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Basic Pharmacology v2

First week of lectures in Drug class

Jaime Diaz

on 2 April 2013

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Transcript of Basic Pharmacology v2

to Pharmacology The essential questions involve: how drugs enter, navigate through, exit the body, and what do they do during this time. First, What is a drug? A drug is any exogenous substance or compound. Second, we must understand that for there to be a particular outcome, behavioral or otherwise, following the taking of a drug, the drug must be present in sufficiently high concentrations at certain receptors (i.e. structures that will recognize the presence of the drug and then cause some change to occur). Here are two concept maps that
illustrate these issues. Routes of Administration - How Drugs Enter the System 1. Oral - namely, eat it.
major limitations.
First, depends on a person that is willing and able to swallow.
Second, if a person has an irritable stomach and is vomiting then the person will be unable to keep a drug dose down.
Third, depending on the contents in the stomach, the absorption from an oral route will be variable.
And finally, the stomach is a rather hostile acid environment which may interfere with the absorption of certain types of drugs. 2. Rectal - One can use the other side of the alimentary canal with the use of special suppositories. For example, a young infant, for whom throwing up is common, may have a drug administered via suppository.
The main limitations of this route is the tremendous variability of absorption depending on the presence of materials at the administration site as well as the speed of intestinal movement. B. Parenteral Routes.
Parenteral routes of drug administration are all those routes that do not make use of the alimentary canal. The time from the administration of a drug to the time that population of drug molecules enter the blood is called "absorption". Capillaries are not solid tubes.
Usually there is ample room between the cells that form the capillaries to allow small things like nutrients and drug molecules to move out of the blood. In the circulation, there will a portion of a given population of drug molecules that will attach, i.e. "bind", to large proteins in the blood, typically albumin. These drug molecules are said to be "bound" as opposed to "free". How are drugs absorbed (how do drugs cross into the capillaries) How drugs distribute
through the system The notable compartments are fat and blood - the circulatory system
All the compartments in our body have one feature in common : they all must make contact and interact with the blood compartment. However, regardless of the route of administration, once in the circulation, a population of drug molecules has access to virtually every compartment of the body. Let us now examine the actual entry point into body compartments- the capillary. When there is a population of drug molecules in the circulation, there is a concentration gradient that is very similar to the one illustrated in figure 2.
These drug molecules will move out wherever it can into all the compartments in its path. Once outside the circulation, the drug molecules are in the fluid surrounding the cells of that particular compartment. These drug molecules can then interact with any drug receptors that are on the surface of the cells in that compartment. Therefore unless there is a specific transport mechanism for that drug molecule in the membrane, then to enter a cell that drug molecule has to go through the membrane, which is to say that it has to go through a double layer of fat. Only drug molecules that can dissolve in fat can accomplish crossing a cell membrane. Thus an important characteristic of drug molecules is their ability to dissolve in fat and that is called "lipid solubility". Since drugs that influence behavior typically alter brain functioning, we should direct our attention to those drugs that have the ability to enter the brain compartment. However, due to a unique protective system, it is much more difficult to enter the brain compartment than any other body compartment. How drugs distribute
and the
Blood-Brain-Barrier There is a basic dilemma : except for a few exceptions, there are no new neurons in the adult brain in any mammal. In fact there are a number of neurons that die every day. However, the brain also has a demanding need for nutrients and oxygen and so blood flow through the brain is quite high which increases the risk of some toxic agent entering the brain. There are two components to the blood-brain-barrier :
1) the capillary beds that feed the brain are specialized to have “tight gaps”; and
2) the presence of a special type of cell - called glial cells. The cells that form the brain capillaries have virtually no gaps between them. These cells are so tightly packed that drug molecules cannot pass between them.
The result of these tight gaps is that a molecule must go through the membrane of the capillary cells in order to get out of circulation and into the brain compartment.
The brain capillaries are wrapped by glial cells that then make contact with neurons. Thus for a molecule to enter the brain compartment it must :
1) go through the cell which forms the capillary, which means it must cross two membranes (one to enter the capillary cell and one to exist from the capillary cell); and 2) go through the glial cell, which means it must cross two additional membranes (one to enter the glial cell and one to exist from the glial cell). The kidneys filter out waste in the blood and collect it in the bladder as urine for eventual excretion. This process is the main mechanism for removing drug molecules from the blood. Drug Biotransformation
and Excretion The functioning of the liver thus becomes a major factor in the excretion of these highly lipid soluble drug molecules. The liver has several critical functions, two of which are :
1) the mobilization of newly ingested nutrients and
2) to protect the body from toxic substances in the blood. the liver performs the critical function of transforming highly lipid soluble drugs into a form that the kidney can excrete. The enzymatic biotransformation that occurs in the liver usually results in a drug molecule that has been changed from a highly lipid soluble molecule to a less lipid soluble (more water soluble) molecule that the kidney can contain and excrete. Thus the primary process of excreting a dose of drug molecules that are psychoactive involves two steps : 1) biotransformation of the molecules by liver enzymes into a less lipid soluble (more water soluble) form; and 2) filtering from the blood, and collection into the urine for subsequent excretion from the body. However, there are some instances when the liver transformation results in a changed molecule that is still highly lipid soluble and able to exert effects on the brain. These molecules are called "active metabolites". The kidneys are not the only avenue for drug excretion. There are three other mechanisms for drug molecules to leave the body. 1) The lungs provide another mechanism which is typical for the gaseous anesthetics, like ether and halothane, that are inhaled (i.e., parenterally administered, via a pulmonary route). 1) The lungs provide another mechanism which is typical for the gaseous anesthetics, like ether and halothane, that are inhaled (i.e., parenterally administered, via a pulmonary route). 2) In the process of biotransformation in the liver cells, some drug molecules may accumulate in the bile to be later released in the intestines. 3) drug molecules will find their way into fluid compartments like sweat and mother's milk. Half-Life and Dose
Response Curves In general, the half life of a drug is the time it takes to clear half of an initial dose from the blood.

It takes approximately 4 1/ 2 half-lifes to clear about 94% of a given dose. Half-life percent remaining
0 100
1 50
2 25
3 12.5
4 6.2
5 3.1
6 1.6 There are two fundamental criteria for calling a structure a "drug receptor".
First, the drug molecule must be able to attach or bind to this structure. Secondly, the presence of the "bound" drug molecule on this structure will alter some normally occurring physiological event. Typically "drug receptors" are proteins and there are at least three distinctive types of drug receptors :
1) receptors for neurotransmitters
2) enzymes
3) membrane transport mechanisms A population of drug molecules in the circulation will bind to as many receptors as its concentration gradients and absolute numbers will allow.
Often the receptors for a drug exists both inside AND outside the CNS. Thus a drug will typically exert a variety of different effects.
A drug never has a single effect, but rather has multiple effects. The greater the number of drug molecules administered (i.e. the higher the dose) the greater the number of receptors that are effected and the greater the overall drug effect. Thus, the dose of a drug can often be correlated to the intensity of any given effect. This relationship is described in the "dose response curve" and it can be expressed in several ways.
One way is to examine the actually intensity of a given response to a drug. If one sees a particular response to a certain dose of a drug, then would that response increase in intensity if one were to give more of that drug ? Another way to express dose response relationships is to examine frequency distributions of a certain response to various drug doses. In this method one looks at the population of subjects and determines how many subjects show a particular behavior at certain doses. Another way of expressing the frequency distributions of certain responses to various drug doses is to plot the cumulative percent of subjects showing the particular drug effects. The percent of the subjects that show a particular response is expressed as in a subscript to the letters "ED". In our example then, dose "A" is the ED10 which means that, dose "A" is the effective dose for 10% of the subjects for eliciting that particular behavior. Recall that a drug has will have multiple effects. A dose response curve can be generated for each of these effects.
Notice that the dose response curve for death, called the "lethal dose" response curve or "LD" curve, occurs at higher doses. The relationship of a particular dose response curve to the lethal dose curve is reflected in the "Therapeutic Index" (TI). The therapeutic index is determined by dividing the dose that will kill 50% of the subjects by the effective dose for half the population (LD50/ED50).
The larger this value the safer the dose range of that drug.
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