(Transcribed from Dr. Babinni’s lecture, 7 June 2000 by Brian Buschman)
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Pharmacokinetics is the study of how the body processes drugs. It encompasses the absorption, distribution and elimination of drugs.
Pharmacodynamics is the study of the effects that drugs have on the body. It includes the effect, actions and mechanisms of actions.
A drug is able to function on either cellular or non-cellular target sites. The target sites may be different from the site where the drug is most concentrated. The site of action may also throw you off on guessing the action. Multiple drug with different effects may have similar target sites.
Non-cellular targets of drug action include water (adjusting permeabilities), H+ or OH- ions and metal ions. The non-cellular targets all center around general chemistry.
Cellular drug targets include effecting cellular macromolecules and membrane lipids.
The main classes of drug receptors are:
1) Enzymes
2) Transport proteins
3) Ion channel proteins
4) Structural proteins
5) Nucleic acids
6) Regulatory proteins
They all seem to be some version of either protein or nucleic acid which are related to proteins.
Drugs interact with the receptors through many types of interactions. The two that are not very common are ionic and covalent bonds. These are seldom used in drug-receptor interactions since they are very high energy (relatively speaking) which make it hard to produce an effect where the drug will be removed so that it can be eliminated. Most drug-receptor interactions are based on hydrophobic, Van der Waals interactions or H-bonds.
Antagonists fail to produce the response when they bind to the receptor.
Agonists can be full, partial or inverse antagonists. A full agonist produces the maximal response when bound to the receptor. A partial agonist a partial response, An inverse agonist will produce a maximal response opposite to that produces by the full agonist.
The ideal drug-receptor interactions have a hyperbolic relationship between the dose and response. The relationship is governed by the occupancy theory which is based on the law of mass action. The mathematical relationships are based on the assumptions that:
1) The law of mass action only applies to one drug molecule interacting with one receptor.
2) The receptors are identical and equally accessible to the drug.
3) The complex dissociated easily.
4) There are many available drug molecules so the available concentration does not change with the binding of a few molecules.
5) Receptors unction in an all-or-none style.
6) Emax comes when all receptors are occupied.
The equations to calculate effect and binding are based on Michaelos-Menten kinetics:
Where: E = effect
Emax = maximal effect
B = binding
Bmax = maximal binding
C = concentration
EC50 = Concentration needed to produce ˝ of Emax
KD = Concentration needed to produce ˝ of Bmax
There is a concept of spare receptors. This goes against one of our assumptions in saying that Emax can be achieved without binding of all of the receptors. (Katzung, Ch. 2). In this case, the receptors may produce an effect even after dissociation of the drug. One can tell there are spare receptors if KD is greater then EC50 for a drug.
Antagonists are drugs that prevent or counteract the effect of another drug. There are four main classes of antagonists:
1) Receptor-block antagonists which can be classified into two subtypes. The first are reversible antagonists which inhibit the action of the drug by competitively binding to and blocking the receptor. The other class is irreversible antagonists that permanently bind to receptors to block them. One example of irreversible antagonists you should know by now are the organophosphates that bind the ACh receptors that Dr. Glasser talked about.
2) Physiological antagonists bind to receptors and cause an effect opposite to the desired effect, just like inverse agonists do.
3) Pharmacokinetic antagonists interact with the receptors and down regulate the effect that is achieved by the binding of the agonist to the receptor. This may be thought of as allosteric inhibition.
4) Chemical antagonists interact directly with the agonist to inactivate or prevent it’s binding to the receptor.
Drugs interact with receptors that cause actions on the inside of the membrane by all of the second messenger systems that we have discussed in physiology (DAG, IP3, adenylate cyclase) or by being coupled directly to a process such as an ion channel.
The graded dose response curve graphs the amount of response of a drug with respect to the dose given in an individual. It can give you Emax, EC50, Bmax and KD.
Quantal dose response curves graph the number of patients in a population that respond to a given dose of a drug. The response measured may be a minimum to achieve a response, to get a tonic response or the LD. The quantal dose response curve will give you the ED50 (effective dose), TD50 (toxic dose) or LD50 (lethal dose).
Compliance is how closely the patient follows the prescription. Non-compliance is often influenced by:
1) Inadequate doctor-patient relationships.
2) Daily changes in symptoms may be less on a given day and the patient may feel they don’t need the drug that day.
3) Patients factors include fear of addiction, fear of the disease implied by the prescription, they are too young or old to follow the directions properly, imperceptions of the severity of the disease.
4) High rates of side effects and how complicated a drug regime is all lead to non-compliance.
Drug-drug interactions are the result of any effect that one drug has on another when both are administered simultaneously. Interactions may occur because of mixing of drugs in their preparation (intentional) or when two drugs are taken at the same time which have a similar site of action. The interactions can be beneficial, harmful or not really make much difference.
Drug interactions are dose dependant and can be of a pharmacokinetic factor (affect how the drug reaches the site) or of a pharmacokinetic nature (hot the drug works on the site). Pharmacodynamic drug interactions fall into four categories:
1) Additive –.The two drugs together produce an effect equal to the sum of the effect that each would produce individually.
2) Synergistic – The two drugs effects work together to produce an effect greater then the sum of the effects the two drugs would produce independently.
3) Potentiation – One drug has no effect on the body but it increases the effectiveness of the other drug.
4) Antagonistic – The two drugs either produce a smaller effect together then the sum of the two produced individually or one works to inhibit the other.
Tolerance to a drug is a state of decreased effectiveness of a drug. The tolerance may be innate or may be learned. Tolerance can result from adaptive changes in homeostatic levels r in changes to the receptors over time. Over time this effect will be reversed in the absence of the drug. The problem with drug tolerance is that it leads to the necessity of higher doses which may approach toxic levels.
It has been shown that a placebo effect does exist and most patients will be effected (either positively or negatively) based on their belief of what the drug will do. The placebo effect is unstable in that it carried from patient to patient based on the environment, physician’s attitude, patient personality and type of placebo.
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