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! 2
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. 3
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 4
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) 5
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 [R t ] = 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. 6
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. 7
How to determine the affinity? Dissociation Constant (K d ) 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+R DR K d = [D] x [R] [DR] [D], [R] and [DR] represent the concentrations of the ligand (drug), target and complex, respectively. 8
K d The value of K d 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 K d value, the weaker the interaction and the lower the affinity. The converse occurs when a drug has a low K d. The binding of the ligand to the receptor is strong, and the affinity is high. 9
Both of these drugs have comparable affinity for μ opioid receptors 10
Are you interested?? Take a look at the following review article... 11
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. 12
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. 13
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] [E max ] = the maximal effect of the drug K d = the dissociation constant for the drug from the receptor. 14
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 15
Efficacy Heroin is a full agonist Codeine is a partial agonist 16
Efficacy 17
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) 18
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. 19
Potency EC 50 or ED 50 The concentration producing an effect that is fifty percent of the maximum is used to determine potency (EC 50 or ED 50 ). EC 50 or ED 50 = drug dose/concentration that shows fifty percent of maximal response. 20
Potency vs Efficacy Drug A has greater biologic activity per dosing equivalent and is thus more potent than drug B or C. 100 A 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. Response %) 50 B Log Drug 21
Which drug is more potent? 22
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 23
Test Yourself! 1. Which drug has the highest potency? 2. Which drugs has the biggest maximal effect? 3. Which drug has the lowest potency? 24
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 = TD 50 / ED 50 TD 50 = the drug dose that produces a toxic effect in half the population ED 50 = 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 LD 50 instead of TD 50 in some text books. 25
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 Toxicity ED 50 = 0.4 TD 50 = 40 TI = 40/0.4 Response %) 50 Log Drug 26
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) 27
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 28
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. 29
Some drugs with a low therapeutic index Lithium Digoxin Carbamazepine Cyclosporin Phenytoin Phenobarbitone Theophylline (Aminophylline) 30
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. 31
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. 32
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Real Scenario? --- Have a look at the following article! Paccaly et al. J Clin Pharmacol.2006; 46: 45-51 34
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. 35
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. 36
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. 37
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. 38
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. 39
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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 41
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 42
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. 44
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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. 46
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. 49
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. 51
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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