (Notice that this is another way of describing exactly the same data-- but it collapses the graph into a smaller frame and changes the shape of the curve from hyperbolic to sigmoidal (S-shaped).)
o This allows a wide range of concentration values to be plotted in a small area.
o This also allows the linear portion of the curve (the therapeutic dosage range) to be mapped out over a large portion of the x-axis.

Front 10

rank specificity of specialized receptor molecules

Back 10

most --> least

proteins > nucleic acids & membrane lipids

Front 11

The log dose response curve

Back 11

Allows measurement of efficacy (what does it do) and potency (how strongly does it do it) of a given drug at various concentrations. Basically just plots response to a drug (y-axis) as a function of the concentration of that drug given (x-axis).

binding is reversible, response is proportional tothe receptors occupied by the drug

Front 12

Potency

Back 12

Defined as the dose of drug that gives 50% of the maximal molecular response (Emax).

Front 13

Affinity/Kd/EC50:

Back 13

• These are terms related to potency.
• EC50 (or ED50): Synonym for potency; ie, the effective concentration (or dose) of the drug at which the effect is exactly 50% of the maximal effect (Emax).
 *Notice the smaller the EC50, the more potent the drug.
• Kd: Defined as the concentration of drug at which 50% of all available receptors are bound to the drug. Notice that this is often used interchangeably with EC50.
• Notice that the potency information of a drug tells you nothing about what the maximal effect actually is- just how much a drug gets you to half that effect.
 Thus: potency is used to figure out how much of a drug to deliver at a time.

Front 14

Efficacy: A measure of the extent of the molecular response or effect possible with a given drug

Back 14

• Notice that this is a pharmacological term. You can give a drug at nowhere near the Emax of that drug (ie there are lots of available receptors not bound to drug) with a complete clinical effect (ie no more pain, remission of cancer, etc). Usually you don't want to give a drug at anywhere near its pharmacological efficacy level (Emax), because a much lower dose will achieve complete clinical efficacy and avoid additional side effects. Clinical efficacy relates to clinical effect.

Front 15

Power/Emax

Back 15

Other terms for pharmacological efficacy (in this context). Emax is the experimentally determined maximum molecular effect, or response, possible for a given drug. Power is sometimes used clinically to refer to what extent a drug produces a clinical outcome (ie analgesia).

Front 16

smaller EC50 means more/less potent drug?

Back 16

smaller EC50 --> MORE POTENT

Front 17

Efficacy:

Back 17

A measure of the extent of the molecular response or effect possible with a given drug.

A measure of the extent of the molecular response or effect possible with a given drug.

Front 18

Pharmacological antagonist

Back 18

binds to same receptor site as the agonist. Most antagonists are pharmacological

reversible
irreversible

Front 19

Reversible antagonism

Back 19

aka competitive inhibition.
The antagonist competes for the active binding site of the receptor with the agonist. Note that it's generally not a winner-take-all situation; at any moment there's likely to be some receptor bound to agonist and some bound to antagonist. How much is which depends on the relative binding affinities of the receptor for the two of them and what their relative concentrations are (a sufficient quantity of agonist can overcome the antagonist activity).
• Dose-response curve effect of reversible antagonists: they shift the curve to the RIGHT (no effect on Emax, but EC50 gets higher, indicating you need a lot more agonist to have the same level of effect. Another way of saying this is that reversible antagonists decrease the potency of a drug).
• Note that most clinically used drugs are competitive agonists (you want a temporary, reversible effect that can be easily titrated to individual metabolisms)

Front 20

Irreversible antagonism

Back 20

aka noncompetitive inhibition. The antagonist can bind either to the active binding site of the receptor or another location on it. It alters the receptor so as to destroy the receptor's affinity for the agonist. Notice that this effect can't be overcome by increasing the relative concentration of the agonist (it's not competing for the binding site with the agonist, it's changing the receptor so that the receptor no longer binds the agonist at all).
• Dose-response curve effect of irreversible antagonists: they shift the curve down (they lower Emax, but EC50 stays the same).
• Note that there aren't many clinically used irreversible antagonists. One simple reason for this is that if you give too much of the drug, you can't back the dosage down-- you've effectively destroyed the patient's response to the agonist. This is a big problem for agonists that can be broadly useful at lower doses (which are most of them).

Front 21

reversible antagonist shifts curve

Back 21

to the right

no effect on Emax
EC50 increases
decrease potentcy of drug

Front 22

irreversible antagonists

Back 22

shift the curve down

lower Emax
EC50 same

Front 23

Physiological antagonist

Back 23

one drug (the antagonist) produces an opposite effect to that of another drug (the agonist) by two separate pathways and receptor systems

Ex. Histamine (bronchoconstriction via hist receptors) and Epi (bronchodilation via adrenergic receptors)
Ex. NE (increase HR via adrenergic receptors) and Ach (decrease HR via muscarinic receptors)

Front 24

Chemical antagonist

Back 24

one drug (the antagonist) binding to and antagonizing the effect of another drug (the agonist). Note that this does not involve the antagonist binding to a receptor (it binds to the agonist itself).

Ex. Carbonate neutralizes stomach acid

Front 25

clincial efectiveness of a drug depends on

Back 25

maximal efficacy

and its ability to reach the revant receptors at its site of action (pharmacokinetic profile in a given patient)

Front 26

what determines teh dose necessary to administer to the patient

Back 26

pharmacologic potency

Front 27

efficacy

Back 27

in therapeutics means the extent a given clinical effect can be achieved in an intact patient

Front 28

non-competititve (irreversible) antagonists duration of action is dependent on

Back 28

the rate of turnover of the endogenous receptor molecules

NOT rate of elmination!

Front 29

Therapeutic index

Back 29

LD50/ED50

all or nothing response
compares modponts in the population ED50 and LD50

Front 30

Standard safety margin

Back 30

looks at extremes in the population ED99 and LD1

Front 31

difference beteween TI and SSM

Back 31

TI compares modponts in the population ED50 and LD50

SSM looks at extremes in the population ED99 and LD1

Front 32

which is a more conservative measure? TI or SSM

Back 32

standard safety margin is more conservative

Front 33

therapeutic window

Back 33

concept that is used to provide an indication of the safety of a drug

between minimum therapeutic concentration and the minimum toxic concentration of a drug