Lecture 2 Drug Receptors and Dose-Response

Pharmacology

Lecture 2 Drug Receptors and Dose-Response

A.  Drug Receptors

1.  Describe the chemical nature of receptors. Receptors are single macromolecules or aggregates of macromolecules (frequently proteins or glycoproteins) located in cell plasma membranes or in the cell cytoplasm that interact with hormones, neurotransmitters or drugs.

2.  Explain the chemical interaction between drugs and receptors. Drugs can act on receptors located on the cell surface (neurotransmitters and peptide hormones), on intracellular receptors (lipid soluble – steroid hormones), and on enzymes within the membrane or in the cytoplasm (enzyme modulators). Drug binding is usually weak and easily reversible. Binding forces include complementary ionic charges, hydrogen bonds, and van der Waals forces. Complementary charges have a specific spatial arrangement. Upon binding conformational changes activate the transducer mechanism to effectuate changes in cellular function.

3.  Give evidence for the existence of drug receptors.

i.  Drug potency indicates sites of interactions, e.g. LSD.

ii.  Similar molecules produce similar effects, e.g. norepinephrine & epinephrine.

iii.  Difference in action of stereoisomers, e.g. dextrophan(-) and levophranol(+).

iv.  Competitive antagonists block specific targets, e.g. atropine blocks acetylcholine but not norepinephrine or other neurotransmitters.

v.  Biochemical radioligand studies show specific sites binding certain drugs.

vi.  Several receptors have been isolated, purified, cloned, reconstituted, and transfected to cell lines for study. Receptors of unknown function – orphans.

4.  Describe the components of drug receptor systems.

i.  Recognition site – binds the drug molecule.

ii.  Transducer mechanism – translates binding to a biochemical change.

iii.  Amplification mechanism – results in alteration of cellular function. May be excitatory or inhibitory.

5.  Define agonist, partial agonist and antagonist drugs in terms of affinity and efficacy.

Agonist – a drug capable of binding to and activating a receptor. A full agonist has affinity for its receptor and full efficacy.

Partial agonist – can occupy all of the receptors but cannot elicit a maximal response. It has affinity for its receptor but is deficient in efficacy.

Antagonist – interacts with receptor recognition site but does not itself induce change in cell function, only blocks access of agonist to receptor site. It has affinity for the receptor but no efficacy.

6.  Define potency, efficacy, competitive antagonist and noncompetitive antagonist.

Potency – the dosage (concentration) required to induce or block a response.

Efficacy – the ability to induce a maximum response.

Competitive antagonist – reversibly binds to the receptor recognition site of the receptor thus preventing the agonist from binding. This effect can be overcome by increasing the concentration of the agonist.

Noncompetitive antagonist – irreversibly binds to the receptor recognition site through covalent bonds. This effect cannot be overcome.

B.  Dose-Response Curves

1.  Be able to plot data on a typical log dose-response curve. Dosage is graphed on the X axis in an increasing logarithmic scale. Response is graphed on the Y axis. The lowest dose that initiates a response is the threshold dose. The dose-response relationship generates a sigmoid curve. A maximum response is eventually reached where increasing the dose will not affect the response. The linear portion of the curve is the most critical and useful portion.

2.  Understand how dose-response curves can be used to determine potency, efficacy, and the nature of drug interactions. Potency is determined by looking at the ED50 where the lower the dose required to reach 50% response indicates higher potency. Efficacy is also determined by looking at the ED50 where the higher response indicates higher efficacy. The nature of drug interactions can be determined by comparing the ED50 of the curve of drug alone with the curve of the drug and the interacting compound. If the ED50 is at a higher dose for the drug plus compound then potency was decreased and if the ED50 is at a lower response then the efficacy was decreased.

3.  Define graded and quantal dose-response curves.

Graded dose-response curves – the response to a given dose of the drug is graded from threshold (initial effect) to maximum (highest effect).

Quantal dose-response curves – the response is present or absent (all-or-none) for a given dose such that patient responses range from a low dose (threshold) to a dose at which all patients experience the effect (maximum).

4.  Explain why potency is often expressed as D50 or ED50. The D50 or ED50 (the median effective dose) is the dose that produces the endpoint effect in 50% of the subjects or half the maximal response. Potency examines only the relative amount of drug needed to produce a given response (ED50) so that efficacy doesn’t affect potency.

5.  Define “therapeutic index” in terms of toxic effects and lethal effects. The median lethal dose (if death is the endpoint) is abbreviated LD50 while the median toxic dose (for a particular measure of toxicity) is the TD50. The therapeutic index is a relative measure of safety, calculated as the ratio of the LD50 (or TD50) to the ED50 for the desired effect (Therapeutic index = LD50/ ED50). A lower therapeutic index indicates a drug could be toxic at therapeutic levels while a higher therapeutic index indicates a wider margin between what is therapeutic and what is toxic.