Intro Pharmacodynamics Flashcards
Pharmacodynamics is the study of the ______ and __________ effects of drugs and their ___________ of ___________
biochemical
physiological
mechanisms of action
Simply put, pharmacodynamics is?
The effects of drug on the body
What is the 2 STATE RECEPTOR MODEL
A receptor may exist in two interchangeable states, active (Ra) & inactive (Ri) which are in equilibrium.
Binding of drug shift this equilibrium in either direction
What is a ligand?
any molecule which attaches selectively to particular receptors.
Define affinity
Affinity is the strength of the reversible interaction between a drug and its receptor
Affinity is measured by
Dissociation constant
What is intrinsic activity?
The capacity to induce a functional change in the receptor
A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells is exhibiting?
High specificity
What are agonist?
Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds
They have affinity and intrinsic activity therefore maximal effect
If a drug binds to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor) the drug is said to be a
Primary agonist
Allosteric agonists….
bind to a different region on the receptor referred to as an allosteric site.
Why would a drug be called an antagonist?
If it blocks or reduces the action of an agonist
5 types of Antagonists
Physical
Chemical
Physiological
Partial
Inverse
Physical antagonists…
… binds to the drug and prevents its absorption
like charcoal binds to alkaloids and prevents their absorption.
Chemical antagonists…
combines with a substance chemically
like chelating agents binds with metals
What is the mode of operation of physiological antagonist
They produces an action opposite to a substance but by binding to the different receptors
How is adrenaline a physiological antagonist of histamine?
adrenaline causes bronchodilatation by binding to β2 receptors, which is opposite to bronchoconstriction caused by histamine through H1 receptors
What are partial agonists?
Agents that are only partly as effective as agonists regardless of the concentration employed.
Many receptors exhibit spontaneous activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed
Inverse agonists
Inverse agonists produce effects that are
Opposite to that of agonist
What is efficacy
It can only be measured with?
A maximal effect (Emax) an agonist can produce.
A graded dose-response curve
What is potency
The amount of the drug needed to produce a given effect.
Potency is determined by?
the affinity of the receptor for the drug.
The dose causing 50% from the maximal effect (EC50) can be obtained from
graded dose-response curve.
In what curve are ED50, TD50 and LD50 are potency variables?
Quantal dose response curve
Tolerance is
Repeated administration of a drug resulting in diminished effect
2 types of Tolerance & define
Tachyphylaxis: is a type of tolerance which occurs very rapidly.
Desensitization: decreased response to the agonist after its repeated injection in small doses.
Tolerance can be due to 3 things. What are they?
- Masking or internalization (endocytosis) of the receptors
2- Loss of receptors (down regulation)- decreased synthesis or increased destruction
3- Exhaustion of mediators (depletion of catecholamine).
Difference between competitive and non competitive antagonist 7
Antagonist binds with the same receptor as the agonist
2. Antagonist resembles chemically with the agonist
3. Parallel rightward shift of agonist DRC
4. The same maximal response can be attained by increasing dose of agonist (surmountable antagonism)
5. The antagonist appears to have inactivated a certain number of agonist molecules
6. Intensity of response depends on the concentration of both agonist and antagonist
7. Examples: ACh-Atropine
Morphine-Naloxone
Noncompetitive
1. Binds to another site of receptor
2. Does not resemble
3. Flattening of agonist DRC
4. Maximal response is suppressed (unsurmountable antagonism)
5. The antagonist appears to have inactivated a certain number of receptors
6. Maximal response depends only on the concentration of antagonist
7. Diazepam–Bicuculline
What is synergism?
When the action of one drug is facilitated or increased by the other, they are said to be synergistic.
In a synergistic pair,….
both the drugs can have action in the same direction or given alone one may be inactive but still enhance the action of the other when given together.
In additive drug combinations
The effect of the two drugs is in the same direction and simply adds up
effect of drugs A + B = effect of drug A + effect of drug B
Types of additive drug combinations 5
Aspirin + paracetamol= as analgesic/
antipyretic
Nitrous oxide + halothane =as general
anaesthetic
Amlodipine + atenolol = antihypertensive
Glibenclamide + metformin = hypoglycaemic
Ephedrine + theophylline = bronchodilator
What is super additive drug combination/ potentiation
The effect of combination is greater than the individual effects
of the components:
effect of drug A+ B > effect of drug A+ effect of drug B
This is always the case when one component is inactive as such
Examples of super additive
Pics
Characteristics of competitive antagonist 6
Same binding site as of agonist
•resembles chemically with agonist
•Right shift of DRC
•Surmountable antagonism by increasing agonist dose
•Inactivation of certain agonist molecules
•Response depends on concentration of both
e.g Ach – Atropine, Morphine - Naloxone
Characteristics of non competitive antagonist 6
Different binding site as of agonist.
•Not resembles chemically with agonist.
•Flattening/downward shift of DRC.
•Unsurmountable antagonism (Maximum response is suppressed).
•Inactivation of certain receptors.
•Maximum response depends on concentration of antagonist
e.g. Diazepam - Bicuculline
6 examples of physiological receptors
GPCR
•Ion channels
•Transmembrane enzymes
•Transmembrane, non-enzymes
•Nuclear receptors
•Intracellular enzymes
2 major functions of physiological receptors
Ligand binding
Message propagation (signaling)
The regulatory actions of a receptor may be exerted on these 3 things
directly on cellular target(s),
on effector protein(s)
may be conveyed by intermediary cellular signaling molecules called transducers.
Which signal transduction pathway is fastest and without intervention of G protein or second messenger with examples
Ion channels (Ligand gated ion channels)
GABA a, 5HT3, NMDA
__________ are signal transducers that convey the information that agonist is bound to the receptor from the receptor to one or more effector proteins.
G proteins GPCRs(G protein coupled receptor)
The G protein heterotrimer is composed of 3 things. These are?
- a guanine nucleotide-binding α subunit, which confers specific recognition to both receptors and effectors
2&3 an associated dimer of β and ϒ
G protein effectors include enzymes like 4
Adenylyl Cyclase
Phospholipase C
Cyclic GMP phosphodiesterase
Membrane ion channels selective for Ca & K+
GPCR characteristics 3
GPCRs span the plasma membrane as a bundle of seven alfa-helices.
•Extracellular binding site for ligand.
•Cytosolic binding site for transducer G-protein.
Adenylyl cyclase
Increase in cAMP - Protein kinase A phosphorylation -
Increase in heart contraction
Smooth muscle relaxation
Glycogenolysis
Lipolysis
Inhibition of secretion
Phospholipase C pathway
Phosphatidyl inositol biophosphate (PIP2) - IP3 + DAG
IP3 - mobile calcium ions
DAG- PKc activation
Contraction
Neural excitation
Cell proliferation
Steps of resensitization and down regulation of receptors
Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm.
- Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, - β arrestin (β-Arr), to the receptor.
3.The receptor- β arrestin complex binds to coated pits, promoting receptor internalization.
4.Dissociation of agonist from internalized receptors reduces - β Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase.
5.Return of receptors to the plasma membrane result in the efficient resensitization of cellular responsiveness
- Repeated or prolonged exposure of feels to agonists favors the delivery of internalized receptors to lysosome, promoting down regulation rather than resensitization
Enzyme linked receptors are of 2 forms
With intrinsic enzymatic activity.
•Without intrinsic enzymatic activity but associated with an enzyme usually a kinase (bind a JAK-STAT kinase on activation)
Viagra is also known
Sidenafil
