Pharmacodynamics PDF

# PHARMACODYNAMICS Clinically useful drugs are formulated by drug companies into preparations that can be administered orally, intravenously or by another route. The formulation of a drug depends on the following factors. - The barriers that the drug is capable of passing. Intravenous drugs are in...

# PHARMACODYNAMICS Clinically useful drugs are formulated by drug companies into preparations that can be administered orally, intravenously or by another route. The formulation of a drug depends on the following factors. - The barriers that the drug is capable of passing. Intravenous drugs are injected directly into the blood stream. In contrast, oral preparations must pass through the wall of the gastrointestinal tract and blood vessel walls before entering the bloodstream. - The setting in which the drug will be used. An intravenous preparation might be appropriate for a drug which is administered during surgery and emergency, but would be inappropriate for home administration of aspirin. - The urgency of the medical situation. The delay before onset of action varies between preparations of the same drug. Emergency situations often call for intravenous administration of agents which might normally be administered by another route. - Stability of the drug. Drugs which are denatured by acid are not good candidates for oral preparations because they may be destroyed in the stomach. ## First Pass Effect Blood from the gastrointestinal tract passes through the liver before entering any other organs. During this first pass through the liver, a fraction of the drug (in some cases nearly all) can be metabolized to an inactive or less active derivative. The inactivation of some drugs is so great that the agents are useless when administered orally ## Pharmacokinetic and pharmacodynamic processes There are four processes in drug therapy: - **The Pharmaceutical Process:** Is the drug getting to the patient? This has to do with the properties of the formulation of a drug (for example the amount of drug in a tablet, drug crystal size, tablet compression, excipients). - **The Pharmacokinetic Process:** Is the drug getting to the site of action? Absorption, distribution and elimination. - **The Pharmacodynamic Process:** Is the drug producing the required pharmacologic effect? - **The Therapeutic process:** Is the pharmacologic effect being translated into an appropriate therapeutic effect? Pharmacodynamics (sometimes described as what a drug does to the body) is the study of the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding (including receptor sensitivity), postreceptor effects, and chemical interactions. Pharmacodynamics, with pharmacokinetics (what the body does to a drug, or the fate of a drug within the body), helps explain the relationship between the dose and response, ie, the drug's effects. The pharmacologic response depends on the drug binding to its target and the concentration of the drug at the receptor site influences the drug's effect. A major barrier to the achievement of this goal is the large variability in the pharmacological effect that is observed following drug administration. The ability to implement drug therapy in a safe and rational manner necessitates an understanding of the factors that cause this variability. One of the most important factor is the concentration of drug that is achieved at the site of action. ## Factors affecting pharmacodynamics A drug's pharmacodynamics can be affected by physiologic changes due to - A disorder or disease - Aging process - Other drugs Disorders that affect pharmacodynamic responses include genetic mutations, thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson disease, and some forms of insulin-resistant diabetes mellitus. These disorders can change receptor binding, alter the level of binding proteins, or decrease receptor sensitivity. Aging tends to affect pharmacodynamic responses through alterations in receptor binding or in postreceptor response sensitivity. Pharmacodynamic drug-drug interactions result in competition for receptor binding sites or alter postreceptor response. Drugs can elicit their pharmacological actions through the following: 1. **Drug action via a receptor** - agonists - antagonists - partial agonists 2. **Drug action via indirect alteration of the effect of an endogenous agonist** - Physiological antagonism - increase in endogenous release - inhibition of endogenous re-uptake - inhibition of endogenous release - prevention of endogenous release 3. **Drug action via inhibition Transport processes** 4. **Drug action via enzyme inhibition** 5. **Drug action via enzymatic action or activation of enzyme activity** 6. **Drug action via other miscellaneous effects** - Chelating agents - Osmotic diuretics - Volatile general anaesthetics - Replacement drugs ### Short and long term effects of drug at receptors - **Short term effects** - **Long term effects** ## Pharmacology at the Cellular Level Receptors are macromolecules involved in chemical signaling between and within cells; they may be located on the cell surface membrane or within the cytoplasm. Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity). Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible or irreversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors A drug's ability to affect a given receptor is related to the drug's affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity- degree to which a ligand activates receptors and leads to cellular response). A drug's affinity and activity are determined by its chemical structure. The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity. Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptor-mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular second messenger substances) may be interposed between the initial molecular drug-receptor interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules can often be used to produce the same desired response. ## Factors influencing receptor binding Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary from tissue to tissue. Drugs, aging, genetic mutations, and disorders can increase (upregulate) or decrease (downregulate) the number and binding affinity of receptors. For example, clonidine downregulates alpha2receptors; thus, rapid withdrawal of clonidine can cause hypertensive crisis. Chronic therapy with beta-blockers upregulates beta-receptor density; thus, severe hypertension or tachycardia can result from abrupt withdrawal. Receptor upregulation and downregulation affect adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance, acquired resistance, postwithdrawal supersensitivity). Ligands bind to precise molecular regions, called recognition sites, on receptor macromolecules. The binding site for a drug may be the same as or different from that of an endogenous agonist (hormone or neurotransmitter). Agonists that bind to an adjacent site or a different site on a receptor are sometimes called allosteric agonists. Nonspecific drug binding also occurs ie, at molecular sites not designated as receptors (eg, plasma proteins). Drug binding to such nonspecific sites, such as binding to serum proteins, prohibits the drug from binding to the receptor and thus inactivates the drug. Unbound drug is available to bind to receptors and thus have an effect. ## Receptor types and their location Receptors are generally proteins or glycoproteins that are present on the cell surface, on an organelle within the cell, or in the cytoplasm. There is a finite number of receptors in a given cell. Thus, receptor-mediated responses plateau upon (or before) receptor saturation. When a drug binds to a receptor, one of the following actions is likely to occur: - An ion channel is opened or closed. - Biochemical messengers often called second messengers (cAMP, cGMP, C++, inositol phosphates) are activated. The biochemical messenger initiates a series of chemical reactions within the cell, which transduce the signal stimulated by the drug. - A normal cellular function is physically inhibited (c.g., DNA synthesis, bacterial cell wall production, protein synthesis) - A cellular function is "turned on" (cg., steroid promotion of DNA transcription). ## Clark's Theory 1 Drug response is proportional to the number of receptors occupied. 2 Assumed that all drug-receptor interactions were reversible 3. Assumed that drug binding to receptors represented only a fraction of available drug. 4. Assumed that each receptor bound only one drug. ## Stephenson's modified theory (generally accepted) 1 Drug response depends on both the affinity of a drug for its receptors and the drug's efficacy. 2. Described spare receptors. Propose that maximal response can be achieved even if a fraction of receptors (spare receptors) are unoccupied. ## Terminology **Affinity:** Affinity refers to the STRENGTH of binding between a drug and its receptor. The number of cell receptors occupied by a drug is a function of equilibrium between drug which is bound to receptors and drug that is free. A high-affinity agonist or antagonist is less likely than a low-affinity drug to dissociate from a receptor once it is bound. **Dissociation Constant (KD):** The dissociation constant is the measure of a drug's affinity for a given receptor. It is the concentration of drug required in solution to achieve 50% occupancy of its receptors. Units are expressed in molar concentration. **Agonist:** Drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors. Usually, a number of receptors must be occupied by agonists before a measurable change in cell function occurs. For example, a muscle cell does not depolarize simply because one molecule of acetylcholine binds to a nicotinic receptor and activates an ion channel. Cathecolamine adrenaline is an agonist at ẞ-adrenoceptor. When it binds to ẞ-adrenoceptor in the heart, it increases the heart rate. Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect. Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule **Strong Agonist:** An agonist which causes maximal effects even though it may only occupy a small fraction of receptors on a cell. **Weak Agonist:** An agonist which must be bound to many more receptors than a strong agonist to produce the same effect. **Partial Agonist:** A drug which fails to produce maximal effects, even when all the receptors are occupied by the partial agonist. **Antagonist:** Antagonists inhibit or block responses caused by agonists. Ligands that prevents an agonists from binding to a receptor and thus prevents its effects is called antagonist However, antagonists do not produce any pharmacological effect mediated by the receptors. For example, propanolol is a ẞ-adrenoceptor antagonist. When it binds to ẞ-adrenoceptor in the heart, it prevents cathecolamine-induced tachycardia (in response to exercise). Another example is acetylcholine receptor blocker such as atropine is antagonist because it prevents access of acetylcholine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body **Competitive Antagonist:** Competes with agonists for receptors. During the time that a receptor is occupied by an antagonist, agonists cannot bind to the receptor. The number of receptors appears un changed because high doses of agonist will compete for essentially all the receptors The agonist affinity, however, appears lower because a higher dose of agonist is required, in the presence of antagonist, to achieve receptor occupancy. Because the antagonism can be overcome by high doses of agonist, competi tive antagonism is said to be surmountable. **Noncompetitive Antagonist:** Binds to a site other than the agonist-binding domain. Induces a conformational change in the receptor such that the agonist no longer "recognizes" the agonist-binding domain. Even high doses of agonist cannot overcome this antagonism. Thus it is considered to be insurmountable. The number of agonist-binding sites appears to be reduced, but the affinity of agonist for the "unantagonized sites" remains unchanged. **Irreversible Antagonist (Nonequilibrium competitive):** Irreversible antagonists are also insurmountable. These agents compete with agonists for the agonist-binding domain. In contrast to competitive antagonists, however, irreversible antagonists combine permanently with the receptor. The rate of antagonism can be slowed by high concentrations of agonist. Once an irreversible antagonist binds to a particular receptor, however, that receptor cannot be "reclaimed" by an agonist. ### Other forms of antagonism In addition to pharmacologic antagonism, there are two other mechanisms by which a drug can inhibit or block the effects of an agonist: - **Physiological Antagonism:** Two agonists, in unrelated reactions, cause opposite effects. The effects cancel one another. - **Antagonism by Neutralization:** Two drugs bind to one another. When combined, both drugs are inactive. Chemicals that are produced in the body and exert there actions through receptors (e.g., acetylcholine, insulin) are termed endogenous ligands. ## Other terminology The following terms describe the actions of drugs on whole organisms. These terms are more likely to be used in a clinical setting than terms relating to drug-receptor interactions. - **Efficacy:** The degree to which a drug is able to induce maximal effects. Efficacy is unrelated to affinity. For example, a low affinity agonist, might produce a response equal to or greater than that produced by a high affinity agonist. Antagonists do not have efficacy, since they do not produce responses. - **Potency:** The amount of drug required to produce 50% of the maximal response that the drug is capable of inducing. The following comparison is made to help the you to distinguish between efficacy and potency: - 'Drug A' maximally reduces heart rate by 20 beats per minute. The dose required to reduce heart rate by 10beals per minute is 200 mg. - 'Drug H' maximally reduces heart rate by 20 beats per minute. The dose required to reduce heart rate by 10 beats per minute is 100 mg. - 'Drug C' maximally reduces heart rate by 10beats per minute. The dose required to reduce heart rate by 5 beats per minute is 200 mg. From these data, we can conclude that: - 'Drug B' is equally effective and twice as potent as 'Drug A'. - 'Drug C is half as effective but equally potent as 'Drug A'. - 'Drug C is half as effective and half as potent as 'Drug B'. - Nothing can be said about the affinity of any of the drugs based on the information provided above. (Remember that affinity is a measure of the "strength" of binding between the drug and its receptor, and cannot be measured clinically). ## Drug action via indirect alteration of the effect of an endogenous agonist. - Physiological antagonism - increase in endogenous release - Inhibition of endogenous re-uptake - Inhibition of endogenous metabolism - Prevention of endogenous release ## Drug action via the inhibition of transport processes - Diuretics - Calcium channel blockers - Insulin - Probenecid - Drug acting on potassium channels ## Drug action via enzyme inhibition - Cholinesterase - neostigmine - Xanthine oxidase – allopurinol - Monoamine oxidase (MAO) inhibitors - Na/K-ATPase – cardiac glycosides - Inositol phosphatises- lithium - Phosphodiesterases – xanthinesamrinone, sildefil - **Other drugs that act via enzyme inhibition include the following:** - Warfarin which inhibits vitamin k reductase - Aspirin and other non-steroidal anti-inflammatory drugs which inhibit yhe enzyme involve in prostaglandin synthesis - Captopril and related drugs which inhibit the angiothesin-converting enzyme - Disulfiram which inhibit aldehide dehydrogenase - Some anticancer drugs such as cytarabine which inhibits DNA polymerase - Some anti infective agents which act by inhibiting bacteria or vira enzyme. For example trimethoprim inhibit bacterial dihyrofolate reductase, the quinolonesinhibit bacteria DNA gyrase and zidovudine and didanosine inhibit the reverse transcriptase of the human immunodeficiency virus (HIV) ## Drug action via direct enzymatic activity or the activation of enzymes - Enzyme replacement in genetic and acquired enzyme deficiencies - Drugs action on the clothing system - cancer chemotherapy - other examples ## Drug action via other miscellaneous effects - **Chelating agents** Drugs that chelates metal can be used to hasten the removal of those metals from the body eg - Calcium sodium edentate chelates many divalent and trivalent metals and used in the treatment of poisoning - Dimercaprol chelates certain heavy metals and its used in treatment mercury poisoning. - Deferoxamine chelates iron and is used in the treatment of iron poisoning and iron overload that occurs in repeated blood transfusion - Penicillamine chelates copper and is used in the treatment of hepatolenticular degeneration (Wilsons disease) in which there is build of copper in the basal ganglia and in the liver. - **Osmotic diuretics** Mannitol is hexahydric alcohol related to mannose and an isomer of alchohol and an isomer of sorbitol. It is freely filtered in glumerulus but reabsorbed to a small extent by the renal tubulus. The increase concentration in the tubule takes water with it, thus increase the urine volume. It is used to produce dieresis used in the treatment of acute poisoning and cerebral edema. - **Volatile general anaesthetics** examples are halothane, methoxyflurane, enflurane and trichloroethhlene and nonhalogenated agents eg nitrous oxide, ether and cyclopropane. which produce similar effects in the brain - **Replacement drugs** examples include the use of ferrous salt in the treatment of anaemia and intramuscular use of hydroxocobalamine in the treatment of vitamin B deficiency ## STEREOISOMERISM AND DRUG ACTION A compound with the same or identical molecular formular having different arrangement of atoms in the public space. These isomers may have different chemical or physical properties. Stereoisomers are of two types enantiomers and diastereoisomers Examples of drug enantiomers include d-propanolol and 1-propanolol, R-warfarin and S-warfarin, L-glucose (laevulose) and D-glucose (Dextrose). Quinine and quinidine are examples of diastereoisomers ## Pharmacokinetic differences between stereoisimers - **Absorption** Both D and L-methotrexate are passively absorbed to small extent, but L-methotrexate transported actively across the gut and D-methotrexate is not. - **Distribution** d-propanolol binds more to plasma albumin than 1-propanolol, s-warfarin is more highly bound to albumin R-warfarin - **Elimination** e.g. the first pass hepatic metabolism of S-metoprolol is less than that of R-metoprolol. ## Pharmacodynamic differences between stereoisomers Different stereoisomers have different pharmacological actions for example L-propanolol is an active stereoisomer that acts ß-adrenoceptor antagonist whereas D-propanolo is not. ## Interaction between stereoisomers Isomers can compete for binding site eg Methadone, S-methadone antagonises the respiration depressant of R-stereoisomer ## Drug interactions and stereoisomers Eg metronidazole and phenybutazone inhibits the metabolism of warfarin. It affects more potent enantiomer S-warfarin. ## Clinical relevance of stereoisomers Most drugs are racemic mixture. For example, phenybutazone inhibits the metabolism of S-warfarin but induces the metabolism R- warfarin. But do not affect the racemic mirxuture In some cases stereoisomers improves the quality of drug therapy eg R-timolol has advantage over S-timolol ## The dose-response curve The dose-response curve is the graphical representation of the relationship between the dose of a drug versus the effects that the drug exerts on the system tested, depicting the magnitude of the response of the organism, either therapeutic or toxic. It is generally plotted on an x/y-axis graph where the x-axis represents the drug dosage or the function of dosage (log concentration), and the y-axis represents the measured effects. The resulting graph is usually a sigmoidal curve with bottom and top plateaus. The response is measured within a range of concentration and often not measured at different times after the biological system is treated with the drug. ### Graded dose-response curves Graph that shows the magnitude of drug actions against the concentration (or dose) of drug required to induce those actions. The curve represents the effects and dose of a drug within an individual animal or tissue rather than in a population. The receptor affinity, absorption, plasma protein binding, distribution, metabolism, and excretion of a drug all affect the dose response curve. A hypothetical dose-response curve has features that vary - Potency (location of curve along the dose axis) - Maximal efficacy or ceiling effect (greatest attainable response) - Slope (change in response per unit dose) The Drug's potency and efficacy can be obtained from the dose response curves. Potency indicates the amount of drug needed to produce an observable effect. Limited clinical significance can be actually obtained from the potency. It is only useful for drug selection if the potency of a drug is so small that a very large dose must be given for any response, so large that it becomes burdensome for the patient to take. On the other hand, the maximum effect that a drug can induce on the tested subjects irrespective of concentration is termed *efficacy*. The steepness of the dose response curve can illustrate the efficacy of the drug. Efficacy is one of the main characteristics for consideration of prescription drugs. - The dose-response curve is one of the most important parameters in the pharmacological field. It helps determine the therapeutic beneficial effects, dosage, and frequency of a drug. It is also used to determine the safety or hazard level of drugs, food, pollutants, or other substances that are consumed by the human body. ## GRADED RESPONSES TO DRUGS: THE DOSE-RESPONSE CURVE IN DRUG THERAPY The pharmacological effect of drug is related to the concentration of at the site of action. That is the higher the dose the greater the pharmacological produced. The relationship between the concentration of drug at the site of action and the intensity of its pharmacological effect is called its *dose-response curve*. This could also be adapted to fit order modes of action of drugs such as enzyme inhibition, enzyme activation, and alteration in ion transport, and indirect actions mediated via receptors. Let us suppose that a drug molecule combines with receptor to produce a pharmacological effect. Let us assume a drug D combines with the receptor R to produce drug-receptor complex DR (D) + (R) ► DR Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in what is often a complex sequence of steps: Drug (D) + receptor-effector (R)>> drug-receptor-effector complex → effect D + R → D-R complex → activation of coupling molecule → effector molecule → effect Inhibition of metabolism of endogenous activator → increased activator action on an effector molecule → increased effect Even in intact animals or patients, responses usually increase in direct proportion to dose of the drug. As doses increase, the response also increases but concentration may be reached at which further increase concentration corresponds to no increase in response. In idealized or in vitro systems, the relation between drug concentration and effect is described by a hyperbolic curve according to the following equation: $E=\frac {E_{max} \times C}{C + EC_{50}}$ where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect. ## Curve characteristics The dose of the applied stimulus is generally plotted on the X axis of the dose-response curve, with the magnitude of response on the Y axis. With these axes, most dose-response curves are sigmoidal, with an exponentially increasing effect per dose unit until a point where increasing the dose has a gradually lesser relative influence on response. Once plotted, the gradient of the dose-response curve can be used to infer the EC50 or other specific metric of interest. ## Importance in pharmacology However, dose-response curves are perhaps most associated with pharmacology, where they are utilized extensively to establish the safety and efficacy of drugs, therapeutics, environmental toxins, and novel treatments within a wide range of living organisms. ## Application in toxicology The dose-response relationship is a central concept in toxicology. It is a framework around which all hazard assessment testing is performed and dose-response model extrapolations are based and from which environmental regulations are derived ## Radiation Measuring and plotting the response to exposure to non-chemical agents such as ratiation is nominally termed a stimulus-response curve. ## Mathematical treatment Numerous mathematical protocols have been developed for the treatment of dose-response data, often for highly particular applicatons, but some of the most common extrapolations include the above-mentioned LD50 and EC50, in addition to median inhibitory concentration (IC50), the concentration required to inhibit a specific function such as protein transcription or cell division, which is perhaps the most commonly reported in determination of drug efficacy. ## Toxicity measurement One of the most commonly measured parameters concerning dose-response curves is the toxicity of a chemical, drug, or toxin towards a specific cell line or tissue in vitro, for example, or animal or genetic sub-group in vivo. In this case, the stimulus under investigation is applied to the organism of interest, and the toxicity is directly interpreted from the dose required to kill a proportion of the population. ## Use of dose-response assessment to develop risk assessment advice ## Drug receptor interactions **Drug Interactions:** Drugs may interact with one another according to the following mechanisms: - **Altered absorption:** Drugs may inhibit absorption of other drugs across biologic membranes(e.g., antiulcer agents that coat the stomach may decrease Gl absorption of other drugs). - **Altered metabolism:** induction or competion for metabolizing enzymes. - **Plasma protein competition:** Drugs that bind to plasma proteins may compete with other drugs for the protein binding sites. Displacement of a 'Drug A' from plasma proteins by 'Drug B' may increase the concentration of unbound 'Drug A' to toxic levels. - **Altered excretion:** Drugs may act on the kidney to reduce excretion of specific agents (e.g., probenecid competes with sulfonamides for the- same carrier, Increasing the risk of sulfonamide toxicity). Addition,. synergism, potentiation or antagonism are the terms used to describe drug interactions ## LD50 LD stands for "Lethal Dose". LD50 is the amount of a material, given all at once, which causes the death of 50% (one half) of a group of test animals. The LD50 is one way to measure the short-term poisoning potential (acute toxicity) of a material. ## LC50 LC stands for "Lethal Concentration". LC values usually refer to the concentration of a chemical in air but in environmental studies it can also mean the concentration of a chemical in water. ## LD50 and LC50 values a measure of acute toxicity Acute toxicity is the ability of a chemical to cause ill effects relatively soon after one oral administration or a 4-hour exposure to a chemical in air. ## Therapeutic Index A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. The larger the therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity The *therapeutic index* (TI; also referred to as *therapeutic ratio*) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms *therapeutic window* or *safety window* refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity. For animals in pre-clinical trials. $Therapeutic Index =\frac{LD_{50}}{ED_{50}}$ For humans in clinical trials. $Therapeutic Index =\frac{TD_{50}}{ED_{50}}$ ## Tolerance, Dependence and Withdrawal **Tolerance** represents a decreased response to a drug. Clinically, it is seen when the dose of a drug must be increased to achieve the same effect. Tolerance can be metabolic. (drug is metabolized more rapidly after chronic use), cellular (decreased number of drug receptors, known as downregulation), or behavioral (an alcoholic learns to hide the signs of drinking to avoid being caught by his colleagues). **Dependence** occurs when a patient needs a drug to "function normally." Clinically, it is detected when cessation of a drug produces withdrawal symptoms. Dependence can be physical (chronic use of laxatives leads to dependence on laxatives to have a normal bowel movement) or may have a psychological component. **Withdrawal** occurs when a drug is no longer administered to a dependent patient. The symptoms of withdrawal are often the opposite of the effects achieved by the drug (cessation of antihypertensive agents frequently causes severe hypertension and reflex tachycardia). In some cases, such as withdrawal from morphine or alcohol, symptoms are complex and may seem unrelated to drug effects. ## Drug potency Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug Y or Z. drugs X and Z have equal efficacy indicated by their maximal attainable response (ceiling effect). Drug Y is more potent than drug Z, but its maximal efficacy is lower. ## Potent power Drug potency refers to the relative amount of a drug required to produce a desired response Drug potency is also used to compare two drugs. If drug X produces the same response as drug Y but at a lower dose, then drug X is more potent than drug Y. ## Dose-response curve As its name implies, a dose-response curve is used to graphically represent the relationship between the dose of a drug and the response it produces. ## Maximum effect On the dose-response curve, a low dose usually corresponds to a low response. At a low dose, a dosage increase produces only a slight increase in response. With further dosage increases, the drug response rises markedly. After a certain point, however, an increase in dose yields little or no increase in response. At this point, the drug is said to have reached maximum effectiveness. ## Margin of safety Most drugs produce multiple effects. The relationship between a drug's desired therapeutic effects and its adverse effects is called the drug's *therapeutic index*. It's also referred to as its *margin of safety*. The therapeutic index usually measures the difference between: - an effective dose for 50% of the patients treated - the minimal dose at which adverse reactions occur. This graph shows the dose-response curve for two different drugs. As you can see, at low doses of each drug, a dosage increase results in only a small increase in drug response (for example, from point A to point B for drug X). At higher doses, an increase in dosage produces a much greater response (from point B to point C). As the dosage continues to climb, however, an increase in dosage produces very little increase in response (from point C to point D). This graph also shows that drug X is more potent than drug Y because it produces the same response, but at a lower dose (compare point A to point E). ## Narrow index = potential danger Drugs with a narrow, or low, therapeutic index have a narrow margin of safety. This means that there's a narrow range of safety between an effective dose and a lethal one. On the other hand, a drug with a high therapeutic index has a wide margin of safety and poses less risk of toxic effects. ## Decreased response... In addition, it's important to remember that certain drugs have a tendency to create drug tolerance and drug dependence in patients. Drug tolerance occurs when a patient develops a decreased response to a drug over time. The patient then requires larger doses to produce the same response. ## ...and increased desire Tolerance differs from drug dependence, in which a patient displays a physical or psychological need for the drug. Physical dependence produces withdrawal symptoms when the drug is stopped, whereas psychological dependence is based on a desire to continue taking the drug to relieve tension and avoid discomfort ## Factors affecting a patient's response to a drug Because no two people are alike physiologically or psychologically, patient response to a drug can vary greatly, depending upon such factors as: - age - cardiovascular function - diet - disease - drug interactions - gender - GI function - hepatic function - infection - renal function.