Download - Receptor And Dose Response Curve
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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