книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Learning Objectives

Differentiate between graded (quantitative) dose-response (D-R), and quantal (cumulative) D-R curves

Use knowledge of signaling mechanisms

Demonstrate understanding of drug development and testing

DEFINITIONS

λPharmacodynamics relates to drugs binding to receptors and their effects.

λAgonist: A drug is called an agonist when binding to the receptor results in a response.

λAntagonist: A drug is called an antagonist when binding to the receptor is not associated with a response. The drug has an effect only by preventing an agonist from binding to the receptor.

λAffinity: ability of drug to bind to receptor, shown by the proximity of the curve to the y axis (if the curves are parallel); the nearer the y axis, the greater the affinity

λPotency: shows relative doses of two or more agonists to produce the same magnitude of effect, again shown by the proximity of the respective curves to the y axis (if the curves do not cross)

λEfficacy: a measure of how well a drug produces a response (effectiveness), shown by the maximal height reached by the curve

GRADED (QUANTITATIVE) DOSE-RESPONSE (D-R) CURVES

Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can reveal information about affinity, potency, and efficacy of these agonists.

Bridge to Biochemistry

Definitions

Affinity: how well a drug and a receptor recognize each other. Affinity is inversely related to the Kd of the drug. Notice the analogy to the Km value used in enzyme kinetic studies.

Potency: the quantity of drug required to achieve a desired effect. In D-R measurements, the chosen effect is usually 50% of the maximal effect, but clinically, any size response can be sought.

Efficacy: the maximal effect an agonist can achieve at the highest practical concentration. Notice the analogy with the Vmax used in enzyme kinetic studies.

% Response

% Response

100

50

X

Y

% Response

Log dose of drug

% Response

+ Partial agonist

50

Partial agonist alone

Log dose of partial agonist

Figure I-2-3. Duality of Partial Agonists

100

% Response

Control Competitive

Potentiation Antagonism

Noncompetitive

Log dose of drug

Section I λ General Principles

Bridge to Biochemistry

Parallels between Receptor Antagonists and Enzyme Inhibitors

Competitive antagonists are analogous to competitive inhibitors; they decrease affinity (↑ Km) but not maximal response (Vmax remains the same).

Noncompetitive antagonists decrease Vmax but do not change the Km.

λPharmacologic antagonism (same receptor)

−Competitive antagonists:

ºCause a parallel shift to the right in the D-R curve for agonists

ºCan be reversed by ↑ the dose of the agonist drug

ºAppears to ↓ the potency of the agonist

−Noncompetitive antagonists:

ºCause a nonparallel shift to the right

ºCan be only partially reversed by ↑ the dose of the agonist

ºAppear to ↓ the efficacy of the agonist

λPhysiologic antagonism (different receptor)

−Two agonists with opposing action antagonize each other

−Example: a vasoconstrictor with a vasodilator

λChemical antagonism:

– Formation of a complex between effector drug and another compound

– Example: protamine binds to heparin to reverse its actions

λPotentiation

−Causes a parallel shift to the left to the D-R curve

−Appears to ↑ the potency of the agonist

QUANTAL (CUMULATIVE) D-R CURVES

λThese curves plot the percentage of a population responding to a specified drug effect versus dose or log dose. They permit estimations of the median effective dose, or effective dose in 50% of a population—ED50.

λQuantal curves can reveal the range of intersubject variability in drug response. Steep D-R curves reflect little variability; flat D-R curves indicate great variability in patient sensitivity to the effects of a drug.

Toxicity and the Therapeutic Index (TI)

λComparisons between ED50 and TD50 values permit evaluation of the relative safety of a drug (the therapeutic index), as would comparison between ED50 and the lethal median dose (LD50) if the latter is known.

Figure I-2-5. Quantal D-R Curves of Therapeutic and Toxic Effects of a Drug

In A Nutshell

Key ANS Receptors

M1, M3, α1:

Gq activation of phospholipase C

M2, α2, D2:

Gi inhibition of adenylyl cyclase

β1, β2, D1:

Gs activation of adenylyl cyclase

Receptors Linked Via Coupling Proteins to Intracellular Effectors

λMany receptor systems are coupled via GTP-binding proteins (G-proteins) to adenylyl cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by activating protein kinase A. These receptors are typically “serpentine,” with seven transmembrane spanning domains, the third of which is coupled to the G-protein effector mechanism.

λProtein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or transcription factors (CREB), thereby affecting their activity.

GS PROTEINS

λBinding of agonists to receptors linked to Gs proteins increases cAMP production.

λSuch receptors include those for catecholamines (beta), dopamine (D1), glucagon, histamine (H2), prostacyclin, and some serotonin subtypes.

GI PROTEINS

λBinding of agonists to receptors linked to Gi proteins decreases cAMP production.

λSuch receptors include adrenoreceptors (alpha2), ACh (M2), dopamine (D2 subtypes), and several opioid and serotonin subtypes.

GQ PROTEINS

λOther receptor systems are coupled via GTP-binding proteins (Gq), which activate phospholipase C. Activation of this enzyme releases the

second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate

(PIP2). The IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby affects their activity.

λThese signaling mechanisms are invoked following activation of recep-

tors for ACh (M1 and M3), norepinephrine (alpha1), angiotensin II, and several serotonin subtypes.

Cyclic GMP and Nitric Oxide Signaling

λcGMP is a second messenger in vascular smooth muscle that facilitates dephosphorylation of myosin light chains, preventing their interaction with actin and thus causing vasodilation.

λNitric oxide (NO) is synthesized in endothelial cells and diffuses into smooth muscle.

λNO activates guanylyl cyclase, thus increasing cGMP in smooth muscle.

λVasodilators ↑ synthesis of NO by endothelial cells.

Receptors That Function as Enzymes or Transporters

λThere are multiple examples of drug action that depend on enzyme inhibition, including inhibitors of acetylcholinesterase, angiotensinconverting enzyme, aspartate protease, carbonic anhydrase, cyclooxygenases, dihydrofolate reductase, DNA/RNA polymerases, monoamine oxidases, Na/K-ATPase, neuraminidase, and reverse transcriptase.

λExamples of drug action on transporter systems include the inhibitors of reuptake of several neurotransmitters, including dopamine, GABA, norepinephrine, and serotonin.

Bridge to Biochemistry

See Chapter 9 of the Biochemistry Lecture Notes for additional discussion of signal transduction.

Clinical Correlate

Drugs acting via NO include nitrates (e.g., nitroglycerin) and M-receptor agonists (e.g., bethanechol).

Endogenous compounds acting via NO include bradykinin and histamine.

Clinical Correlate

Imatinib is a specific tyrosine-kinase (TK) inhibitor, while sorafenib is a non-specific TK inhibitor.

Receptors That Function as Transmembrane Enzymes

λThese receptors mediate the first steps in signaling by insulin and growth factors, including epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). They are membrane-spanning macromolecules with recognition sites for the binding of insulin and growth factors located externally and a cytoplasmic domain that usually functions as a tyrosine kinase. Binding of the ligand causes conformational changes (e.g., dimerization) so that the tyrosine kinase domains become activated, ultimately leading to phosphorylation of tissue-specific substrate proteins.

λGuanyl cyclase−associated receptors: stimulation of receptors to atrial natriuretic peptide activates the guanyl cyclase and ↑ cyclic GMP (cGMP)

Receptors for Cytokines

λThese include the receptors for erythropoietin, somatotropin, and interferons.

λTheir receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]).

λJAKs phosphorylate signal transducers and activators of transcription (STAT) molecules.

λSTATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription.