Drug ReceptorDrug Receptor A macromolecular component of a cell A macromolecular component of a cell

with which a drug interacts to produce a with which a drug interacts to produce a responseresponse

Usually a proteinUsually a protein

Drug Receptors and Drug Receptors and PharmacodynamicsPharmacodynamics

The The action of a drug on the bodyaction of a drug on the body, including , including receptor interactions, dose-response receptor interactions, dose-response

phenomena, and mechanisms of phenomena, and mechanisms of therapeutic and toxic action.therapeutic and toxic action.

PharmacodynamicsPharmacodynamics(how drugs work on the body(how drugs work on the body))

many drugs inhibit many drugs inhibit enzymesenzymes Enzymes control a number of metabolic processesEnzymes control a number of metabolic processes A very common mode of action of many drugsA very common mode of action of many drugs

in the patient (ACE inhibitors)in the patient (ACE inhibitors) in microbes (sulfas, penicillins)in microbes (sulfas, penicillins) in cancer cells (5-FU, 6-MP)in cancer cells (5-FU, 6-MP)

some drugs bind to:some drugs bind to: proteins (in patient, or microbes)proteins (in patient, or microbes) the genome (cyclophosphamide)the genome (cyclophosphamide) microtubules (vincristine)microtubules (vincristine)

most drugs actmost drugs act (bind) (bind) on on receptorsreceptors in or on cellsin or on cells form tight bonds with the form tight bonds with the ligandligand exacting requirements (size, shapeexacting requirements (size, shape, ,

stereospecificitystereospecificity)) can be can be agonists agonists (salbutamol), or (salbutamol), or antagonists antagonists

(propranolol)(propranolol) receptors have receptors have signal transduction signal transduction

methodsmethods

SSignal transductionignal transduction

1. enzyme linked(multiple actions)

2. ion channel linked(speedy)

3. G protein linked(amplifier)

4. nuclear (gene) linked(long lasting)

1. G protein-linked receptors

Structure:

•Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices

•There’s a G protein attached to the cytoplasmic side of the membrane (functions as a switch).

2. Tyrosine-kinase receptors

Structure:

•Receptors exist as individual polypeptides

•Each has an extracellular signal-binding site

•An intracellular tail with a number of tyrosines and a single å helix spanning the membrane

3. Ion channel receptors

Structure:

•Protein pores in the plasma membrane

B.B. Second MessengersSecond Messengers Small, nonprotein, water-soluble molecules or ionsSmall, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusionReadily spread throughout the cell by diffusion Two most widely used second messengers are:Two most widely used second messengers are:

1.1. Cycle AMPCycle AMP 2.2. Calcium ions Ca2+Calcium ions Ca2+

2. Calcium Ions (Ca2+) and Inositol Trisphosphate

•Calcium more widely used than cAMP

•used in neurotransmitters, growth factors, some hormones

•Increases in Ca2+ causes many possible responses:

•Muscle cell contraction

•Secretion of certain substance

•Cell division

Two benefits of a signal-transduction pathwayTwo benefits of a signal-transduction pathway 1.1. Signal amplificationSignal amplification 2.2. Signal specificitySignal specificity

A.A. Signal amplificationSignal amplification Proteins persist in active form long enough to process Proteins persist in active form long enough to process

numerous molecules of substratenumerous molecules of substrate Each catalytic step activates more products then in the Each catalytic step activates more products then in the

proceeding stepsproceeding steps

D + RD + R DR ComplexDR Complex

Affinity – measure of propensity of a drug to bind Affinity – measure of propensity of a drug to bind receptor; the attractiveness of drug and receptorreceptor; the attractiveness of drug and receptor Covalent bonds are stable and essentially Covalent bonds are stable and essentially

irreversibleirreversible Electrostatic bonds may be strong or weak, but Electrostatic bonds may be strong or weak, but

are usually reversibleare usually reversible

Drug - Receptor BindingDrug - Receptor Binding

Affinity

Drug Receptor InteractionDrug Receptor Interaction

Efficacy (or Intrinsic Activity) – ability of a Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way bound drug to change the receptor in a way that produces an effect; some drugs possess that produces an effect; some drugs possess affinity but NOT efficacyaffinity but NOT efficacy

DR Complex Effect

PotencyPotency

Relative position of the dose-effect curve along Relative position of the dose-effect curve along the dose axisthe dose axisHas little clinical significance for a given Has little clinical significance for a given therapeutic effecttherapeutic effectA more potent of two drugs is not clinically A more potent of two drugs is not clinically superiorsuperiorLow potency is a disadvantage only if the dose is Low potency is a disadvantage only if the dose is so large that it is awkward to administerso large that it is awkward to administer

Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency

All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)

SEMILOG DOSE-SEMILOG DOSE-RESPONSE CURVERESPONSE CURVE

EFFEC

T

POTENCY

EFFICACY

ED50

Maximal Effect

Log [Dose]

Drug Concentration

ED50

50% Effect

Maximal Effect

Eff

ect

or

AAgonists and antagonistsgonists and antagonists

agonist has affinity plus intrinsic activity antagonist has affinity but no intrinsic activity partial agonist has affinity and less intrinsic activity competitive antagonists can be overcome

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Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves

Agonists and AntagonistsAgonists and Antagonists

RECEPTOR RESERVE OR SPARE RECEPTORS.RECEPTOR RESERVE OR SPARE RECEPTORS. Maximal effect does not require occupation of all Maximal effect does not require occupation of all

receptors by agonist.receptors by agonist. Low concentrations of competitive irreversible Low concentrations of competitive irreversible

antagonists may bind to receptors and a maximal antagonists may bind to receptors and a maximal response can still be achieved.response can still be achieved.

The actual number of receptors may exceed the The actual number of receptors may exceed the number of effector molecules available.number of effector molecules available.

Cumulative distribution of population responding to drug A/ Cumulative distribution of population responding to drug A/ quantal dose quantal dose response curvesresponse curves (used in populations, response is yes/no)(used in populations, response is yes/no)

Quantal Dose-response CurvesQuantal Dose-response Curves

1 10 100

Dose (mg/kg) log scale

% p

opu

lati

on r

esp

ondin

g

ED50ED90ED10

Quantification of drug safetyQuantification of drug safety

Therapeutic Index = TD50 or LD50

ED50

dose

Drug B

sleepdeath

100

50

0ED50 LD50

PercentResponding

The therapeutic index

The higher the TI the better the drug.

TI’s vary from: 1.0 (some cancer drugs)

to: >1000 (penicillin)

Drugs acting on the same receptor or enzyme system often have the same TI: (eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of indapamide)

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