QUIZLET Unit 2 - Drug Receptors and Pharmacodynamics (2) Flashcards
mitochondria3000
- 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
