Flashcards in pharmacodynamics Deck (107):
1
drug interaction
1 + 1 = 2
Response elicited by combined drugs is equal to the combined response of the individual drugs
Sedative(chlorpheniramine maleate found in decongestants like Neozep + ethanol)
1. ADDITIVE
2
drug interaction
1 + 1 = 3
Response elicited by combined drugs is greater than the combined responses of each individual
Penicillin G (antibiotic) removes the cell wall of the organism
Gentamicin (aminoglycoside antibiotic) inhibits protein synthesis in the organism
2. SYNERGISTIC
3
drug interaction
0 + 1 = 2
Drug which has no effect enhances the effect of the second drug
Cimetidine + heparin (anticoagulant
(Cimetidine enhances the anticoagulation)
3. POTENTIATION
4
drug interaction
1 + 1 = 0
Drug inhibits the effect of another drug
Heparin + protamine
4. ANTAGONISM
5
study of detailed mechanism of action by which drug produce their pharmacologic effects
-provides a scientific basis for the selection and use of drugs
PHARMACODYNAMICS –
6
– specific cell molecules by which drugs interact to produce their effects
-most ligands (drugs or neurotransmitters) bind to protein molecules
-Determine the quantitative relations between dose or concentration of drug and pharmacologic effects
RECEPTORS
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– largest family of receptors for pharmaceutical agents
G protein-coupled receptors (GPCRs)
8
CLASSIFICATION OF RECEPTORS
• 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
1. REGULATORY PROTEIN
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CLASSIFICATION OF RECEPTORS
• Inhibited (or less commonly, activated) by binding a drug
• Eg, dihydrofolate reductase, the receptor for methotrexate
2. ENZYMES
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CLASSIFICATION OF RECEPTORS
• Eg, tubulin, the receptor for colchicine, an anti-inflammatory drug
4. STRUCTURAL PROTEINS
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CLASSIFICATION OF RECEPTORS
• Eg, Na+/K+ ATPase, the membrane receptor for digitalis
3. TRANSPORT PROTEINS
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• Specific binding region of the macromolecule
• High and selective affinity to the drug molecule
• Interaction between the drug and the receptor is the fundamental event that initiates the action of the drug
RECEPTOR SITE/RECOGNITION SITE
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• Same site as the endogenous ligand
• Drugs directly compete for the receptor site
ORTHOSTERIC SITE
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• Different site
• Alters the response of the endogenous ligand binding to the ligand-gated ion channel and increase or decrease the flow of ions
ALLOSTERIC SITE
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• 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, albumin
INERT BINDING SITES
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• Receptor-like proteins predicted from the human genome for which an endogenous ligand is not identified
• Target for the development of new drugs
ORPHAN RECEPTORS
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In most cases, drugs bind to their receptor by forming (what kinds of bonds) bonds with a receptor site.
hydrogen, ionic, or hydrophobic (van der Waals)
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• weak bonds
• reversible and enable the drug to dissociate from the receptor as the tissue concentration of the drug declines
HYDROGEN, IONIC, OR HYDROPHOBIC (VAN DER WAALS) BONDS
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• Drug must bind to one stereoisomer only
STEREOSPECIFICITY
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• A substance that can exist in the L or D form
• L may be the better drug
ENANTIOMER
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• Drug having both the L & D form; cannot be separated
• Patient will experience both the therapeutic and toxic effects.
RACEMIC MIXTURE
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• Binding is permanent, irreversible
• Prolonged duration of effect
COVALENT BOND
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The weaker the bond, the more _____ it becomes.
selective
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• Tendency of a drug to combine with its receptor is
• A measure of the strength of the drug-receptor complex
•
AFFINITY
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↑ affinity, __ binding
↓
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• Describes the pathway from ligand binding to conformational changes in the receptor, receptor interaction with an effector molecule (if present), and other downstream molecules called second messengers.
• This cascade of receptor-mediated biochemical events ultimately leads to a physiologic effect.
• Pathway for drug to enter the cell
SIGNAL TRANSDUCTION
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• Ability of a drug to initiate a cellular effect
• Efficacy is not directly related to receptor affinity and differs among various drugs that bind to a receptor and start the signal transduction pathway.
EFFICACY OR INTRINSIC ACTIVITY
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• Binds to the receptor and directly or indirectly bring about an effect
• Full activation of the effector system
•
• Both agonists and antagonists have common components sufficient for receptor affinity, but only agonists have the structure required for efficacy.
AGONIST
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Drugs that have both receptor affinity and efficacy
AGONIST
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Produce the maximal response obtainable in a tissue
FULL AGONISTS
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agonists with maximal efficacy
FULL AGONISTS
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agonists that Increase the rate of signal transduction when it binds to the receptor, whereas an inverse agonist
FULL AGONISTS
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• agonists that Produce only a submaximal response
PARTIAL AGONISTS
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agonists that Produces less than the full effect, even when it has saturated the receptors
PARTIAL AGONISTS
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agonists Acts as an inhibitor in the presence of a full agonist
PARTIAL AGONISTS
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• Also called negative antagonists
• Involved in a special type of drug-receptor interaction
• Decreases the rate of signal transduction
INVERSE AGONISTS
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• Binds but do not activate the receptors
• Blocks or competes with agonist
• Prevent the action of agonists and inverse agonists by occupying binding sites on the receptor.
ANTAGONIST
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• Response of a particular receptor-effector system is measured against increasing concentration of a drug
• Sigmoid curve
GRADED DOSE-RESPONSE CURVE
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• Efficacy (Emax) and potency (EC50) are derived from this curve
GRADED DOSE-RESPONSE CURVE
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• Graph of the response versus the drug dose
• Tells the EFFICACY of the drug
GRADED DOSE-RESPONSE CURVE
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• Maximal Efficacy
• Potency
PARAMETERS OF THE GRADED-DOSE CURVE
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• Maximal response that can be produced by a drug
• All receptors are occupied
• No response even if the dose is increased
Emax
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• Concentration of drug that produces 50%of maximal effect
• Smaller EC50–more potent
EC50
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• Total number of receptor sites
• All receptors have been occupied
Bmax
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• Equilibrium dissociation constant
• Concentration of drug required to bind 50%of the receptors
KD
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• Measure of the affinity of a drug for its binding site on the receptor
• Almost similar to EC50
KD
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• Smaller KD___ affinity of drug to receptor
- greater affinity of drug to receptor
48
type of antagonist
• 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
COMPETITIVE ANTAGONIST
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type of antagonist
Concentration-effect curve is shifted to higher doses (ie, horizontally to the right of the dose axis)
COMPETITIVE ANTAGONIST
50
type of antagonist
Same maximal effect is reached
COMPETITIVE ANTAGONIST
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type of antagonist
• Effects are overcome by adding more agonist
• Increases the median effective dose (ED50)
COMPETITIVE ANTAGONIST
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IRREVERSIBLE ANTAGONIST
type of antagonist
• Binds with the receptor via covalent bonds
• Eg, phenoxybenzamine binding with alpha receptors
IRREVERSIBLE ANTAGONIST
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type of antagonist
Antagonist’s affinity to the receptor maybe so high
• Receptor is not available to bind the agonist
IRREVERSIBLE ANTAGONIST
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type of antagonist
Concentration-effect curve moves downward
• No shift of the curve in the dose axis
IRREVERSIBLE ANTAGONIST
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type of antagonist
Emax is not reached
• No increase in median effective dose (ED50) unless there are spare receptors
IRREVERSIBLE ANTAGONIST
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type of antagonist
Duration of action is relatively independent of its own rate of elimination
• More dependent on the rate of turnover of receptors
IRREVERSIBLE ANTAGONIST
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type of 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
CHEMICAL ANTAGONISM
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type of 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
PHYSIOLOGIC ANTAGONISM
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Response gradually diminishes even if the drug is still there (after reaching an initial high level of response)
Reason is not known
RECEPTOR DESENSITIZATION
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• Graph of the fraction of a population that shows a specified response to increasing doses of a drug
• Minimum dose (not right to check for Emax in humans because of its toxic effects) required to produce a specific response is determined in each member of the population
• Sigmoid curve
• Involves human population
QUANTAL DOSE-RESPONSE CURVE
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• Median effective dose
• 50%of the individuals manifested the desired therapeutic effect
ED50
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• Median toxic dose
• 50%of the individuals manifested the Toxic effects
TD50
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• Median lethal dose
LD50
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• Ratio of the TD50 (or LD50 ) to theED50 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
THERAPEUTIC INDEX
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• 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 than therapeutic index
THERAPEUTIC WINDOW
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• Measured with a graded dose-response curve but not with quantal dose-response curve
MAXIMAL EFFICACY
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• 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 LD50are variables in 50%of the population
POTENCY
68
• Short-term effect of agonist exposure
DESENSITIZATION OR TACHYPHYLAXIS
69
In contrast, continuous or repeated exposure to antagonists initially can increase the response of the receptor, called
supersensitivity.
70
Through internalization and regulation of the receptor gene, the number of receptors on the cell membrane decreases.
This longer-term adaptation is called
down-regulation.
71
With chronic exposure to antagonists, the number of receptors on the membrane surface (density) increases via
up-regulation.
72
VARIATION OF RESPONSES IN INDIVIDUALS
• Caused by differences in metabolism (genetic) or immunologic mechanisms
• Response to the drug is unknown or unusual
1. IDIOSYNCRATIC RESPONSE
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VARIATION OF RESPONSES IN INDIVIDUALS
• Intensity of the drug is decreased
• Large dose of the drug is needed to have an effect
2. HYPOREACTIVE RESPONSE
74
VARIATION OF RESPONSES IN INDIVIDUALS
• Intensity of the drug is increased or exaggerated
3. HYPEREACTIVE RESPONSE
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VARIATION OF RESPONSES IN INDIVIDUALS
• Decreased sensitivity acquired as a result of exposure to the drug
4. TOLERANCE
76
VARIATION OF RESPONSES IN INDIVIDUALS
IDIOSYNCRATIC
HYPOREACTIVE
HYPEREACTIVE
TOLERANCE
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• Tolerance develops after a few doses
TACHYPHYLAXIS
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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
4. Changes in 2ndmessengers
5. Clinical selectivity
79
Decrease in # of receptors
DOWN REGULATION
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Increase in the # of receptors
UP REGULATION
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Drug has been taken for a long time, then abruptly discontinued
Eg, propranolol (beta-blocker)
Gradual decrease of taking the drug by decreasing/tapering the dose
OVERSHOOT PHENOMENON/ REBOUND HYPERTENSION
81
No drug causes a single specific effect only. True or false?
True
82
A molecule to which a drug binds to bring about a change in function of the biologic system
Receptor
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Drugs are selective but never ____
Specific
83
A molecule to which a drug may bind without changing any function
Inert binding molecule or site
83
Beneficial and toxic effects may be mediated by the same receptor-effector mechanism (because drugs are never specific)
REMEMBER THAT
84
The maximal effect that can be achieved with a particular drug, regardless of dose
Efficacy, maximal efficacy
85
The concentration of drug that binds 50% of the receptors in the system
Kd
86
In graded dose-response curves, the concentration or dose that causes 50% of the maximal
effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a
specified response in 50% of the population under study
EC50, ED50, TD50, etc
87
A graph of the fraction of a population that shows a specified response at progressively
increasing doses
Quantal dose-response curve
88
A graph of increasing response to increasing drug concentration or dose
Graded dose-response curve
89
Specific region of the receptor molecule to which the drug binds
Receptor site
90
A drug that binds to the inactive state of receptor molecules and decreases constitutive
activity (see text)
Inverse agonist
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A drug that binds to its receptor but produces a smaller effect at full dosage
than a full agonist
Partial agonist
92
antagonist A drug that binds to a receptor molecule without interfering with normal agonist binding
but alters the response to the normal agonist
Allosteric agonist
93
A drug that counters the effects of another by binding the agonist drug (not the receptor)
Chemical antagonist
94
A drug that counters the effects of another by binding to a different receptor and causing
opposing effects
Physiologic antagonist
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Receptor that does not bind drug when the drug concentration is sufficient to produce
maximal effect; present when Kd > EC50
Spare receptor
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A pharmacologic antagonist that cannot be overcome by increasing agonist concentration
Irreversible antagonist
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A pharmacologic antagonist that can be overcome by increasing the concentration
of agonist
Competitive antagonist
98
A drug that binds without activating its receptor and thereby prevents activation
by an agonist
Pharmacologic antagonist
99
A drug that activates its receptor upon binding
Agonist
100
Component of a system that accomplishes the biologic effect after the receptor is activated
by an agonist; often a channel or enzyme molecule, may be part of the receptor molecule
Effector
103
Type of antagonisn between protamine and heparin
Chemical
104
Type of antagonism between phenoxybenzamine and alpha receptors
Irreversible
105
Type of antagonism between glucocorticoids and insulin
Physiologic
106