pharmacodynamics Flashcards by Carmina Mislang

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

pharmacodynamics

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Specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system

RECEPTORS

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Determine the quantitative relations between
dose or concentration of drug and
pharmacologic effects

RECEPTORS

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Selective in choosing a drug molecule to bind
to avoid constant activation by promiscuous
binding of many different molecules

RECEPTORS

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Changes its function upon binding in such a
way that the function of the biologic system
is altered in order to have pharmacologic
effect

RECEPTORS

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Selective in ligand-binding characteristics
(respond to proper chemical signals and
not to meaningless ones)
Mediate the actions of both pharmacologic
agonists and antagonists

RECEPTORS

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Majority are proteins which provide the
necessary diversity and specificity of
shape and electrical charge

RECEPTORS

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Specific binding region of the macromolecule

High and selective affinity to the drug molecule

RECEPTOR SITE/RECOGNITION SITE

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is the fundamental event that initiates the action

of the drug

Interaction between the drug and the receptor

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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

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

ENZYMES

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CLASSIFICATION OF RECEPTORS

Eg, Na+/K+ ATPase, the membrane receptor
for digitali

TRANSPORT PROTEINS

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CLASSIFICATION OF RECEPTORS

Eg, tubulin, the receptor for colchicine,
an anti-inflammatory drug

STRUCTURAL PROTEINS

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Molecules that translate the drug-receptor
interaction into a change in cellular activity
Eg, adenyl cyclase

EFFECTORS

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Response of a particular receptor-effector
system is measured against increasing
concentration of a drug
Graph of the response versus the drug
dose

GRADED DOSE-RESPONSE CURVE

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Sigmoid curve
Efficacy (Emax) and potency (EC50) are
derived from this curve
The smaller the EC
50, the greater the
potency of the drug

GRADED DOSE-RESPONSE 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 EC
50–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

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Measure of the affinity of a drug

for its binding site on the receptor

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Smaller KD

–greater affinity of drug to receptor

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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

COUPLING

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Maximal drug response is obtained at less
than maximal occupation of the receptors
Not qualitatively different from nonspare
receptors, not hidden or unavailable

SPARE RECEPTORS

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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

SPARE RECEPTORS

Compare concentration for 50% of maximal effect (EC50) with concentration for 50% maximal binding (KD) KD > EC50 with spare receptors

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

SPARE RECEPTORS

Non-regulatory molecules of the body Binding with these molecules will result to no detectable change in the function of the biologic system

INERT BINDING SITES

``` Buffers the concentration of the drug Bound drugs do not contribute directly to the concentration gradient that drives diffusion Eg, albumin ```

INERT BINDING SITES

Binds to the receptor and directly or indirectly bring about an effect Full activation of the effector system

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

PARTIAL AGONIST

Binds but do not activate the receptors | Blocks or competes with agonist

ANTAGONIST

CLASSIFICATION Competes with agonist receptor Binds to the receptor reversibly without activating the effector system

COMPETITIVE ANTAGONIST

CLASSIFICATION Antagonist increases the agonist concentration needed for a given degree of response Concentration-effect curve is shifted to higher doses (ie, horizontally to the right of the dose axis) Same maximal effect is reached

COMPETITIVE ANTAGONIST

CLASSIFICATION | Effects are overcomed by adding more agonist Increases the median effective dose ED50

COMPETITIVE ANTAGONIST

2 THERAPEUTIC IMPLICATIONS | produced by the competitive antagonist depends on the

(1) Degree of inhibition

2 THERAPEUTIC IMPLICATIONS concentration of antagonist (eg, propranolol) depends on the concentration of agonist that is competing for binding to the receptor

(2) Clinical response to a competitive antagonist

CLASSIFICATION Binds with the receptor via covalent bonds Antagonist’s affinity to the receptor maybe so high Receptor is not available to bind the agonist

IRREVERSIBLE ANTAGONIST

CLASSIFICATION Concentration-effect curve moves downward No shift of the curve in the dose axis Emax is not reached No increase in median effective dose (ED50) unless there are spare receptors

IRREVERSIBLE ANTAGONIST

CLASSIFICATION 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

IRREVERSIBLE 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 ```

CHEMICAL ANTAGONISM

Eg, protamine used to counteract the effect of heparin making it unavailable for interaction with proteins involved in the formation of blood

CHEMICAL ANTAGONISM

``` 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

5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS crossing the plasma membrane and acts on intracellular receptor (eg, steroids)

(1) Lipid soluble drug

5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS intracellular enzymatic activity is regulated by a ligand that binds to the protein’s extracellular domain

(2) Transmembrane receptor protein

5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS that binds and stimulates a protein tyrosine kinase (eg, insulin)

(3) Transmembrane receptor

``` 5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS which regulates the opening of the ion channel (eg, GABA, excitatory acetylcholine) ```

(4) Ligand-gated transmembrane ion | channel

5 BASIC TRANSMEMBRANE SIGNALING MECHANISMS is coupled with an effector enzyme by G protein which modulates production of an intracellular second messenger [eg, cathecolamine (epinephrine)]

(5) Transmembrane receptor

INTRACELLULAR 2ND MESSENGERS ``` Mediates hormonal responses Mobilization of stored energy (breakdown of carbohydrates in the liver stimulated by cathecolamines Conservation of water by the kidneys mediated by vasopressin ```

A. cAMP

INTRACELLULAR 2ND MESSENGERS Bind to receptors linked to G proteins while others bind to receptor tyrosine kinases

B. CALCIUM AND PHOSPHOINOSITIDES

INTRACELLULAR 2ND MESSENGERS Crucial step is the stimulation of membrane enzyme phospholipase C

B. CALCIUM AND PHOSPHOINOSITIDES

INTRACELLULAR 2ND MESSENGERS Few signaling roles in a few cell types like the intestinal mucosa and vascular smooth muscle cells

C. cGMP

INTRACELLULAR 2ND MESSENGERS Causes relaxation of vascular smooth muscles by a kinase-mediated mechanism

C. cGMP

Response gradually diminishes even if the drug is still there (after reaching an initial high level of response) Reason is not known

RECEPTOR DESENSITIZATION

STRUCTURE ACTIVITY RELATIONSHIP

Cells use more than one signaling mechanism | to respond to the drug

Graph of the fraction of a population that shows a specified response to increasing doses of a drug

QUANTAL DOSE-RESPONSE CURVE

Minimum dose required to produce a specific response is determined in each member of the population Sigmoid curve

QUANTAL DOSE-RESPONSE CURVE

Median effective dose 50% of the individuals manifested the desired therapeutic effect

ED50

Median toxic dose | 50% of the individuals manifested the toxic effects

TD50

Median lethal dose

LD50

Ratio of the TD 50 (or LD50 ) to the ED50 determined from the quantal dose-response curves Increased therapeutic index-wide margin of safety

THERAPEUTIC INDEX

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 Eg, ED50 of 3mg and the LD50 is 150 mg Therapeutic index is 50 (150/3)

THERAPEUTIC INDEX

``` 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 ```

THERAPEUTIC WINDOW

normal value MEC

7-10 mg/L (average of 8 mg/L)

normal value Therapeutic window

8-18 mg/L

normal value MTC

15-20 mg/L (average of 18 mg/L)

ex of therapeutic window

theophylline

``` 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 ```

MAXIMAL EFFICACY

Measured with a graded dose-response curve but not with quantal dose-response curve

MAXIMAL EFFICACY

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)

POTENCY

In the quantal dose-response curve, ED50, TD50, and LD50 are variables in 50% of the population

POTENCY

VARIATION OF RESPONSES IN INDIVIDUALS Caused by differences in metabolism (genetic) or immunologic mechanisms Response to the drug is unknown or unusual

IDIOSYNCRATIC RESPONSE

VARIATION OF RESPONSES IN INDIVIDUALS Intensity of the drug is decreased Large dose of the drug is needed to have an effect

HYPOREACTIVE RESPONSE

VARIATION OF RESPONSES IN INDIVIDUALS Intensity of the drug is increased or exaggerated

HYPEREACTIVE RESPONSE

VARIATION OF RESPONSES IN INDIVIDUALS Decreased sensitivity acquired as a result of exposure to the drug

TOLERANCE

VARIATION OF RESPONSES IN INDIVIDUALS Tolerance develops after a few doses

TACHYPHYLAXIS

VARIATIONS IN DRUG RESPONSIVENESS that reaches the receptor due to absorption, distribution and elimination differences

1. Alteration on the concentration of the drugq 2. Variation in the concentration of the endogenous 3. Alterations in number/function of receptors 4. Changes in 2nd messengers 5. Clinical selectivity

VARIATIONS IN DRUG RESPONSIVENESS ``` 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

VARIATIONS IN DRUG RESPONSIVENESS 3. Alterations in number/function of receptors Decrease in # of receptors

DOWN REGULATION

VARIATIONS IN DRUG RESPONSIVENESS 3. Alterations in number/function of receptors Increase in the # of receptors

UP REGULATION

WHAT TO DO TO AVOID/CIRCUMVENT | TOXIC EFFECTS

Give low doses Carefully monitor the patient Employ ancillary procedures

VARIATIONS IN DRUG RESPONSIVENESS Beneficial and toxic effects may be mediated by the same receptor-effector mechanism D + R DR X (beneficial/toxic)

5. Clinical selectivity

WHAT TO DO TO AVOID/CIRCUMVENT | TOXIC EFFECTS

Use a safer drug if possible Beneficial and toxic effects are mediated by identical receptors but in different ways

Low doses for prevention of blood clots Very high doses causes internal bleeding Monitor PT, PTT and bleeding parameters

HEPARIN

``` Give lowest dose possible Give adjunctive drugs Anatomic selectivity (lungs-by inhalation) ```

STEROIDS

pharmacodynamics Flashcards

(85 cards)