QUIZLET Unit 2 - Drug Receptors and Pharmacodynamics (2) Flashcards
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- 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 an appropriate therapy for a particular symptom or disease.
Pharmacodynamics
- 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 binding in such a way that the function of the biologic system is altered in order to have pharmacologic effect.
- Selective in ligand-binding characteristics (respond to proper chemical signals) and not to meaningless ones.
Receptors
- Mediate the actions of both pharmacologic agonists and antagonists.
- Majority are proteins which provide the necessary diversity and specificity of shape and electrical charge.
RECEPTORS
Interaction between the ____and the _______
is the fundamental event that initiates the action of the drug.
drug and the receptor
- Regulatory Proteins
- Enzymes
- Transport Proteins
- Structural Proteins
CLASSIFICATION OF RECEPTORS
o Best characterized drug receptors
o Mediates the action of endogenous chemical signals like
neurotransmitters, autacoids, and hormones.
o Mediates the effects of the most useful therapeutic agents.
Regulatory Proteins
o Inhibited (or less commonly, activated) by binding a drug.
o E.g., dihydrofolate reductase, the receptor for methotrexate.
Enzymes
What to do to avoid/circumvent toxic effects?
o Give low doses
o Carefully monitor the patient
o Employ ancillary procedures
o Use a safer drug
Transport Proteins examples
Na+/K+ ATPase, the membrane receptor for digitalis.
Structural Proteins Examples
tubulin, the receptor for colchicine, an anti-inflammatory drug
- Molecules that translate the drug-receptor interaction into a change in cellular activity.
o E.g., adenyl cyclase
- Some receptors are also effectors.
- A single molecule may incorporate both the drug binding site and the effector mechanism.
Effectors
Known transmembrane signaling mechanisms:
1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may be an
enzyme or a regulator of gene transcription);
2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain;
3: the signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates;
4: the signal binds to and directly regulates the opening of an ion channel;
5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A, C, substrates; B,
D, products; R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.)
SIGNALING MECHANISMS
There are the 5 basic transmembrane signaling mechanisms T/F
T
Name 5 basic transmembrane signaling mechanisms
- Lipid-soluble drug crossing the plasma membrane and acts on intracellular receptor (e.g., steroids).
- Transmembrane receptor protein – intracellular enzymatic activity is regulated by a ligand that binds to the protein’s extracellular domain.
- Transmembrane receptor that binds and stimulates a protein tyrosine kinase (e.g., insulin).
- Ligand-gated transmembrane ion channel which regulates the opening of the ion channel (e.g., GABA, excitatory acetylcholine).
- embrane receptor is coupled with an effector enzyme by G protein which modulates production of an intracellular second
messenger [e.g., catecholamine (epinephrine)].
3 intracellular 2nd messengers
- cAMP (CYCLIC ADENOSINE MONOPHOSPHATE)
- CALCIUM AND PHOSPHOINOSITIDES
- cGMP (CYCLIC GUANOSINE MONOPHOSPHATE)
- Mediates hormonal responses
o Mobilization of stored energy (breakdown of carbohydrates in the liver stimulated by catecholamines.
o Conservation of water by the kidneys mediated by vasopressin.
o Calcium homeostasis by parathyroid hormone.
o Heart rate and contraction by beta-adrenomimetic
catecholamine.
- It also regulates the production of adrenal and sex steroids (in response to corticotropin or follicle-stimulating hormone), relaxation of smooth
muscle, and many other endocrine and neural processes.
a. cAMP (CYCLIC ADENOSINE MONOPHOSPHATE)
b. CALCIUM AND PHOSPHOINOSITIDES
c. cGMP (CYCLIC GUANOSINE MONOPHOSPHATE)
A. cAMP (CYCLIC ADENOSINE MONOPHOSPHATE
- Bind to receptors linked to G proteins while others bind to receptor tyrosine kinases.
- Crucial step is the stimulation of membrane enzyme phospholipase C.
a. cAMP (CYCLIC ADENOSINE MONOPHOSPHATE)
b. CALCIUM AND PHOSPHOINOSITIDES
c. cGMP (CYCLIC GUANOSINE MONOPHOSPHATE)
b. CALCIUM AND PHOSPHOINOSITIDES
- Few signaling 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.
- Unlike cAMP, the ubiquitous and versatile carrier of diverse messages, cGMP has established signaling roles in only a few cell types.
a. cAMP (CYCLIC ADENOSINE MONOPHOSPHATE)
b. CALCIUM AND PHOSPHOINOSITIDES
c. cGMP (CYCLIC GUANOSINE MONOPHOSPHATE)
c. cGMP (CYCLIC GUANOSINE MONOPHOSPHATE)
o Maximal response that can be produced by a drug.
o All receptors are occupied.
o No response even if the dose is increased.
o Dose of the drug to get maximal response means that even if more doses are added, it will have no response because all receptors are occupied already.
o Like in a restaurant, if all the tables are occupied and the kitchen is already busy, they cannot accommodate new customers further.
o Measures efficacy
Emax- maximal effect
- 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 drug.
GRADED DOSE-RESPONSE CURVE
o Concentration of drug that produces 50% of maximal effect
o Smaller EC50 = more potent
o Measures potency
EC50 (half maximal effective concentration)
o Total number of receptor sites.
o All receptors have been occupied
o Same x-axis as Emax but different y-axis.
o What you’re just checking here is the
amount of receptors occupied.
o Example:
§ At 50 mg, all receptors are occupied. Is it possible to occupy all receptors even if Bmax is not yet reached? Yes. It
means that the drug is not efficacious. Ideally, Emax = Bmax.
Bmax (total density or concentration of receptors)
o Concentration of drug required to bind 50% of the receptors.
o Measure of the affinity of a drug for its binding site on the receptor.
o Smaller KD = greater affinity of drug to receptor
o The receptors are on the y-axis, therefore, you’re looking for
dissociation constant.
o This means that at 5 mg, 50% of the receptors are already
occupied.
o It is good if the KD is equal to EC50
o But it is bad if the 50% of the receptors are occupied already but the EC50 is not reached yet.
o If at 0.5 mg, the EC50 is already reached and not the KD, it means that the drug is very potent because the drug has so much affinity to the receptors
o It is ideal if the KD coincides with EC50 but it is more ideal if the EC50 is reached without occupying all receptors.
Kd
o Maximal drug response is obtained at less than maximal
occupation of the receptors.
o Not qualitatively different from non-spare receptors, not hidden or unavailable.
o Temporal in character, when occupied, they can be coupled to respond, there is still effect.
o Drugs with low binding affinity for receptors will be able to produce full response even at low concentration.
o Compare concentration for 50% of maximal effect (EC50) with concentration for 50% maximal binding (KD).
o High KD but achieved EC50 would mean that there are more spare receptors. Effect of the drug-receptor interaction may persist for a longer time than the interaction itself.
o Actual number of receptors may exceed the number of effectors available.
o If you reach your EC50 and it is equal to your KD50, wala ka na spare receptors.
o If you reach your EC50 and it is less than your KD50, meron ka pa spare receptors.
o Ang pinaka-worst is na reach mo na KD50 mo, di mo pa na reach EC50 mo, occupied na lahat ng receptors.
Spare receptors
- Agonist response in the absence of antagonist.
- EC50 and Emax are reached.
Curve A
- 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.
- If a low concentration of antagonist is added, the curve shifts to the right.
- It means that it would need more doses of agonist to reach EC50.
- If these distractions
(antagonist) are added, they will compete with the agonist for binding in the receptor
- Still reached EC50 and Emax
CURVE B
- Produced after larger concentration of antagonist, the available receptors are no longer “spare”, sufficient to mediate an undiminished maximal response.
- If a higher concentration of antagonist is added, the curve further shifts to the right because there are still spare receptors
- However, if there are no spare receptors, the EC50 will not be reached
- It still reached Emax and EC50 but It will need a higher agonist to elicit it again
CURVE C
- 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.
- If there is continuous increase of antagonist concentration, it
competes with the agonist for the same receptors until there
are no receptors left; thus it will not reaching Emax, and worse,
even EC50 is not reached.
CURVE D AND E
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
o Non-regulatory molecules of the body.
o Binding with these molecules will result to no detectable change in the function of the biologic system.
o Inert means it has nothing to do with the activity.
o Buffers the concentration of the drug.
§ The purpose of buffering the drug is yung prodrug. Ang bilis
mag-activate, mabilis ma-absorb, patay. Nakuha mo yung
Emax, nakuha mo yung EC50, nakuha mo yung side effects.
This is not ideal.
§ This is important for drugs that can easily cause side-effects,
especially those with a narrow therapeutic dose.
o Bound drugs do not contribute directly to the concentration gradient
that drives diffusion.
§ E.g., albumin
Inert Binding Sites
- Agonist
- Partial Agonist
- Inverse Agonist
- Antagonist
DRUG-RECEPTOR INTERACTIONS
o Binds to the receptor and directly or indirectly bring about an effect.
o Full activation of the effector system.
Agonist
o Produces less than the full effect, even when it has saturated the
receptors.
o Acts as an inhibitor in the presence of a full agonist.
o It binds to the same active binding site, but it does not elicit the same effects of reaching the Emax and the EC50.
Partial Agonist
o Inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
o Binds to the same active site.
o Why is this not an antagonist? The inverse agonist binds to the Ri, while an antagonist binds to the Ra site.
Inverse Agonist
o Binds but do not activate the receptors.
o Blocks or competes with agonist.
Antagonist
4 CLASSIFICATIONS OF ANTAGONISTS
- Competitive Antagonist
- Irreversible Antagonist
- Chemical Antagonist
- Physiologic Antagonist
o Competes with agonist receptor.
o Binds to the receptor reversibly without activating the effector system.
§ Usually has electrostatic bonds or hydrophobic bonds.
o Antagonist increases the agonist concentration needed for a given degree of response.
o Concentration-effect curve is shifted to higher doses (i.e., horizontally to the right of the dose axis).
o Same maximal effect is reached.
o ED50 – median effective dose
§ EC50 – concentration
§ EC50 – dose
o Effects are overcome by adding more agonist.
o Increases the median effective dose (ED50).
competitive antagonist
2therapeutic Implications of Competitive antagonist
§ Degree of inhibition produced by the competitive antagonist depends on the concentration of antagonist (e.g., propranolol). Propranolol is a beta-blocker, which serves as the antagonist to the neurotransmitters that bind to the betareceptors causing vasoconstriction. Kung gaano kalala ang response na vasoconstriction, ganun din kadaming antagonist ang ibibigay natin.
§ Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to the receptor. More antagonist, more agonist needed.
o Binds with the receptor via covalent bonds. B
§ This makes the bond so strong that it is “irreversible”
§ Just an increase in the agonist does not solve it alone because agonist cannot forcefully remove bound antagonist
from the receptor.
o Antagonist’s affinity to the receptor maybe so high.
o Receptor is not available to bind the agonist.
o Duration of action is relatively independent.
o More dependent on the rate of turnover of receptors.
o E.g., phenoxybenzamine binding with alpha receptors
o Concentration-effect curve moves downward.
o No shift of the curve in the dose axis.
o Emax is not reached.
§ Efficacy and potency both drop.
o No increase in median effective dose (ED50) unless there are spare
receptors.
§ To overcome this effect, an increase in the agonist and spare
receptors are necessary
Irreversible antagonist
o Does not depend on interaction with the agonist’s receptor.
o Drug that interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target.
o E.g., protamine used to counteract the effect of heparin making it unavailable for interaction with proteins involved in the formation of blood.
o Poison and antidotes
Chemical Antagonist
o Makes use of the regulatory pathway.
o Effects that are less specific and less easy to control.
o Binds to a different receptor producing an effect opposite to that produced by the drug it is antagonizing.
o Non-specific
o Examples:
§ Glucocorticoids
§ Histamine
§ Steroids
Physiologic Antagonist
act upon inflammation, which is useful for identifying unknown problems in a patient.
Steroids
causes bronchoconstriction in asthmatic patients, opposed by bronchodilators like salbutamol and epinephrine.
Histamine
catabolic effects of increase in sugar is
physiologically opposed by insulin.
Glucocorticoids
*Response gradually diminishes even if the drug is still there (after reaching an initial high level of response).
- Reason is unknown.
RECEPTOR DESENSITIZATION
Cells use more than one signaling mechanism to respond to the drug.
STRUCTURE ACTIVITY RELATIONSHIP
- 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
QUANTAL DOSE-RESPONSE CURVE
o Median effective dose
o 50% of the individuals manifested the desired therapeutic effect.
o 50% of the population ng tao ng binigyan mo ng gamut, Nakita mo
na yung therapeutic effect.
ED50
o Median lethal dose
o 50% na ng population mo, patay na.
LD50
o median toxic dose
o 50% of the individuals manifested the toxic effects.
TD50
o Ratio of the TD50 (or LD50) to the ED50 determined from the quantal dose-response curves.
o Increased therapeutic index-wide margin of safety.
o Represents an estimate of the safety of the drug.
o A very safe drug might be expected to have a very large toxic dose
and a much smaller effective dose.
Therapeutic Index
o Dosage range between the minimum effective therapeutic
concentration or dose (MEC) and the minimum toxic concentration
or dose (MTC).
o More clinically relevant index of safety; greater practical value in
choosing the dose for a patient.
Therapeutic Window
o Maximal effect (Emax) an agonist can produce if the dose is taken to very high levels.
o Determined mainly by the nature of receptors and its associated effectors.
o Measured with a graded-dose response curve but not with quantal dose-response curve.
Maximal Efficacy
o Amount of drug needed to produce a given effect.
o In the graded dose-response curve, the effect chosen is the 50% of the maximal effect and the dose is (EC50).
o In the quantal dose-response curve, ED50, TD50, and LD50, are variables in 50% of the population.
- Drug B is the most potent. Drugs A, C, and D have equal maximal efficacy and greater maximal efficacy than Drug B.
Potency
5 VARIATION OF RESPONSE IN INDIVIDUALS
- Idiosyncratic Response
- Hyporeactive Response
- Hyperactive Response
- Tolerance
- Tachyphylaxis
WHAT VARIATION OF RESPONSE IN INDIVIDUALS:
o Caused by differences in metabolism (genetic) or immunologic mechanisms.
o Response to the drug is unknown or unusual.
o Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients.
Idiosyncratic Response
WHAT VARIATION OF RESPONSE IN INDIVIDUALS:
o Intensity of the drug is decreased.
o Large dose of the drug is needed to have an effect.
Hyporeactive Response
WHAT VARIATION OF RESPONSE IN INDIVIDUALS:
o Decreased sensitivity acquired as a result of exposure to the drug.
o With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases,
responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug’s effects.
Tolerance
WHAT VARIATION OF RESPONSE IN INDIVIDUALS:
o Tolerance develops after a few doses.
o When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis.
Tachyphylaxis
5 VARIATIONS IN DRUG RESPONSIVENESS
- Alteration on the concentration of the drug that reaches the receptor due to absorption, distribution, and elimination differences.
- Variation in the concentration of the endogenous ligands
(chemicals produced by the body that binds to receptors, e.g.,
catecholamines).
- Alteration in number/function of receptors
- Changes in 2nd messengers.
- Clinical Selectivity
