Pharmacodynamics of Drugs PDF

Pharmacodynamics of Drugs  Pharmacodynamics of Drugs It may be defined as the study of: I. The pharmacological actions of drugs. II. The mechanisms of action of drugs. Drug Actions I. Factors affecting drug actions: 1.Size of the patient 2.Age of the patient 3.Gender of the patient...

Pharmacodynamics of Drugs  Pharmacodynamics of Drugs It may be defined as the study of: I. The pharmacological actions of drugs. II. The mechanisms of action of drugs. Drug Actions I. Factors affecting drug actions: 1.Size of the patient 2.Age of the patient 3.Gender of the patient 4.Genetic factors 5.Nutritional factors 6.Health conditions 7.Time of drug administration 8.Emotional status of the patient. 9.Drug interactions  Cont. Factors affecting drug action 1.Size of the patient: This can be expressed in terms of body weight or body surface area. The administered drug is distributed throughout the body. Thus, for a given dose, the larger the body the lower will be the plasma concentration, and lower effect.  Cont. Factors affecting drug action 2. Age of the patient: ▪ The response of the drug varies according to the age of the patient. ▪ These variations are related to differences in drug absorption, metabolism and excretion. ▪ In neonates and infants, the excretory and metabolizing systems are undeveloped, while old patients have some degenerative changes in these systems that may reduce their activities.  Cont. Factors affecting drug action 3. Genetic factors: Enzymes (usually in the liver) break down many drugs and this terminates their actions. Therefore, congenital deficiency in one of these metabolizing enzymes may affect drug plasma level and therefore its response. 4. Nutritional factors: Metabolic enzymes are made of protein. Severe malnutrition can affect the response to a drug due to the reduction of enzyme activity which can occur as a result of protein deficiency.  Cont. Factors affecting drug action 5. Gender: In the medication of women as a rule, the doses of potent drugs may be somewhat reduced. The body weight of women generally is composed of a higher % of fatty tissue than that of men. Oxidation rates of drugs are slower in fatty tissue than in skeletal muscle and hence the effect of a drug is more pronounced in women. During lactation some drugs may be excreted in the milk. Bitter drugs and hypnotics excreted in the milk discourage breast-feeding or cause depression of the infant, respectively.  Cont. Factors affecting drug action 6. Health conditions: Individuals with liver or kidney diseases show differences in their response to drugs. These differences are due to reduction in drug metabolism and excretion as compared to normal persons. 7. Time of Administration: Daylight is a stimulant, enhancing the effect of "stimulating drugs" and diminishing the action of hypnotics. Darkness is a sedative, hypnotics are more effective at night.  Cont. Factors affecting drug action 8. Emotional Status: A placebo administered by a physician may be followed by considerable improvement in sleep, appetite, well-being etc. 9. Drug Interactions: Concurrent administration of two drugs may influence the therapeutic value of each one of them in different ways. Drug interaction occurs by several principal mechanisms. These include acceleration or inhibition of drug metabolism, displacement of plasma protein-bound drug, impaired uptake of drug from the gastrointestinal tract, altered renal clearance of a drug or interaction at the level of drug receptors. Mechanisms of drug actions Mechanisms of drug actions include: 1. Drug-receptor interaction (receptor theory) 2. Antimetabolites 3. Enzyme inhibitors 4. Action on cell membrane  1. Drug-Receptor Theory Definition of Receptors: Receptors are specific sites inside a cell or on its surface that are occupied by the drug and mediate its action.  Cont. The drug-receptor theory Drug combines with the specific receptor in order to produce its effect. The drug is thought to fit onto a receptor rather as a key fits a lock (Key & Lock Theory). It may then either stimulate the receptor and produces an effect, agonist. (Agonist = affinity + efficacy). Or it may occupy the receptor without producing any effect , antagonist. (Antagonist = affinity, no effecacy).  Cont. The drug-receptor theory Interaction of an agonist and antagonist with the receptors Molecule of Ac ety lc holine Molecule of Ac ety lc holine Musc arinic rec ept ors Receptors are oc cupied by the in s mmoth mus cle agonis t and t he mus cel is s timulat ed Molecule of Ac ety lc holine Atropine Receptors are bloc ked by atropine; ac et y lc holine has no ef f ect Cont. The drug-receptor theory The recognition of a drug by a receptor triggers a biologic response (Agonistic effect).  Cont. Mechanisms of Drug Actions 2. Enzyme inhibitors: Enzymes are substances that speed up many chemical reactions within the body. Some drugs have the property of inhibiting the activity of some enzymes.  Cont. Mechanisms of Drug Actions 3. Action on cell membrane: The function of nerves and muscles depends on ions passing across the cell membrane. Certain drugs, such as local anesthetics interfere with the movement of these ions and thus prevent nerve function.  Cont. Mechanisms of Drug Actions 4. Antimetabolites: The drug may be similar in structure to a substance (metabolite) which is used by the cells for their function. Thus, in the presence of the drug, the cell cannot use its endogenous metabolites and fails to multiply. Example: The anticancer agent. 6-mercaptopurine which competes with purine bases in the synthesis of DNA, interfers with cell devision. Dose-Response Relationships The effect of dose on the magnitude of drug binding.  Dose-Response Relationships An agonist is defined as an agent that can bind to a receptor and elicit a biologic response. The magnitude of the drug effect depends on the drug concentration at the receptor site. As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The relationship between dose and response is a continuous one. Drug + Receptor Drug-Receptor Complex The response is a graded effect, meaning that the response is continuous and gradual. A graph of this relationship is known as a graded response curve. Plotting the magnitude of the response against increasing doses of a drug produces a graph that has the general shape shown in the following figure. The curve can be described as a rectangular hyperbola - a very familiar curve in biology. The effect of dose on the magnitude of drug binding. The effect of dose on the magnitude of pharmacologic response. Panel A is a linear graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose that shows fifty percent of maximal response.  Potency Potency is a measure of the amount of drug necessary to produce an effect of a given magnitude. The concentration producing an effect that is fifty percent of the maximum is used to determine potency, designated as the EC50. In the previous Figure, the EC50 for Drugs A and B are indicated. Drug A is more potent than Drug B because less Drug A is needed to obtain 50 percent effect. An important contributing factor to the dimension of the EC50 is the affinity of the drug for the receptor. By plotting the log of the concentration, the curves become sigmoid in shape. It is also easier to estimate the EC50.  Efficacy (intrinsic activity) This is the ability of a drug to illicit a physiologic response when it interacts with a receptor. Efficacy is dependent on the number of drug-receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses. The following Figure shows the response to drugs of differing potency and efficacy. Typical dose-response curve for drugs showing differences in potency and efficacy. (EC50 = drug dose that shows fifty percent of maximal response.)  Agonists If a drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand, it is known as an agonist. For example, phenylephrine is an agonist at adrenoceptors, because it produces effects that resemble the action of the endogenous ligand, norepinephrine. In general, a full agonist has a strong affinity for its receptor and good efficacy.  Antagonists Antagonists are drugs that decrease the actions of another drug or endogenous ligand. Antagonism may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist. Antagonists, however, have no intrinsic activity and, therefore, produce no effect by themselves. They are able to bind to target receptors because they possess strong affinity. If both the antagonist and the agonist bind to the same site on the receptor, they are said to be competitive. Plotting the effect of the competitive antagonist characteristically causes a shift of the agonist dose-response curve to the right. If the antagonist binds to a site other than where the agonist binds, the interaction is noncompetitive or allosteric. Note: A drug may also act as a chemical antagonist by combining with another drug and rendering it inactive. Effects of drug antagonists. EC50 = drug dose that shows fifty percent of maximal response.  Functional antagonism An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite to those of the agonist. A classic example is the antagonism by epinephrine to histamine-induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax.  Partial agonists Partial agonists have efficacies (intrinsic activities) greater than zero, but less than that of a full agonist. Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist. (Emax = maximum effect of the drug) A partial agonist may act as an antagonist of a full agonist. Consider what would happen to the Emax of an agonist in the presence of increasing concentrations of a partial agonist. As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist.  Drug Tolerance Tolerance can be described as a decreased response to the usual dose of a drug after repeated administration. It is sometimes described as desensitization or tachyphylaxis. Tolerance to drugs may be due to: – a change or loss of receptors, – exhaustion of mediators, – increased metabolic degradation of the drug – or physiological adaptation by the body.  Drug Dependence This describes an aspect of drug abuse, which means that the individual is dependent on a certain drug. When the drug is stopped, withdrawal symptoms occur. Dependence may be: a. Psychological dependence, e.g. tobacco smoking. b. Physical dependence, e.g. morphine, ethyl alcohol or barbiturates.  Drug-Drug Interactions When two drugs are administered together, one of the following phenomena could be observed: a) Additive effect: This occurs if the two drugs have similar effects. In this case, the effect produced due to the combined administration is equal to that produced by a double dose of an individual drug, i.e., 1+1=2. b) Synergism: Both drugs are biologically active, and when combined, the net effect is greater than the sum of their individual effects, i.e., 1+1>2. Example: Combination of ethyl alcohol and barbiturates.  Cont. Drug-Drug Interactions c) Potentiation: It occurs when a drug which has no effect, by itself, increases the effect of another active drug, i.e., 0+1>1. Example: Barbiturates potentiate the analgesic activity of salicylates although they have no analgesic action on their own. d) Antagonism: This is observed when drugs of opposite effects are given simultaneously. Antagonism could be chemical, physiological or pharmacological.  Drug-Food Interactions 1. The presence of food may affect drug absorption from gastro- intestinal tract. a) Drug absorption is generally less efficient when food is present in the stomach. Food reduces the rate of absorption of fenoprofen, indomethacin and isoniazid. b) Food increases the rate of absorption of ascorbic acid and metoclopramide. c) Food has no effect on the absorption of methyl-dopa and phenyl butazone.  Cont. Drug-Food Interactions 2. The type of food may also reduce the gastric emptying (e.g. fats and sugars), and consequently decreases the rate and extent of absorption of certain drugs, e.g. para-amino benzoic acid (PABA). 3. Drug interaction with certain constituents of food reduces also the drug absorption. The absorption of tetracycline is reduced through the complexation with Ca++ present in dairy foods.  Therapeutic Index and Margin of Safety All drugs in high doses produce toxic responses. The ratio of the minimum dose of a drug that produces toxicity and the minimum dose that produces the therapeutic response is called therapeutic index (or safety margin).  Cont. Therapeutic Index and Margin of Safety Therapeutic index is also determined by the ratio between the dose that kills 50% of the animals and the dose that produces 50% of therapeutic effect in animals. It is a key factor in classifying a drug as easy or difficult to use. When this ratio is 2 or less, the compound is considered to be toxic. Similarly, a drug of a ratio of 10 is safer than that of a ratio of 2.,i.e., the greater the ratio the more safe is the drug.  Unwanted Drug Effects a). Adverse effects related to dosage: 1. A drug typically produces several effects, but usually only one is considered as the primary goal of treatment. Most of the other effects are referred to as undesirable or side effects of that drug. 2. Toxic effects of drugs may be classified as pathological, or genotoxic (alterations of DNA). Their incidence and severity are related to the concentration of the toxic chemical in the body.  Cont. Unwanted Drug Effects 3. Most toxic effects of drugs take place in a predictable short time after administration. However, this is not always the case; Chloramphenicol- induced aplastic anemia may take place weeks after its administration. Carcinogenic effects of some chemicals have a long latency period (20-30 years).  Cont. Unwanted Drug Effects b). Adverse effects unrelated to dosage: 1- Idiosyncratic reactions: Idiosyncrasy is defined as a genetically- determined abnormal reactivity to a chemical. The observed response is qualitatively similar in all individuals, but it may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of the agent. For example, many black males (about 10%) develop a serious hemolytic anemia when they receive primaquine. Such individuals have a deficiency of erythrocytic glucose-6-phosphate dehydrogenase. Genetically-determined resistance to the anticoagulant action of warfarin is due to an alteration in the receptor for the drug.  Cont. Unwanted Drug Effects 2- Allergic reactions: ▪ Chemical allergy is an adverse reaction that results from previous sensitization to a particular chemical or to one that is structurally similar. Such reactions are mediated by the immune system. ▪ The terms hypersensitivity and drug allergy are often used to describe the allergic state. ▪ Allergic responses have been divided into four general categories: Type I (immediate hypersensitivity reactions), Type II, Type III and Type IV (delayed -hypersensitivity reactions).