Pharmacodynamics

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Drug-Receptor Interactions

Drugs typically exert their effects by interacting with a macromolecule (receptor)

Drug-receptor interactions have been important in:

new drug development

therapeutic decisions

Major roles of receptors:

Determines quantitative relationships between drug dose and pharmacological effect.

Determines drug action selectivity

Mediates antagonist (blocking) as well as agonist (activating) effects

Molecular characteristics of receptors:

Usually proteins, specifically regulatory proteins -- mediating effects of:

neurotransmitters

autacoids (histamine, serotonin, endogenous peptides, prostaglandins, leukotrienes)

hormones

Some receptors are enzymes --may be inhibited or occasionally activated by drugs

e.g. dihydrofolate reductase (receptor) -- methotrexate(drug inhibitor)

Other receptors are transport proteins:

e.g. Na/K ATPase (receptor for digitalis glycosides {digoxin (Lanoxin, Lanoxicaps), digitoxin(Crystodigin)}

Still other receptors are structural proteins:

tubulin-- receptor for certain anticancer drugs and anti-inflammatory drugs

Signal Transduction

Signal transduction is the process by which extracellular inputs (drug-receptor interactions) leads to intracellular messages that modulate cellular physiology.

Molecular mechanisms of signal transduction:

Five basic mechanisms:

Drug crosses the cellular membrane: activates an intracellular receptor

Transmembrane receptor protein: intracellular enzyme activity affected by drug binding to a site on the enzyme that can alter its activity.

Drug- transmembrane receptor protein complex binds and stimulates a second protein, such as a protein tyrosine kinase.

A tyrosine kinase enzyme promotes phosphorylation of proteins (at the aminoacid tyrosine site)

Drug binding to a transmembrane ion channel changes the ion channel conductance property--affecting membrane potential

Agonist drug binding to a transmembrane receptor causes stimulation of a GTP-binding signal transducer protein (G protein) -- leading to an increase in intracellular second messenger that results in many secondary intracellular responses.

Intracellular receptors:

lipid-soluble drugs, after crossing the cell membrane barrier, interact with intracellular receptors. Example:nitric oxide (NO)-- stimulates guanylyl cyclase, increasing cGMP levels

The agents below bind to DNA response elements that control transcription, including steroids, thyroid hormone, and retinoids

Drug (ligand)-regulated transmembrane enzymes (may involve receptor tyrosine kinases)

mediate signaling first step by:

insulin

epidermal growth factor (EGF)

platelet-derived growth factor (PDGF)

atrial natriuretc factor (ANF)

Cytokine receptors

activated by many diverse peptide ligands:

growth hormone

erythropoietin

some interferons

other growth and differentiation regulators

Ligand-gated Channels

Introduction: Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.

Introduction: Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.

Endogenous ligand include:

acetylcholine

gamma amino butyric acid (gaba, inhibitory action)

excitatory amino acids:

glycine

aspartate

glutamate

Receptor example: nicotinic acetylcholine receptor:

Activation:

acetylcholine binds

receptor channel opens

Na enters (down its concentration and electrical gradient)

depolarization occurs (EPSP)

Other multisubunit ligand-gated examples:

glutamate receptor

GABAA receptor

benzodiazepines (diazepam {Valium} enhance chloride conductance by allosteric modification of the GABAA receptor

glycine receptor

5-HT3 receptor

G proteins and Second Messengers

Second messenger effects:

increases in cAMP

Ca2+ concentration changes

phosphoinositides effects

Four steps:

drug binding

G protein activation (cytoplasmic side)

activity of effector (ion channel or enzyme) changed

intracellular second messenger concentration changes

cAMP: effector enzyme -- adenylyl cyclase, converting ATP to cAMP

Adenylyl cyclase activated by a G protein

G proteins may be activated by many neurotransmitters and hormones

Receptor desensitization:

The magnitude of receptors-mediated responses decrease with repeated drug administration.

Desensitization is often reversible.

Concentration-Response Relationship
Drug effect (assuming the drug acts reversibly with the receptor) is thought proportional to the number of occupied receptors.
Drug (D) + Receptor (R) Ť DR leads to Effect (equation 1)
Observed Drug Effect = (maximal drug effect ˇ [D]) / Kd + [D] (equation 2)
where [D] is the free drug concentration;
Kd is the dissociation constant for the drug-receptor (DR) complex
Equation 2 describes drug potency -- the dependency of drug effect on drug concentration
Drug antagonists bind either to the receptor itself or to some component of the effector mechanism to prevent the agonist action.
Antagonists themselves have no effect.
If the antagonist-mediated inhibition can be overcome by increasing agonist concentration ultimately reaching the same maximal effect, the antagonist is termed competitive.
Competitive inhibition is based on reversible binding at receptor sites.
With competitive inhibition, the dose-effect curve will be shifted to the right.
With competitive inhibition, the maximal drug effect will not be affected.
By contrast, a non-competitive antagonist will prevent the agonist from producing a maximal effect (and any agonist concentration)
If the antagonist binds at the active site and is a reversible antagonist, the inhibition will be competitive.
If the antagonist binds that the active site and is an irreversible antagonist, the inhibition will be noncompetitive

Ligand-gated Channels

Introduction:Many drugs mimic or block the action of normally occurring (endogenous) agents that effect ion conductance of membrane integrated ion channels.

Endogenous ligand include:
acetylcholine
gamma amino butyric acid (gaba, inhibitory action)
excitatory amino acids:
glycine
aspartate
glutamate
Receptor example: nicotinic acetylcholine receptor:
Activation:
acetylcholine binds
receptor channel opens
Na+ enters (down its concentration and electrical gradient)
depolarization occurs (EPSP)

G Protein Coupling

G-protein coupled receptors are involved in signal transduction for:

biogenic amines

eicosanoids

peptide hormones

G-Protein systems influence other important regulatory molecules, such as:

adenylyl cyclase (cAMP)

phospholipases A2, C and D.

Ca 2+, K+, Na+ channels

transport proteins

Second Messenger Systems: cAMP, Calcium & Phosphoinositides, cGMP

cAMP: intracellular second messenger

Hormone response mediator:

carbohydrate breakdown (liver)

triglyceride breakdown (fat cells)

conservation of water (renal -- vasopressin)

calcium homeostasis

cardiac chronotropic (rate) and inotropic (contractility) state

adrenal and sex steroids regulation (responding to corticotropin and follicle stimulating hormone)

smooth muscle relaxation

other endocrine/neural effects

Specificity:

due to the presence of different protein substrates, associated with different cell types:

Liver:

Fat cells

Smooth muscle

Termination of effect:

Proteins which were phosphorylated by cAMP dependent processes are dephosphorylated by the action of specific and nonspecific enzymes (phosphatases).

cAMP is degraded to 5'-AMP (inactive) by cyclic nucleotide phosphodiesterases.

some pharmacological effects of caffeine, theophylline, and other methylxanthines may be due to competitive inhibition of cAMP degradation

Calcium and Phosphoinositides

G protein or tyrosine kinase receptor linked

Central Steps:

stimulation of phospholipase C

subsequent cascade of steps results in:increased intracellular calcium enhances calcium binding to calmodulin

calmodulin regulates enzyme activities, including calcium-dependent protein kinases.

cGMP:

cGMP-based signal transduction may be more limited than cAMP-based systems.

Intestinal mucosa and vascular smooth muscle:

Vascular smooth muscle

Signaling mechanisms -- interrelationships:

activation of calcium-phosphoinositide and cAMP signaling systems may produce complementary or opposing results:

Opposition: vasopressor induced smooth muscle contraction: IP3-mediated increase in calcium; compounds that cause smooth muscle relaxation often do so by increasing cAMP concentration.

Complementary: cAMP and phosphoinositides second messenger systems act both to stimulate hepatic glucose release.

Nitric Oxide

Blood vessel endothelium is required for ACh-mediated smooth muscle relaxation.
The endothelial cell layer modulates vessel responsiveness to autonomic and hormonal influences.
Endothelial cell elaborate endothelium-derived relaxing factor (EDRF,NO) and a contracting factor.
Pharmacological actions of:
serotonin
histamine
bradykinin
purines
thrombin are mediated to some degree by stimulation of NO release.
EDRF is nitric oxide.
Endothelial-released nitric oxide:
diffuses into vascular smooth muscle
increases cGMP
facilitates vascular smooth muscle relaxation

Catecholamine Refractoriness

Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
Regulation of catecholamine responsiveness occurs at several levels: Receptors, G proteins, Adenylyl cyclase, and Cyclic nucleotide phosphodiesterase.

Characteristics of refractoriness depends on the nature and extent of involvement of the above components.