pharmacodynamics reviewer
DESCRIPTION
compilation of powerpoint presentation notes from pharmacodynamics discussionTRANSCRIPT
DRUG RECEPTORS AND PHARMACODYNAMICS
Pharmacodynamics Actions/effects of the drug on the body Determines the group in which the drug is
classified and plays a major role in deciding whether a group is appropriate therapy for particular symptom or disease
Receptors Specific molecules in a biologic system
with which drugs interact to produce changes in the function of the system
Determine the quantitative relations between dose or concentration of drug and pharmacologic effects
Selective in choosing a drug molecule to bind to avoid constant activation by promiscuous binding of many different molecules
Changes its function upon bidning in such a way that the function of the biologic system is altered in order to have pharmacologic effect
Selectiv in ligand-binding characteristics (respond to proper chemical signals and not to meaningless ones)
Mediate the actions of both pharmacologic agonists and antagonists
Majority are proteins which provide the necessary diversity and specificity of shape and electrical charge
Interaction between the drug and the receptor is the fundamental event that initiates the action of a drug
Receptor Site/Recognition Site - Specific binding region of the
macromolecule- High and selective affinity to the drug
molecule Classification of Receptors
A. Regulatory Protein- Best characterized drug receptors- Mediates the action of endogenous
chemical signals like neurotransmitters, autacoids and hormones
- Mediates the effects of the most useful therapeutic agents
B. Enzymes- Inhibited (or less commonly, activated) by
binding a drug- Eg, dihydrofolate reductase, the receptor
for methotrexate C. Transport Proteins- Eg, Na+/K+ ATPase, the membrane
receptor for digitalis
D. Structural Proteins- Eg, tubulin, the receptor for colchicine, an
anti-inflammatory drugEffectors
Molecules that translate the drug-receptor interaction into a change in cellular activity
Eg, adenyl cyclase Some receptors are also effectors A single molecule may incorporate both
the drug binding site and the effector mechanism
Drug Concentration and ResponseGraded Dose-Response Curve
Response of a particular receptor-effector system is measured against increasing concentration of a drug
Graph of the response versus the drug dose
Sigmoid curve Efficacy (Emax) and potency (EC50) are
derived from this curve The smaller the EC50, the greater the
potency of the drugEmax
Maximal response that can be produced by a drug
All receptors are occupied No response even if the dose is increased
EC50 Concentration of drug that produces 50%
of maximal effect Smaller EC50 – more potent
Bmax Total number of receptor sites All receptors have been occupied
Kd Equilibrium dissociation constant Concentration of drug required to bind
50% of the receptors
DRUG RECEPTORS AND PHARMACODYNAMICS
Measure of the affinity of a drug for its binding site on the receptor
Smaller Kd – greater affinity of drug to receptor
Curve A Agonist Response in the absence of
antagonistCurve B
After treatment with low concentration of antagonist, the curve is shifted to the right
Maximal response is preserved because the remaining available receptors are still in excess
Curve C Produced after larger concentration of
antagonist, the available receptors are no longer “spare”, sufficient enough to mediate an undiminished maximal response
Curve D and E With higher concentrations of antagonist,
reduce the number of available receptors to the point that maximal response is diminished
EC50 may approximate the Kd that characterizes the binding affinity of the agonist for the receptor
Coupling Transduction process between the
occupancy of receptors and production of specific effect
Highly efficient coupling can be elicited by a full agonist and spare receptors
Spare Receptors Maximal drug response is obtained at less
than maximal occupation of the receptors Not qualitatively different from nonspare
receptors, not hidden or unavailable Temporal in character, when occupied,
they can be coupled to respond, there is still effect
Drugs with low binding affinity for receptors will be able to produce full response even at low concentration
Compare concentration for 50% of maximal effect (EC50 with concentration for 50% maximal binding Kd)
Kd > EC50 with spare receptors Effect of the drug-receptor interaction may
persist for a longer time than the interaction itself
Actual number of receptors may exceed the number of effectors available
Inert Binding Sites Non-regulatory molecules of the body Binding with these molecules will result to
no detectable change in the function of the biologic system
Buffers the concentration of the drug Bound drugs do not contribute directly to
the concentration gradient that drives diffusion
Eg, albuminAgonist
Binds to the receptor and directly or indirectly bring about an effect
Full activation of the effector system Partial Agonist
Produces less than the full effect, even when it has saturated the receptors
Acts as an inhibitor in the presence of a full agonist
Antagonist Binds but do not activate the receptors Blocks or competes with agonist
Classification of AntagonistA. Competitive Antagonist
DRUG RECEPTORS AND PHARMACODYNAMICS
- Competes with agonist receptor- Binds to the receptor reversibly without
activating the effector system - Antagonist increases the agonist
concentration needed for a given degree of response
- Concentration-effect curve is shifted to higher doses (eg, horizontally to the right of the dose axis)
- Same maximal effect is reached - Effects are overcome by adding more
agonist- Increases the median effective dose
(ED50)
- 2 Therapeutic Implications 1) Degree of inhibition produced by
the competitive antagonist depends on the concentration of antagonist (eg, propanolol)
2) Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to the receptor
B. Irreversible Antagonist- Binds with the receptor via covalent bonds- Antagonist’s affinity to the receptor maybe
so high- Receptor is not available to bind the
agonist- Concentration-effect curve moves
downward - No shift of the cruve in the dose axis- Emax is not reached- No increase in median effective dose
(ED50) unless there are spare receptors - Duration of action is relatively independent
of its own rate of elimination- More dependent on the rate of turnover of
receptors
- Eg, phenoxybenzamine binding with alpha
receptors
C. Chemical Antagonist- Does not depend on interaction with the
agonist’s receptor- Drug that interacts directly with the drug
being antagonized to remove it or to prevent it from reaching its target
- Eg, protamine used to counteract the effect of heparin making it unavailable for interaction with proteins involved in the formation of blood
D. Physiologic Antagonist - Makes use of the regulatory pathway- Effects that are less specific and less easy
to control- Binds to a different receptor producing an
effect opposite to that produced by the drug it is antagonizing
- Examples o Glucocorticoids catabolic effects of
increase in sugar is physiologically opposed by insulin
o Histamine causes bronchoconstriction in asthmatic patients, opposed by bronchodilators like salbutamol and epinephrine
Signalling MechanismsA. Lipid soluble drugB. Transmembrane receptor-protein
intracellular enzymatic activity is regulated by a ligand that binds to the protein’s extracellular domain
C. Transmembrane receptor that binds and stimulates a protein tyrosine kinase (eg, insulin)
D. Ligand-gated transmembrane ion channel which regulates the opening of the ion
DRUG RECEPTORS AND PHARMACODYNAMICS
channel (eg, GABA, excitatory acetylcholine)
E. Transmembrane receptor is coupled with an effector enzyme by G protein which modulates production of an intracellular second messenger (eg, cathecolamine (epinephrine))
Intracellular 2nd MessengersA. cAMP- Mediates hormonal responses
o Mobilization of stored energy (breakdown of carbohydrates in the liver stimulated by cathecolamines)
o Conservation of water by the kidneys mediated by vasopressin
o Calcium homeostasis by parathyroid hormone
o Heart rate and contraction by beta-adrenomimetic cathecolamines
B. Calcium and Phosphoinositides - Bind to receptors linked to G proteins
while others bind to receptor tyrosine kinases
- Crucial step is the stimulation of membrane enzyme phospholipase C
C. cGMP- Few signalling roles in a few cell types like
the intestinal mucosa and vascular smooth muscle cells
- Causes relaxation of vascular smooth muscles by a kinase-mediated mechanism
Receptor Desensitization Response gradually diminishes even if the
drug is still there (after reaching an initial high level of response)
Reason is not known Structure Activity Relationship
Cells use more than one signalling mechanism to respond to the drug
Quantal Dose-Response Curve Graph of the fraction of a population that
shows a specified response to increasing doses of a drug
Minimum dose required to produce a specific response is determined in each member of the population
Sigmoid curve ED50
Median effective dose 50% of the individuals manifested the
desired therapeutic effect TD50
Median toxic dose
50% of the individuals manifested the toxic effects
LD50 Median lethal dose
Therapeutic Index Ratio of the TD50 (or LD50) to the ED50
determined from the quantal dose-response curves
Increased therapeutic index – wide margin of safety
Represents an estimate of the safety of the drug
A very safe drug might be expected to have a very large toxic dose and a much smaller effective dose
o Eg, ED50 of 3 mg and the LD50 is 150 mg
o Therapeutic index is 50 (150/3) Therapeutic Window
Dosage range between the minimum effective therapeutic concentration or dose (MEC) and the minimum toxic concentration or dose (MTC)
More clinically relevant index of safety Eg, theophylline
o MEC = 7-10 mg/L (average of 8 mg/L)
o MTC = 15-20 mg/L (average of 18 mg/L)
o Therapeutic window = 8-18 mg/LMaximal Efficacy
Maximal effect (Emax) an agonist can produce if the dose is taken to very high levels
Determined mainly by the nature of receptors and its associated effectors
Measured with a graded dose-reponse curve but not with quantal dose-response curve
Potency Amount of drug needed to produce a given
effect In the graded dose-response curve, the
effect chosen is the 50% of the maximal effect and the dose is (EC50)
In the quantal dose-response curve, ED50, TD50, and LD50 are variables in 50% of the population
Drug B is the most potent
DRUG RECEPTORS AND PHARMACODYNAMICS
Drugs A, C, and D have equal maximal efficacy and greater maximal efficacy than Drug B
Variation of Reponses in IndividualsA. Idiosyncratic Response- Caused by differences in metabolism
(genetic) or immunologic mechanisms- Response to the drug is unknown or
unusual B. Hyporeactive Response - Intensity of the drug is decreased- Large dose of the drug is needed to have
an effect C. Hypereactive Response - Intensity of the drug is increased or
exaggerated D. Tolerance- Decreased sensitivity acquired as a result
of exposure to the drug E. Tachyphylaxis - Tolerance develops after a few doses
Variations in Drug Responsiveness 1. Alteration on the concentration of the drug
that reaches the receptor due to absorption, distribution and elimination differences
2. Variation in the concentration of the endogenous ligands (chemicals produced by the body that binds to receptors, eg, cathecolamines)
3. Alterations in number/function of receptors- Down regulation : decrease in # of
receptors- Up regulation : increase in the # of
receptors - Overshoot Phenomenon/Rebound
Hypertension o Drug has been taken for a long
time, then abruptly discontinued
o Eg, propanolol (beta-blocker)o Gradual decrease of taking the
drug by decreasing/tapering the dose
4. Changes in 2nd messengers5. Clinical selectivity - Give the drug that really acts on the
disease- No drug causes a single specific
effect only, they are selective but never specific
- Beneficial and toxic effects may be mediated by the same receptor-effector mechanism
What to Do to Avoid/Circumvent Toxic Effects Give low doses Carefully monitor the patient Employ ancillary procedures Use a safer drug if possible Beneficial and toxic effects are mediated
by identical receptors but in different ways o Heparin
Low doses for prevention of blood clots
Very high doses causes internal bleeding
Monitor PT, PTT and bleeding parameters
o Steroids Give lowest dose possible Give adjunctive drugs Anatomic selectivity (lungs-
by inhalation)o Antihistamines
H1 receptors – H1 blocker H2 receptors – H2 blocker