pharmacodynamics

=HHP621= = = =__Pharmacodynamics__ is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect. It is often summarily stated that pharmacodynamics is the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.=

YOU TUBE VIDEOS [|PHARMACODYNAMICS SUMMARY]

[|PHARMACODYNAMICS]

Desired activity
The desired activity of a drug is mainly due to one of the following:
 * **Cellular membrane** disruption
 * **Chemical reaction**
 * Interaction with **enzyme** proteins
 * Interaction with structural proteins
 * Interaction with **carrier** proteins
 * Interaction with **ion channels**
 * **Ligand binding** to **receptors:**
 * **Hormone** receptors
 * **Neuromodulator** receptors [|Neuromodulator]
 * **Neurotransmitter** receptors
 * General anesthetics** were once thought to work by disordering the neural membranes, thereby altering the Na+ influx. **Antacids** and **chelating agents** combine chemically in the body. **Enzyme-substrate binding** is a way to alter the production or metabolism of key chemicals, for example **aspirin** irreversibly inhibits the enzyme **prostaglandin synthetase (cyclooxygenase)** thereby preventing [|**the prostaglandin induced inflammatory**]**response**. **Colchicine**, a drug for gout, interferes with the function of the structural protein **tubulin** **a key protein in spindle fiber formation** while **Digitalis**, a drug still used in heart failure, inhibits the activity of the carrier molecule, **Na-K-ATPase pump**. The widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their __normal action__ (**AGONIST**), __blocked action__ (**ANTAGONIST**).

In principle, a pharmacologist would aim for a certain **plasma concentration** of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and levels cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance. **Genetic factors** may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage. The field of **pharmacogenetics** studies these effects. = = __Genetic, environmental, and developmental factors that can interact, causing variations in drug response among patients__. ||
 * =**pharmacogenetic factors**=
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Undesirable effects
Undesirable effects of a drug include:
 * Increased probability of cell **mutation** (**carcinogenic activity**)
 * A multitude of simultaneous assorted actions which may be deleterious
 * Interaction (additive, multiplicative, or metabolic)
 * Induced physiological damage, or abnormal chronic conditions

Receptor binding
The binding of ligands (drug) to receptors is governed by the **law of mass action** which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. Although the receptors are fixed to a 2-dimensional membrane, an arbitrary control volume can be used to calculate the //dissociation constant//, where //L//=ligand, //R//=receptor, square brackets [ denote concentration] The fraction of bound receptors is found as //(1+[R]/[L·R])-1//, which can then be expressed using Kd as, Semi-log plots of two agonists with different Kd. This expression is one way to consider the **efficacy of a drug**, __in which the response may be directly proportional to the fraction of bound receptors__. Often the response is determined as a function of //log[L]// to consider many orders of dosage range. It is useful to note that 50% of the receptors are bound when //[L]=Kd//. A plot of the function for the bound fraction of receptors forms a typical model for the **dose response** of a drug. The graph shown represents the dose-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a **higher potency** (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The efficacy increases as a function of concentration.


 * Dose-response relationships and receptor activation by agonists**: An __important concept__ of **Pharmacodynamics** is the __dose-response relationship__ i.e. how much does a response changes when you increase drug dose. We use dose-response curves to: 1) determine a drug's potency and efficacy in order to compare its effects with other drugs (agonists) producing the same response and 2) determine how safe a drug is to use. In **Fig 1** (below), ISO, EPI and NE all interact with the same receptor and produce the same maximal effect (indicated by the vertical arrow labeled **EFFICACY**). Thus ISO, EPI and NE are equally **effective or efficacious**. Efficacy is proportional to the number of receptors activated, so ISO, EPI and NE all activate the same number of receptors and are described as full agonists**. But the dose-response curves don't look the same - what's different**


 * figure 1**

The difference is the dose (i.e.the amount of drug) required to activate a similar number of receptors. In order to compare the 3 drugs, we assess the concentration of each which produces a half-maximal increase in response. Since the maximal response for ISO, EPI and NE is 100%, the half-maximal response is 50%. But how much of each drug is required to cause that 50% increase in response? 1 mg of ISO (see the vertical red arrow), 3 mg of EPI (see vertical blue arrow - a dose 3 times higher than that for ISO) and 10 mg of NE (see vertical green arrow - a dose 10 times higher than that for ISO).

The difference between the 3 drugs is their **POTENCY**. ISO is more __potent__ than EPI and EPI is more potent than NE (ISO > EPI > NE), __but all 3 drugs are equally effective__ (i.e. **__produce the same max. response__**). **EFFICACY**


 * figure 2**

(EPI >NE>phenylephrine>ephedrine). Notice that EPI, NE and phenylephrine are equally effective (producing a 30% increase in blood pressure), but the maximal response to ephedrine is only a 20 % increase in blood pressure. **Since the size of the response is proportional to the number of receptors activated**, ephedrine activates fewer receptors than EPI, NE or phenylephrine. Thus ephedrine is an agonist (i.e. binds to a receptor and produces a response) which is only partially as effective as EPI, NE or phenylephrine. **Therefore ephedrine is described as a __partial agonist__**.
 * Dose-Response Curves for Full and Partial Agonists**: **Fig 2** shows 4 drugs that differ in potency

Antagonists will also have an effect on the dose-response curves for receptor agonists. In Fig 3 (below), EPI's potency (i.e. that concentration of EPI producing a half-maximal increase ) is 0.1 mg (see the **red curve, solid line**). When we examine the EPI dose-response curve in the presence of 1 mg of prazosin (**red** **curve**, **dashed line**, we notice that it takes 0.1 mg of EPI to produce a half-maximal response (i.e. EPI's potency has decreased from 0.1 to 0.3 mg/kg body wt). This is 3 times the amount of EPI it takes in the absence of prazosin (**red curve, solid line****).** When the dose of prazosin in increased 10 mg, EPI's potency is 1 mg/100 kg body wt (now EPI's potency has decreased from 0.1 mg to 1 mg or it is 1/10 as potent in the presence of prazosin) However, prazosin alone (i.e. when EPI concentration is 0) has no effect by itself (**gray triangles and line**), while blocking (i.e. //antagonizing//) the ability of EPI to do so. When prazosin in present at a fixed concentration, low doses of EPI have less of an opportunity to bind to the receptor. Since the number of receptors activated determines the size of the response, those receptors occupied by prazosin do not contribute to EPI's response. Because prazosin antagonizes EPI's effects, and reduces EPI's potency but not its efficacy, prazosin is described as a **//competitive antagonist//**. Notice how the drug phenoxybenzamine affects EPI's dose-response curve (**red curve, dashed line**. Once again EPI's potency has been reduced, but something else has changed as well -- EPI's maximum response has been reduced to 70% of the response to EPI alone. Since the response to EPI is proportional to the number of receptors it can activate, this means that phenoxybenzamine has prevented some receptors from being activated, no matter how high the concentration of EPI. Unlike the situation with prazosin, no amount of EPI can overcome the blockade of EPI receptors by phenoxybenzamine. Since EPI cannot compete for the receptors occupied by phenoxybenzamine, phenoxybenzamine is defined as a **//non-competitive antagonist//** [|Still not sure how antagonists work?] **PHARMACOKINETICS** The intensity of a biological response produced by a drug is related to the concentration of the drug at the site of action which is in turn affected by a variety of factors grouped together under the heading **//PHARMACOKINETICS.//** There are 4 pharmacokinetic phases which all affect drug concentration at the site of action. These phases are:
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 * Fig. 3**
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 * Effects of antagonists on agonist dose-response relationships:** Many therapeutic agents are designed to block the body's responses to naturally- occurring receptor agonists. In order to do this, these drugs must bind to agonist receptors, but must not activate them. Drugs which bind to receptors, do not activate them and prevent agonists from binding are called **//antagonists//**.
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 * Fig. 4**
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 * 1) Absorption: The ability of a drug to enter the blood stream. It is expressed as a rate (amount per time e.g. g/min, cc/hour) and indicates the speed with which the drug leaves its site of administration and the degree to which this occurs. Absorption is affected by the **//physiochemical properties//** of the drug - a drug's size, shape and charge all affect how well it will be absorbed (if you'd like to review the effect of pH on drug charge click [|here]), the //**types of transporters**// - remember that most drugs move by **//passive diffusion//** (i.e. from areas of high to areas of low concentration). However some drugs also ulitize **//carrier-mediated transporters//** for active transport process and facilitated diffusion, **//nature of the absorbing surface, blood flow to the site of absorption, drug concentration//** //(i.e. dose;// the easiest way to increase a drug response is to increase the dose), **//dose form//** and the **//route of administration//**
 * 2) **//Distribution//** is defined as the movement of a drug throughout the body to various tissue sites. Distribution is affected by the **//physiochemical properties of the drug, cardiac output and blood flow, the blood brain barrier//** and **//drug reservoirs//** (if you want to review the effects of drug reservoirs on drug distribution click [|here])
 * 3) **//Biotransformation//** reactions alter the chemical structure of a drug. Biotransformation occurs primarily in the liver and involves the enzymatic breakdown of drugs. The goal of biotransformation is to increase the charge on drugs and target them for excretion (i.e. increase their solubility in urine (water)) not necessarily to inactivate them. Thus while biotransformation reactions convert active drugs to inactivate metabolites, they also convert active drugs into active metabolites and inactive drugs into active metabolites.
 * 4) **//Excretion//** is the removal of drugs and biotransformation products from the body. This occurs primarily in the kidney. || ||

=**DRUG LEGISLATION & FDA**= The purpose of all drug legislation is to protect the consumer from false claims of benefit, harmful effects of drugs, and inappropriate administration of drugs. One way this has been achieved is to standardize drug doses. This is accomplished by requiring drug manufacturers to comply with standards established by the **United States Pharmacopeia (USP).** In order for a drug to carry the USP label, the amount of active ingredient present in the preparation must be within 95-105% of that indicated on the label. Thus 200 mg of USP ibuprofen must contain between 190 and 210 mg/tablet.

One of the most flexible pieces of legislation is the **Control Substances Act** which categorizes (schedules I-V) drugs according to their medical usefulness and potential for abuse and dependence. Drugs are scheduled from I (no accepted medical used, high abuse potential, and high risk of dependence) to V (accepted medical uses, low abuse potential, low risk of dependence). Drugs can move up or down depending upon changes in abuse potential (e.g. diazepam [VALIUM] has been a Schedule III and a Schedule IV drug), older drugs can be scheduled even if they hadn't been in the past (e.g. anabolic steroids are now Schedule III drugs) and illicit designer drugs of abuse (e.g. methamphetamine) can be added to the schedules.

The Food and Drug Administration (FDA) is the government agency which regulates the production and distribution of new drugs. All new drugs must go through animal studies and clinical trials in humans before they are approved for distribution. Animal studies are designed to identify tissues/organs sensitive to the drug's actions and to determine the **pharmacodynamic and pharmacokinetic** properties of the drugs. Testing in at least 2 animal species is required by law. After successful completion of animal studies, drugs enter clinical trials. In **phase I** clinical trials, new drugs are tested in normal volunteers to compare human data with those in animals and determine safe doses and assess safety. **Phase II** trials are performed in homogenous populations of patients (50-300 patients) with one group receiving the drug and another a placebo (called double-blind studies). These studies are designed to evaluate efficacy and safety and to establish dose-form. In **phase III** clinical trials, the FDA releases the drug into limited circulation. These studies usually last several years and are performed in a large patient population (several thousand) to evaluate phase II efficacy, and monitor the nature and incidence of side effects. After successful completion, drug companies can apply to market the drug. **Phase IV** trails compare drugs with others on the market, and examine long-term effectiveness and cost-effectiveness compared to other drugs on the market. Highly promising therapeutic agents do not necessarily go though all 3 phases of clinical trials, but early release can also have ethical concerns. Another important aspect of drug legislation is the control of generic drugs. Generic drugs by law must contain the same active ingredients as brand name drugs (e.g. Equate ibuprofen 200 mg and ADVIL ibuprofen 200 mg, respectively), and they must be present at a concentration of 80-120% of the amount indicated on the label (for generic ibuprofen 200 mg this means tablets must contain between 160 and 240 mg ibuprofen. However, there is no requirement that the inactive ingredients (i.e. chemical used to tablet the drugs or color the tablets) be the same. Since inactive ingredients can affect how well drugs are absorbed, generic drugs may not have the same bioavailability (i.e. fraction of the unchanged drug that reaches the systemic circulation following administration by any route) as a brand name preparation. This means that the amount of drug present in the blood and available for therapeutic effect may not be the same for a generic drug compared to a brand name drug.