Receptor And Dose Response Curve

Drug Receptor A macromolecular component of a cell with which a drug interacts to produce a response  Usually a protein 

Drug Receptors and Pharmacodynamics The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

Pharmacodynamics (how drugs work on the body)   

many drugs inhibit enzymes Enzymes control a number of metabolic processes A very common mode of action of many drugs   

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

some drugs bind to:   

proteins (in patient, or microbes) the genome (cyclophosphamide) microtubules (vincristine)

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most drugs act (bind) on receptors   

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in or on cells form tight bonds with the ligand exacting requirements (size, shape, stereospecificity) can be agonists (salbutamol), or (propranolol)

receptors have signal transduction methods

antagonists

Signal transduction 1.

enzyme linked (multiple actions)

1.

ion channel linked (speedy)

1. G protein linked (amplifier)

1. nuclear (gene) linked (long lasting)

Structure:

1.

G protein­linked receptors

•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.

Tyrosine­kinase receptors Structure: •Receptors exist as individual polypeptides •Each has an extracellular signal­binding  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

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

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1. Cycle AMP 2. 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

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Two benefits of a signal-transduction pathway 1. Signal amplification 2. Signal specificity A. Signal amplification Proteins persist in active form long enough to process numerous molecules of substrate  Each catalytic step activates more products then in the proceeding steps 

Drug - Receptor Binding D+R

DR Complex Affinity

Affinity – measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor  Covalent bonds are stable and essentially irreversible  Electrostatic bonds may be strong or weak, but are usually reversible

Drug Receptor Interaction DR Complex

Effect

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

Potency Relative position of the dose-effect curve along the dose axis Has little clinical significance for a given therapeutic effect A more potent of two drugs is not clinically superior Low potency is a disadvantage only if the dose is so large that it is awkward to administer 

Relative Potency hydromorphone morphine codeine

Analgesia

aspirin

Dose

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 DOSERESPONSE CURVE

50% Effect Drug Concentrati on

Maxim al Effect EFFEC T

Effect or

Maximal Effect

P OTE NCY E D50

EFFIC ACY

E D 5 Log 0 [Dose]

10

Agonists 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

Agonist Dose Response Curves Full agonist Partial agonist

Response

Dose

Agonists and Antagonists RECEPTOR RESERVE OR SPARE RECEPTORS. Maximal effect does not require occupation of all receptors by agonist.  Low concentrations of competitive irreversible antagonists may bind to receptors and a maximal response can still be achieved.  The actual number of receptors may exceed the number of effector molecules available. 

Quantal Dose-response Curves

% population responding

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

ED50 ED90

ED10 1

10

100

Dose (mg/kg) log scale

Quantification of drug safety

Therapeutic Index =

TD50 or LD50 ED50

Drug B 100

Percent Responding

sleep

death

50

0

ED50

dose

LD50

9

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)