Download Drug Interaction - Department of Health Science and Technology

General Principles of
Pharmacology and Toxicology
Parisa Gazerani, Pharm D, PhD
Assistant Professor
Center for Sensory-Motor Interaction (SMI)
Department of Health Science and Technology
Aalborg University
Pharmacodynamic II
• Today, we’ll explore the Dose response curves, Affinity, Efficacy,
Potency, long term drug effects and Drug Interactions and a bit
more!
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Drug-Receptor Interactions
What is the importance?
•
Most drugs interact with receptors that will determine therapeutic and toxic
effects of the drug.
•
Receptors largely determine the quantitative relations between dose of a
drug and pharmacologic effect.
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Dose --- Concentration, make it clear Doc!
•
The term "dose" is often used loosely. The term "dose" strictly only
applies to experiments performed with animals or people, where you
administer various doses of drug. You don't know the actual
concentration of drug -- you know the dose you administered.
•
Term "dose-response curve" is also used more loosely to describe in vitro
experiments where you apply known concentrations of drugs. The term
"concentration-response curve" is a more precise label for the results of
these experiments.
Check it out!
http://homepage.mac.com/mattocks/morfz/rx/drugcalc.html
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Dose - Response Curves
Two important properties of drugs can be determined by dose - response curves:
• Efficacy of a drug
• Potency of a drug
However first the drug needs to bind... (affinity)
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Drug–receptor binding
•
We can mathematically express the relationship between the percentage (or
fraction) of bound receptors and the drug concentration:
[D] = the concentration of free drug;
[DR] = the concentration of bound drug
[Rt] = the total concentration of receptors (sum of the concentrations of unbound
(free) receptors and bound receptors)
Kd = the dissociation constant for the drug from the receptor.
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Affinity and Intrinsic Activity
•
All ligands have affinity for a receptor/target
•
Remember that ligand is an agonist or an antagonist, if it binds, it has affinity
•
A drug's action is affected by the quantity of drug that reaches the receptor and the
degree of attraction (affinity) between it and its receptor.
•
Once bound to their receptor, drugs vary in their ability to produce an effect (intrinsic
activity).
•
Drugs vary in their affinity and intrinsic activity:
•
Drugs that activate receptors (agonists) must have both great affinity and intrinsic
activity: They must bind effectively to their receptors, and the drug bound to its
receptor (drug-receptor complex) must be capable of producing an effect in the
targeted area.
•
Drugs that block receptors (antagonists) must bind effectively but have little or no
intrinsic activity, because their function is to prevent an agonist from interacting
with its receptors.
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How to determine the affinity? Dissociation Constant (Kd)
•
The dissociation constant is commonly used to describe the affinity between
a ligand (D) and its target/Receptor (R) i.e. how tightly a ligand binds to a
particular receptor.
[D] x [R]
D+R
DR
Kd =
[DR]
[D], [R] and [DR] represent the concentrations of the ligand (drug), target and
complex, respectively.
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Kd
•
The value of Kd can be used to determine the affinity of a drug for its receptor.
•
Affinity describes the strength of the interaction (binding) between a ligand and
its receptor.
•
The higher the Kd value, the weaker the interaction and the lower the affinity.
•
The converse occurs when a drug has a low Kd. The binding of the ligand to the
receptor is strong, and the affinity is high.
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Both of these drugs have comparable affinity for μ opioid receptors
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Are you interested??
Take a look at the following review article...
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Efficacy and Potency
•
A drug's effects can be evaluated in terms of:
• strength (potency)
or
• effectiveness (efficacy)
•
Efficacy refers to the potential maximum therapeutic response that a drug can
produce.
• For example, the diuretic furosemide (LASIX) eliminates much more salt
and water through urine than does the diuretic chlorothiazide (DIURIL).
Thus, LASIX has greater efficacy than DIURIL.
•
Potency refers to the amount of drug (usually expressed in milligrams) needed to
produce an effect, such as relief of pain or reduction of blood pressure.
• For instance, if 5 milligrams of drug A relieves pain as effectively as 10
milligrams of drug B, drug A is twice as potent as drug B.
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However….
• Greater potency or efficacy does not necessarily mean
that one drug is preferable to another.
• When judging the relative merits of drugs for a patient,
doctors consider many factors, such as side effects,
potential toxicity, duration of effect (which determines
the number of doses needed each day), and cost.
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Relationship of binding to effect ---- Efficacy
•
The binding of the drug to its receptor initiates events that ultimately lead to
a measurable biologic response.
[E] = the effect of the drug at concentration [D]
[Emax] = the maximal effect of the drug
Kd = the dissociation constant for the drug from the receptor.
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Efficacy
•
Efficacy refers to the potential maximum therapeutic response that a drug
can produce.
•
So by definition, antagonists have no efficacy. Efficacy is a function of
receptor activation, and antagonist binding does not change receptor
activation.
Heroin is a full agonist
Naloxone (antagonist) has no efficacy
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Efficacy
Heroin is a full agonist
Codeine is a partial agonist
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Efficacy
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Efficacy
In general, a full agonist has a strong affinity for its receptor and good efficacy.
The concentration-response curve is shown here for a full agonist and a partial agonist.
The partial agoinst, in this case, can only produce 60% of the maximal response.
Partial agonists (e.g. buspirone, aripiprazole, buprenorphine, or norclozapine)
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Potency
Potency refers to the amount of drug needed to produce an effect. It is an
expression of the activity of a drug, in terms of the concentration or amount
needed to produce a defined effect.
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Potency – EC50 or ED50
•
The concentration producing an effect that is fifty percent of the maximum is
used to determine potency (EC50 or ED50).
•
EC50 or ED50 = drug dose/concentration that shows fifty percent of maximal
response.
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Potency vs Efficacy
100
•
•
Drug A has greater biologic
activity per dosing equivalent
and is thus more potent than
drug B or C.
Drugs A and C have equal
efficacy, indicated by their
maximal attainable response
(ceiling effect).
Drug B is more potent than
drug C, but its maximal efficacy
is lower.
C
Response ´%)
•
A
B
50
Log Drug
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Which drug is more potent?
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Real Scenario!
•
Candesartan and irbesartan are angiotensin–receptor blockers that are used
alone or in combination to treat hypertension.
•
Candesartan is more potent than irbesartan because the dose range for
candesartan is 4 to 32 mg, as compared to a dose range of 75 to 300 mg for
irbesartan.
Candesartan
Irbesartan
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Test Yourself!
1. Which drug has the highest potency?
2. Which drugs has the biggest maximal effect?
3. Which drug has the lowest potency?
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Therapeutic Index or Therapeutic ratio
•
The therapeutic index of a drug is the ratio of the dose that produces toxicity to
the dose that produces a clinically desired or effective response in a population of
individuals:
Therapeutic ratio = TD50 / ED50
•
•
TD50 = the drug dose that produces a toxic effect in half the population
ED50 = the drug dose that produces a therapeutic response in half the population.
•
The therapeutic index is a measure of a drug's safety, because a larger value
indicates a wide margin between doses that are effective and doses that are
toxic.
•
You may see LD50 instead of TD50 in some text books.
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Determination of therapeutic index
•
In humans, the therapeutic index of a drug is determined using drug trials and
accumulated clinical experience. These usually reveal a range of effective
doses and a different (sometimes overlapping) range of toxic doses.
100
Efficacy
ED50 = 0.4
TD50 = 40
TI = 40/0.4
Response ´%)
Toxicity
50
Log Drug
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Small and Large Therapeutic Index
warfarin, an oral anti-coagulant with a narrow therapeutic index (A)
penicillin, an antimicrobial drug with a large therapeutic index (B)
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Warfarin
• Variation in patient response is most
likely to occur with a drug showing a
narrow therapeutic index, because the
effective and toxic concentrations are
similar.
• For agents with a low therapeutic dose
is critically important
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Penicillin
•
For drugs such as penicillin, it is safe
and common to give doses in excess
(often about ten-fold excess) of that
which is minimally required to achieve
a desired response.
•
In this case, bioavailability does not
critically alter the therapeutic effects.
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Some drugs with a low therapeutic index
Lithium
Digoxin
Carbamazepine
Cyclosporin
Phenytoin
Phenobarbitone
Theophylline (Aminophylline)
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Therapeutic window
•
Do not confused this with therapeutic
index!
•
Therapeutic window is the range of
plasma concentrations of a drug that
will elicit the desired response in a
population of patients.
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Selectivity in drug action
•
It is related to the structural specificity
of drug binding to receptors.
•
Propranolol binds equally well to β1
and β2 adrenoreceptors, while Atenolol
and Metoprolol bind selectively to and
block β1 adrenoreceptors.
•
Salbutamol is a selective β2
adrenoreceptor agonist and
selectiveity could be achived by
inhaling the drug to reach to the site of
action in lungs.
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Real Scenario? --- Have a look at the following article!
Paccaly et al. J Clin Pharmacol .2006; 46: 45-51
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Tolerance
•
Tolerance is a person's diminished response to a drug, which occurs when
the drug is used repeatedly.
•
When morphine or alcohol is used for a long time, larger and larger doses
must be taken to produce the same effect.
•
Usually, tolerance develops because metabolism of the drug speeds up
(often because the liver enzymes involved in metabolizing drugs become
more active) and because the number of sites (cell receptors) that the drug
attaches to or the strength of the bond (affinity) between the receptor and
drug decreases.
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Dependence
•
Tolerance is not the same as dependence or addiction.
•
Dependence, which may be physical or psychologic, refers to a strong
desire to experience the effects of the drug.
• In physical dependence, the person may experience symptoms of
withdrawal when the drug is stopped.
• Addiction is compulsive use and overwhelming involvement with a drug.
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Resistance
•
Strains of microorganisms (bacteria or viruses) are said to develop
resistance when they are no longer killed or inhibited by the antibiotics and
antiviral drugs that are usually effective against them (or, in practice, when
significantly higher than normal doses are required to have an effect).
•
Cancer cells may develop resistance to chemotherapy drugs.
•
Resistance appears because of the mutations that take place spontaneously
in any group of growing cells, whether exposed to drugs or not. Most such
mutations change the cell's structure or biochemical pathways in a harmful
way. But some mutations change the parts of the cell that are affected by
drugs, decreasing the drug's ability to work (that is, causing resistance).
•
Once tolerance or resistance has developed to a drug, doctors may increase
the dose or use a different drug.
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Drug Interaction - Mechanisms
Interactions can be pharmacodynamic or pharmacokinetic. Some drug
interactions are due to a combination of mechanisms. There are also
pharmaceutical interactions.
Pharmaceutical Interactions
• These can be classified as those interactions that occur prior to systemic
administration. For example incompatibility between two drugs mixed in an
IV fluid. These interactions can be physical (e.g. with a visible precipitate) or
chemical with no visible sign of a problem.
Pharmacokinetic Interactions
• This is when one drug affects the availability (absorption), distribution,
metabolism or excretion of another drug. A change in blood concentration
causes a change in the drug’s effect.
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Pharmacodynamic Interactions
•
These interactions are due to competition at receptor sites or activity of the
interacting drugs on the same physiological system. There is no change in the
plasma concentrations of interacting drugs.
• Antagonist (Drugs with opposing pharmacological actions acting on the same receptor)
• E.g. salbutamol (a β2 agonist) with metoprolol (a β2 antagonist)
• Additive/synergistic (Drugs with a similar pharmacological action may have an additive
effect)
• E.g. Fluoxetine (an SSRI) with clomipramine (a tricyclic antidepressant
with serotonergic activity) can cause serotonin syndrome in some
patients.
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Drug Interaction Resources
Dalhousie University:
http://dir.pharmacy.dal.ca/drugprobinteraction.php
Drug Interactions Checker:
http://www.drugs.com/drug_interactions.html
P450 data:
http://medicine.iupui.edu/flockhart/table.htm
Grapefruit Juice:
http://www.cop.ufl.edu/fdic/profe.php?interaction_category=9
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Drug Interaction Resources
Stockley’s Drug Interactions, 8th Edition
Edited by Karen Baxter BSc MSc MRPharmS. Published by Pharmaceutical
Press, London, UK, 2008. ISBN 978-0-85369-754-1. Clothbound,
vii + 1464 pp. (28.5 × 22.5 cm), $250. www.pharmpress.com
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Study Hours --- A group work!
Find at least one pharmacodynamic, one pharmacokinetic drug
interaction for your drug of choice with related mechanism
43
We’ll meet again on Friday... And will explore the term ”pharmacogenetics”
together.
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Test your pharmacodynamic knowledge!
If agonists and antagonists occupy the same receptor site, an effective antagonist
should exhibit
High intrinsic activity and high affinity
Low intrinsic activity and low affinity
High intrinsic activity and low affinity
No intrinsic activity and high affinity
4
1.
2.
3.
4.
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Test …
Which of the following are necessary requirements for a chemical to be termed a
drug? (more than one answer)
Must selectively localize at the receptor site
Must possess sufficient potency
Must change the basic function of a tissue or organ tissue
Must to some degree be lipid or water soluble
Must usually be reversible in action
2,4,5
1.
2.
3.
4.
5.
47
Test …
If drug A has a greater efficacy than drug B, then drug A
Is more toxic than drug B
Has a greater affinity for the receptor than drug B
Has a greater margin of safety than drug B
Is capable of producing a greater maximum effect than drug B
4
1.
2.
3.
4.
48
Test …
In Figure 1, three different doses of drug A are tested for activity. In Figure 2, three
doses of drug B are tested for activity in the same test system. In Figure 3, three
doses of drug A are tested in the presence of the high dose of drug B. Based upon the
responses seen, which of the following statements best describe drugs A and B?
Drug A is a partial agonist; drug B is an antagonist
Drug A is an antagonist; drug B is an agonist
Drug A is an agonist; drug B is an antagonist
Drug A is an agonist; drug B is a partial agonist
Drug A is an agonist; drug B is neither an agonist nor antagonist
5
1.
2.
3.
4.
5.
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Test …
When comparing drugs with respect to intensity of response, the drug that
produces the greatest maximum effect is the one with the highest
Affinity
Potency
Efficacy
Therapeutic index
3
1.
2.
3.
4.
50
Test …
Which of the following is an action of a noncompetitive antagonist?
Alters the mechanism of action of an agonist
Alters the potency of an agonist
Shifts the dose-response curve of an agonist to the right
Decreases the maximum response to an agonist
Binds to the same site on the receptor as the agonist
4
1.
2.
3.
4.
5.
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Test …
All of the following statements regarding receptor classes are true EXCEPT
Ion channels are confined to excitable tissue
Each cell is capable of producing only one G protein
Steroids bind to intracellular receptors
A hormone or neurotransmitter receptor may be an ion channel
Certain growth factors interact with receptors that have tyrosine-specific
protein kinase activity
2
1.
2.
3.
4.
5.
52
Test …
The maximum effect (Emax) achieved by a drug is a measure of
Potency
Efficacy
The quantal response
Antagonist magnitude
The therapeutic index (TI)
2
1.
2.
3.
4.
5.
53
Test …
The ED50 of a drug is:
The effective dose of a drug in 50% of the subjects tested
Half of the effective or therapeutic dose
The dose that gives 50% of the maximum effect
Is a measure of toxicity
3
1.
2.
3.
4.
54
Test …
In order to be therapeutically useful, the selective effect of drugs on cellular
components must be
Reversible
Irreversible
Rapid
Continuous
Sustained
1
1.
2.
3.
4.
5.
55
Test …
Two drugs, A and B, have the same mechanism of action. Drug A in a dose of 5
mg produces the same magnitude of effect as drug B in a dose of 500 mg.
Drug B is less efficacious than drug A
Drug A is 100 times more potent than drug B
The toxicity of drug A is lower than that of drug B
Drug A is a better drug if maximal efficacy is needed
Drug A has a shorter duration of action
2
1.
2.
3.
4.
5.
56
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