2004-2005. module 2 # 1 pharmacodynamics kash desai 966-2723 hsc a120 [email protected]
TRANSCRIPT
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Drug Receptors and Pharmacodynamics(how drugs work on the body)
The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.
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Pharmacodynamics(how drugs work on the body)
many drugs inhibit enzymesEnzymes control a number of metabolic processes A very common mode of action of many drugs
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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Pharmacodynamics
most drugs act (bind) on receptors
in or on cells
form tight bonds with the ligand
exacting requirements (size, shape, stereospecificity)
can be agonists (salbutamol), or antagonists (propranolol)
receptors have signal transduction methods
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Drug Receptor
• A macromolecular component of a cell with which a drug interacts to produce a response
• Usually a protein
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Types of Protein Receptors
1. Regulatory – change the activity of cellular enzymes
2. Enzymes – may be inhibited or activated
3. Transport – e.g. Na+ /K+ ATP’ase 4. Structural – these form cell parts
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dose response curves
[D] + [R] [DR] effect
k 1
k -1
at equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k1/k-1 = affinity const.
k-1/k1 = dissociation const.(kd)
the lower the kd the more potent the drug
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D + R DR Complex
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 Binding
Affinity
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Drug Receptor Interaction
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
DR Complex Effect
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0.00 0.25 0.50 0.75 1.00
Per
cent M
axim
um
0
25
50
75
100
Isolated Muscle Contraction
Arithmetic Scale
Dose (ug/ml)
Where:
D = drug concentration
DR= concentration of drug-receptor complex
100 - DR = free receptor concentration
Drug + Free Receptor Drug-receptor ComplexD (100 - DR)
k1
k-1 DR
Drug-receptor interaction
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Drug-receptor interaction
• At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k-1/k1 = dissociation constant (kd)
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What can we learn?
• Ke (k1/k-1) is called the affinity constant
• DR is the response; D is concentration of drug
• when DR = 50 percent (effect is half maximal), D (or EC50) is equal to kd or the reciprocal of the affinity constant
• response is a measure of efficacy
• drugs that have parallel dose-response curves often have the same mechanism of action
• At equilibrium:
[D] x [R] x k1 = [DR] x k-1
so that: [DR] = k1
[D] [R] k-1
k-1/k1 = dissociation constant (kd)
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dose response curves-2
effect = [DR] = Emax * [D]/([D]+EC50)
% occupancy
Concept: spare receptors
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Arithmetic Dose Scale
• Rate of change is rapid at first and becomes
progressively smaller as the dose is increased
• Eventually, increments in dose produce no
further change in effect i.e., maximal effect for
that drug is obtained
• Difficult to analyze mathematically
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Log Dose Scale
• transforms hyperbolic curve to a sigmoid (almost a straight line)
• compresses dose scale
• proportionate doses occur at equal intervals
• straightens line
• easier to analyze mathematically
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5.28 5.40 5.52 5.64 5.76 5.88 6.00
Num
ber
Res
pondin
g
0
10
20
30
Ethyl Alcohol: Sleep
0.10.31 3 100
10
20
30
40
50
L-NAMEControl
Acetylcholine nmol/kg
% fa
ll in
blo
odpr
essu
re
-2 -1 0 1 20
10
20
30
40
50
L-NAME
Acetylcholine nmol/kg
Control
0.1 0.3 1 3 10
% fa
ll in
blo
od p
ress
ure
Arithmetic vs log scale of dose
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Potency
Relative position of the dose-effect curve along the dose axisHas little clinical significance for a given therapeutic effectA more potent of two drugs is not clinically superiorLow potency is a disadvantage only if the dose is so large that it is awkward to administer
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Analgesia
Dose
hydromorphone
morphine
codeine
aspirin
Relative Potency
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Why are there spare receptors?
allow maximal response without total receptor occupancy – increase sensitivity of the system
spare receptors can bind (and internalize) extra ligand preventing an exaggerated response if too much ligand is present
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The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC50=kd. Sometimes, full effect is seen at a fractional receptor occupation
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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
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Agonist Drugs
• drugs that interact with and activate receptors; they possess both affinity and efficacy
• two types
– Full – an agonist with maximal efficacy
– Partial – an agonist with less then maximal efficacy
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Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves
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Antagonist Drug
• Antagonists interact with the receptor but do NOT change the receptor
• they have affinity but NO efficacy
• two types– Competitive
– Noncompetitive
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Competitive Antagonist
• competes with agonist for receptor
• surmountable with increasing agonist concentration
• displaces agonist dose response curve to the right (dextral shift)
• reduces the apparent affinity of the agonist i.e., increases 1/Ke
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Noncompetitive Antagonist
• drug binds to receptor and stays bound
• irreversible – does not let go of receptor
• produces slight dextral shift in the agonist DR curve in the low concentration range
• this looks like competitive antagonist
• but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect
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Desensitization
agonists tend to desensitize receptors
homologous (decreased receptor number)
heterologous (decreased signal transduction)
antagonists tend to up regulate receptors
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dose response curves-3quantal dose response curves (used in populations, response
is yes/no)
Therapeutic index =Toxic Dose50/Effective Dose50 (TD50/ED50)
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DR Curve: Whole Animal
• Graded – response measured on a continuous scale
• Quantal – response is an either/or event– relates dose and frequency of response in
a population of individuals
– often derived from frequency distribution of doses required to produce a specified effect
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Effectiveness, toxicity, lethality
• ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves
• TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect
• LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects
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Quantification of drug safety
Therapeutic Index = TD50 or LD50
ED50
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dose
Drug A
sleepdeath
100
50
0ED50 LD50
PercentResponding
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dose
Drug B
sleepdeath
100
50
0ED50 LD50
PercentResponding
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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)
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Signal transduction
1. enzyme linked(multiple actions)
2. ion channel linked(speedy)
3. G protein linked(amplifier)
4. nuclear (gene) linked(long lasting)
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1. G protein-linked receptorsStructure:
•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).
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2. Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding site
•An intracellular tail with a number of tyrosines and a single å helix spanning the membrane
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3. Ion channel receptors
Structure:
•Protein pores in the plasma membrane
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Intracellular receptors
Not all signal receptors are located on the plasma membrane.
Some are proteins located in the cytoplasm or nucleus of
target cells.
• The signal molecule must be able to pass through
plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone)
and thyroid hormones of animals).
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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:
1. Cycle AMP
2. Calcium ions Ca2+
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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
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Summary
most drugs act through receptors there are 4 common signal transduction methods the interaction between drug and receptor can be described
mathematically and graphically agonists have both affinity (kd) and intrinsic activity () antagonists have affinity only antagonists can be competitive (change kd) or non-competitive (change ) when mixed with agonists agonists desensitize receptors. antagonists sensitize receptors.
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