Pharmacology Basics

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Transmembrane receptors with enzymatic cytosolic domains: types

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Tyrosine Kinase
Tyrosine Phosphatases
Tyrosine Kinase-associated
Serine/Threnoine Kinases
Guanylyl Cyclases

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Transmembrane receptors with enzymatic cytosolic domains: examples

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insulin
epidermal growth factor
platelet-derived growth factor
atrial natriuretic factor
transforming growth factor-P

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enzymatic cytosolic domains

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cross-phosphorylation occurs resulting in downstream signaling (kinases)
ligand binding results in endocytosis of receptor; new receptors for via de novo synthesis

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phosphorylation

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almost all second messager systems involve reversible phosphorylation, which performs two principal functions in signaling: amplification and flexible regulation.

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median effective dose

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ED50

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median toxic dose

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(TD50)

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median lethal dose

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(LD50)

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relates the dose of a drug required to produce a desired effect to that which produces an undesired effect

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therapeutic index

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the ratio of the TD50 to the ED50 for some therapeutically relevant effect

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therapeutic index

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dihydrofolate reductase

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example of enzyme receptor:
antineoplastic drug methotrexate

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transport proteins

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Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides

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structural proteins

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tubulin, the receptor for colchicine, an anti-inflammatory agent

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Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, γ-aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate). All of these agents are synaptic transmitters.

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Ligand-Gated Channels

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transmembrane receptors: examples

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growth hormone
erythropoietin
interferons
other growth and differentiation regulators

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transmembrane ion channels

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allow passage of ions and other hydrophilic molecules across plasma membrane

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transmembrane ion channels: functions

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neurotransmission, cardiac conduction, muscle contraction

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transmembrane ion channels: types

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1-ligand gated, where binding of ligand to channel causes altered ion conductance
2-voltage-gated, where change in transmembrane voltage gradient causes altered ion conductance

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transmembrane ion channels, ligand-gated: examples

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synaptic transmitters: acetylcholine, GABA, EAAs (excitatory amino acids: glycine, aspartate, glutamate)

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nicotinic acetylcholine receptor can be in closed or open state

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in closed state, the channel is occluded by amino acid side chains; in the open state, binding of 2 ACh molecules causes a conformation change that opens the channel

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the maximal response that can be produced by a drug

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Emax

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Transmembrane ion channels

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allow passage of ions and other hydrophilic molecules across the plasma membrane; can be closed, open, refractory, inactive

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Transmembrane ion channels: functions

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neruotransmission, cardiac conduction, muscle contraction

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ligand-gated transmembrane ion channel domains

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extracellular, within the channel or intracellular

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voltage-gated transmembrane ion channel states

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closed, open or inactivated
ex. block by local anesthetics

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Transmembrane G Protein Coupled Receptors

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-most abundant class
-receptors transverse the membrane and have intracellular domains that interact with G proteins

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Transmembrane G Protein Coupled Receptors: site

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extracellular surface of cell membrane

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G proteins & second messengers

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different ligand are associated with different second messenger system; G protein coupled signaling is involved in many processes

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cAMP protein and effector element

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G8; adenyl cyclase (converts ATP to cAMP)

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G proteins & second messengers: first component

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extracellual ligand couples with cell surface receptor

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G proteins & second messengers: second component

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activation of G protein

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G proteins & second messengers: third component

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changes the activity of an effector element, usually an enzyme or ion channel

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G proteins: function

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increase (amplifies signal) cellular second messengers such as cAMP, calcium or phosphoinositides

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Intracellular second messengers

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cyclic adenosine monophosphate or cAMP; calcuim and phosphoinositides; cyclic guanosine monophosphate (cGMP); kinases

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receptor-less drugs

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antacids, laxative, chelating agents, osmotic diuretics

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types of receptor regulation

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receptor desensitization; down regulation; up-regulation

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recptor down regulation

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produced by agonist-induced decreases in receptor biosynthesis and increases in receptor internalizaion and degradation, usually occurs over hours to days

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Kd

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point where 50% of receptors are bound

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Emax

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maxium effect or efficacy of a drug

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EC50 or ED50

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concentration or dose required to produce 50% of the maximum effect

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potency

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concentration of a drug required to produce 50% of that drug's maximal effect (EC50)

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potency depends on

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the affinity (Kd) of receptors for binding the drug and the efficiency with which drug-receptor interaction is coupled to response

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agonists

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act on receptors to promote the biological response; result is hyperbolic curve on a linear scale

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used to get a graded dose-response curve that is a sigmoid curve with a linear midsection that can be more easily analyzed

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log concentration of a drug

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spare receptors

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exist when the maximal response can be elicited when fewer than 100% of the drug's receptors are occupied

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spare receptors: how determined

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graded dose response curve in which the dose producing the EC50 is less than the dose for Kd50

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Kd (point where 50% of receptors are bound)

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relationship between bound and free drug concentration; if Kd is low, binding affinity is high; if Kd is high, binding affinity is low

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spare receptors: mechanisms

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-when the effect of the drug-receptor interaction persists for a much longer time than the interaction itself
-when the actual number of recptors exceed the number of effector molecules available

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quantal dose-response curves

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percentage or frequency of (all or nothing) patient responses plotted against the log dose of the drug

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quantal dose-effect curves

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dose of drug rquired to produce a specified magnitude of effect

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Efficacy (Emax) is measured how?

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With a graded does-response curve, NOT a quantal dose-response curve

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Quantal dose-response measures of potency: ED50

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median effective dose

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Quantal dose-response measures of potency: TD50

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toxic dose

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Quantal dose-response measures of potency: LD50

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lethal dose

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Therapeutic Index (TI)

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Ratio of TD50 or LD50 to the ED50 determined from quantal-dose response curves

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Therapeutic Index (TI)

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-an estimate (ppor) of the safety of a drug
-a safe drug is one that has a small effective dose while requiring a very large dose to elicit a toxic response

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Therapeutic window

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the dosage range between the minimum effective therapeutic concentration (threshold) and the minium toxic concentration (dose)

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Therapeutic window

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-clinically relevant index of saftey

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Certain Safety Factor (CSF)

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-the ratio between the dose that is lethal in 1% of the subjects (LD1) and the dose that produces a therapeutic effect in 99% of the subjects (ED99)

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Clinical effectiveness of a drug depends on

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potency (ED50)
maximal efficacy
ability to reach the relevant receptors (site of action)
pharmacokinetics