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Development Team Drug Concentration and Therapeutic Response Development Team Principal Investigator Prof. Farhan J Ahmad Jamia Hamdard, New Delhi Paper Coordinator Dr. Javed Ali Jamia Hamdard, New Delhi Dr. Shadab Md. School of Pharmacy, Content Writer International Medical University (IMU), Kuala Lumpur, Malaysia Dr. Sonal Gupta, KL Mehta Dayanand college, Content Reviewer Faridabad Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 0 Drug Concentration and Therapeutic Response Drug Concentration and Therapeutic Response Content 1. Introduction 2. Dose/Concentration response relationship 3. Types of dose and response relationship 3.1. Potency 3.2. Efficacy 3.3. Selectivity 3.4. Affinity 4. Therapeutic Window 4.1. Therapeutic Index 5. The relationship between drug concentration and pharmacological effects in the whole animal/human 6. Pharmacodynamic model 7. Onset and Duration of Action Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 1 Drug Concentration and Therapeutic Response I. Introduction To produce therapeutic/beneficial effect or minor, major, serious and severe toxic effects, drugs interact with receptors, ion channels, membrane carriers or enzymes in the body; this is called pharmacodynamics action of drug. The drug-receptor interactions usually occur in the tissue which is in equilibrium with the unbound drug (not bound to the plasma protein) present in the plasma. Drugs bind and interact in a structurally specific manner with these protein receptors. Activation of receptors in response to drug binding leads to activation of a second messenger system, resulting in a physiological or biochemical response such as changes in intracellular calcium concentrations leading to muscle contraction or relaxation. There are four main types of receptor families i. Ligand-gated ion channels ii. G-protein-coupled receptors (GPCRs) iii. Enzyme-linked receptors iv. Intracellular receptors. The most common receptors that are targets for drugs are the GPCRs; these are transmembrane receptors linked to guanosine triphosphate binding proteins (G proteins) which activate second messenger systems such as adenylyl cyclase (activated by, for example, β-adrenoceptors) or the inositol triphosphate pathway (activated by, for example, α-adrenoceptors). A drug which binds to a receptor having affinity, intrinsic activity and produces a maximum effect is called a full agonist. A drug which binds to receptor, produces intermediate efficacy and produces Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 2 Drug Concentration and Therapeutic Response submaximal response is called as partial agonist. Partial agonists produce a therapeutic effect if no agonist is present, but can act as antagonists in the presence of a full agonist. Pindolol (β blocking agent) is a partial agonist, produces a smaller decrease in heart rate than that produced by pure antagonists such as propranolol. Drugs which bind to receptor but do not have intrinsic activity and have zero efficacy is called antagonist. Antagonists produce their effects by counteracting the access of the natural transmitter (agonist) to the same receptor such as atropine (Antagonist) vs acetylcholine (agonist) on muscarinic receptor. An inverse agonist is a molecule that binds to the same site as an agonist but produce an opposite response (negative efficacy). Currently there are several drugs such as haloperidol, chlorpromazine that have inverse agonist activity at dopamine and serotonin receptors are used clinically. Antagonists comprises of mainly two subcategories competitive and noncompetitive. Competitive antagonists involve competition between antagonist and agonist and bind reversibly to the same receptor site. Antagonist inhibitory effects for the same receptor can be overcome by addition of a higher concentration of agonist. In the presence of competitive antagonist higher agonist concentrations are needed to produce the same effect as in absence of antagonist. The presence of a competitive antagonist causes a rightward shift of the dose response curve of the agonist. The majority of clinically used drugs act as receptor antagonists are reversible competitive antagonists. Agonist (Isoproterenol) and the antagonist (Propranolol) are good example of competitive antagonist. Noncompetitive antagonists can bind irreversibly by covalent bonds for the same receptor site as the agonist or bind to a different site of same receptor which Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 3 Drug Concentration and Therapeutic Response reduces the binding capability of the agonist by an allosteric mechanism. Due to irreversible strong binding to receptor site, the effect of a noncompetitive antagonist cannot be reversed even at high concentration of agonist, because the law of mass action does not apply. The primary effect of noncompetitive antagonist causes rightward shift of dose response curve and reduction in the maximal effect produced by the agonist. There are three other types of drug antagonism. Physiologic antagonism involves when one drugs antagonises the action of other drug by acting on different receptors and mechanism. Example: Acetylcholine (vasodilation) and norepinephrine (vasoconstriction) Chemical antagonism involves when a one drug antagonises another drug by chemical interaction and leads to a reduced response. Example: Interaction of positively charged drug protamine sulfate which neutralises the effect of negatively charged drug heparin. Pharmacokinetic antagonism occur when one drug suppressing or accelerating the effect of a second drug by change in pharmacokinetics of drug such as increase/decrease in absorption, distribution, metabolism and elimination. e.g. phenobarbital increases the metabolic degradation of anticoagulant warfarin. Selectivity in drug action is associated to the structural specificity of drug binding to receptors. Propranolol binds equally well to β1 and β2 adrenergic receptor, whereas metoprolol and atenolol bind selectively antagonist at β1- adrenergic receptor. Salbutamol is a selective β2-adrenergic receptor agonist and in this case, additional selectivity is achieved by inhaling the drug directly to its site of action in the lungs. Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 4 Drug Concentration and Therapeutic Response II. Dose/Concentration response relationship Regardless of how a drug effect occurs through binding or chemical interaction, the concentration of the drug at the site of action controls the effect. However, the relationship between response and concentration may be complex and is often nonlinear. Generally, when discussing the drug action at the tissue level, we refer to drug ‘concentration’, while when referring to drug action in the whole animal/person, we refer to the drug ‘dose’. When a drug is administered to an animal or human, the relationship between the drug dose, regardless of route used, and the drug concentration at the cellular level is even more complex. The concept of the dose-response curve, or concentration-response curve is one of the most important parts of pharmacology. A dose-response curve describes the relationship between an effect of a drug and the amount of drug given. Dose-response curves are essential to understand the drug's safe and hazardous levels, so that the therapeutic index can be determined and dosing guidelines can be created. Dose-response curves are charted on an X-Y axis, with the drug dosage measured (usually in milligrams, micrograms, or grams per kilogram of body-weight for oral exposures or milligrams per cubic meter of ambient air for inhalation exposures) typically on the X axis and the response to the medication typically on the Y-axis. When considering responses at the tissue level, the quantity of drug is expressed as its concentration, usually expressed as a molar concentration, although where the molecular weight is unknown we would express the concentration as microgram/nanogram/ ml as appropriate. As the relationship between response and increasing Pharmaceutical Biopharmaceutics and Pharmacokinetics sciences Drug Concentration and Therapeutic Response 5 Drug Concentration and Therapeutic Response dose or concentration is best described by a logarithmic plot, dose-response curves (or concentration-response curves) are graphed with the dose or concentration on a logarithmic scale (X axis) as opposed to a linear scale; in such cases the curve is typically sigmoidal, with the steepest portion in the middle (This is discussed in more detail in the final section of this module see material under ‘The relationship between drug concentration and pharmacological effects in the whole animal/human’) When evaluating a dose-response curve (or concentration-response curve), one of the main characteristics is a graded relationship between the response and the dose or concentration; this means that as the amount of drug given is increased so is the response to the drug. There are three phases of a dose-response curve (or concentration-response curve). First, the curve is flat as the quantity of drug given is not sufficiently great to initiate a response. The first point along the graph where a response above zero (or above the control response) is reached is usually referred to as a threshold-dose. In the second phase, the curve
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