Pharmacodynamics Flashcards
What is a drug?
Any substance that when administered to a living organism, produces a biological effect
What is pharmacology ?
The study of how the function of living systems is affected by chemical agents
What are pharmocokinetics?
The study of absorption, distribution, metabolism and excretion of drugs
What are pharmacodynamics?
The study of effects of drugs and their mechanisms of action
What is clinical pharmacology or Pharmacotherapeutucs?
The study of the use of drugs in the prevention and treatment of diseas
What is pharmacotherapy?
Use of drugs to treat disease
What is toxicology?
The study of adverse effects of drugs
What are drug actions?
Drugs are chemicals that alter basic processes in body cells
They can stimulate or inhibit normal cellular functions
What is the mechanism of drug action?
Drug molecules must bind to macromolecular components of the organism in order to produce an effect
What is a drug receptor / drug target?
The component of the organism with which a drug interacts is called a drug receptor or drug target
Most drug targets are proteins
How does a drug initiate a cellular response?
First it must bind to a drug receptor
In most cases, drugs bind to their receptor by forming hydrogen, ionic or hydrophobic bonds with the receptor
- These weak bonds are reversible
- In a few cases, drugs form covalent bonds with their receptor
What determines drug selectivity ?
Drug receptors are responsible for the selectivity of drug action
- The size, shape, and charge of a drug determine whether it will bind to a particular receptor or set 9r receptors
- For a drug to be useful as a therapeutic tool it must act selectively on particular types of receptors, ie, it must show a high degree of binding selectively
What are the major types of drug targets?
- Ion channels
- G-protein linked receptors
- Enzyme linked receptors
- Nuclear receptors
- Enzymes
- Transporters
- Structural proteins
What are ion channels?
Several classes of drugs act by altering the conductance of ion channels
Examples:
-Local anaesthetics
- Sedative-hypnotics
- Antileptics
What are G-protein linked receptors?
Approximately 60% of prescription drugs act by binding to G protein linked receptors
Examples:
- Albuterol, a B2 agonist, is used for asthma
- Propranolol, a B-antagonist, is used for hypertension
What are the enzyme- linked receptors?
The largest group is the receptor tyrosine kinase family
This class of receptors includes the : -Insulin receptor
-Epidermal growth factor receptor (EGFR)
What are the tyrosine kinase receptors?
Tyrosine kinase receptors play an important role in cellular growth and differentiation
- Gain of function mutations in these receptor can lead to cancer
- Inhibitirs of tyrosine kinase receptors are used as anti cancer agents
- An example is imantib, which is effective for leukemia
What drugs use nuclear receptors?
These are intracellular
- nuclear receptors regulate the expression of genes controlling metabolism and development
- Members of the nuclear receptor superfamily include receptors for:
- Steroid hormones
- Thyroid hormones
- Vitamin D
Describe enzyme as drug targets
These are a common drug target
Most drugs that target enzymes act by inhibiting enzyme activity.
- Aspirin
- Ibuprofin
- Omeprazole
Describe transporters as sources of drug targets
- Neurotransmitter transporters are the targets of drugs used in the treatment of psychiatric disorders
- Some antidepressant drugs act by blocking serotonin reuptake
Describe structural proteins as targets to drugs
- Some anti cancer drugs bind to tubulin and prevent the polymerization of this molecule into microtubules
- As a consequence cells are arrested in metaphase
- An example is vinblastine
What drugs aren’t mediated by binding to receptors?
Some drugs don’t act by interacting with macromolecular components of the organism
-Antacids neutralize gastric acid
What are the types of dose response curves?
- Graded
2. Potential
In a grade dose-response curves, what is the correlation between drug concentration and effect?
The relation between drug concentration and effect is described by a hyperbolic curve according to the following equation:
E= (Emax x C)/ (C+EC50)
E is the effect
Emax is the maximal response produced by the drug
EC50 is the drug concentration that produces 50% of the maximal effect
What is the relationship of receptor binding of drugs?
The relation between drug bound (B) to receptors and the concentration (C) of free drug is described by the equation:
B= (Bmax x C)/(C+ KD)
Bmax= total concentration of receptor sites
KD = equilibrium dissociation constant
KD= the concentration of drug required to occupy half of the receptors- this characterizes the receptor’s affinity for the drug
What is affinity in relation to drug receptor binding?
The tendency of a drug to combine with its receptor: its a measure of the strength of the drug-receptor complex
-If KD is low, binding affinity is high, and vice versa
Why is the shape of dose response curve, and binding curve similar?
The shape of the dose-response curve is similar to the binding curve because the response to the drug is a consequence of the binding of the drug to the receptor
What is a graded dose-response curve?
Dose-response data is frequently plotted as the drug effect against the logarithm of the concentration
This transforms the hyperbolic curve into a sigmoidal curve
Why is EC50 lower than KD?
An agonist doesn’t have to occupy all receptors to evoke a full response
Therefore EC50 is lower than KD
Because of this certain number of receptors are said to be “spare”
The presence of spare receptors indicates that there is signal amplification
What is efficacy?
Efficacy is the magnitude of the response a drug produces
-Maximal efficacy (sometimes refferred to simply as efficacy), is the greatest effect a drug can produce (Emax)
What is potency?
This is a measure of the concentration or amount of drug necessary to produce an effect of a given magnitude
-The EC50 of a drug is usually used to determine potency
What are agonists and antagonists?
An agonist is a drug that binds to and activates a receptor in a way that brings about an effect
- An antagonist inhibits the action of an agonist but has no effect in the absence of an agonist
- Agonists have receptor affinity and efficacy
- Antagonists have receptor affinity but no efficacy
What’s a receptor antagonist?
Binds to the same receptor to which the agonist binds
What is competitive antagonism ?
Competitive antagonists bind to the agonist binding site on the receptor
Binding of antagonist to the agonist binding site prevents the binding of agonist to the receptor
Binding of antagonist to the receptor May be reversible or irreversible
What is reversible competitive antagonism ?
The presence of the competitive antagonist increases the concentration of agonist required for a given degree of response
So, the agonist concentration-effect curve shifts to the right
-High concentrations of agonist can surmount the effect of a given concentration of the antagonist: the Emax for the agonist remains the same.
What is irreversible competitive antagonism?
A receptor bound by an irreversible antagonist cannot respond to the binding of an agonist
The Emax of the agonist is reduced
This antagonism is insurmountable
Some authors refer to this type of antagonism as noncompetitive
Summarize noncompetitive antagonism
Also called allosteric antagonism
-Noncompetitive antagonists bind to the receptor at a site different from the agonist binding site
This type of antagonism is insurmountable
-Emax is decreased
What is nonreceptor antagonism ?
A nonreceptor antagonist doesn’t bind to the receptor to which the agonist binds
What is physiological antagonism?
One drug opposes another drug, but through different receptors.
Give an example of physiological antagonism?
Epinephrine—> increase in blood pressure and bronchodilation
Histamine—> decrease in blood pressure and bronchoconstriction
What is chemical antagonism?
A chemical antagonist reacts chemically with an agonist to form an inactive product
-For example, Protamine, a protein which is positively charged, counteracts the effects of heparin, an anticoagulant that is negatively charged
What are full and partial agonists?
Agonists activate the receptor that they occupy
Antagonists cause no activation
But the ability of a drug molecule to activate the receptor is a graded property
- Full agonists produce a maximal response
- Partial agonists produce a sub maximal response
- Partial agonists produce a lower response, at full receptor occupancy, than do full agonists
How can a partial agonist act as a competitive antagonist ?
A partial agonist can act as a competitive antagonist in the presence of a full agonist, by competing with the full agonist for receptor occupancy, thus reducing the response to the full agonist
What are inverse agonists?
-Many receptor systems exhibit some activity in the absence of an agonist, suggesting that a fraction of the receptors is always in the active state
Activity in the absence of an agonist is called constitutive activity
Inverse agonists reverse the constitutive activity of the receptors
What are Quantal-dose effects?
The quintal dose-response relationship plots the fraction of the population the responds to a given dose of drug as a function of the drug dose.
The responses are defined as either present or not present (I.e., quantal, not graded), such as prevention of convulsions, arrhythmia, or death
How is the Quantal dose effect curve characterized?
By stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect
What is the median toxic dose(TD50)?
The dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50)
What is the median lethal dose 50 (LD50)?
The dose required to cause death in 50% of animals is called the median lethal dose (LD50)
What is the therapeutic index?
The therapeutic index is defined as the ratio of the TD50 or the LD50 to the ED50 for a therapeutically relevant effect
TI= (TD50)/(ED50)
Or
TI= (LD50)/(ED50)
Is the therapeutic index known in humans?
The therapeutic index of a drug in humans is almost never known with real precision
- The TI represents an estimate of the safety of the drug
- A very safe drug will have a very large toxic dose and a small effective dose
What is the therapeutic window?
The therapeutic window is a more clinically relevant index of safety
-It is the dosage range between the minimum effective therapeutic concentration and the minimum toxic concentration
