Sunday 7/10/2012 Pharmacology Lecture no. 7 There are four major families of receptors that are responsible for drug responses: 1. Ligand gated ion receptors: Channels across the plasma membrane that bind to ligands and regulate ion flow. 2. G protein coupled receptors: Receptors at the inner surface of the plasma membrane that regulate or facilitate effector proteins. 3. Enzyme linked receptors: Receptors that bind to ligands from the extra cellular domain activating or inhibiting related cytosolic enzymes. 4. Intracellular receptors: Receptors inside the cell. In this case the ligand diffuses into the cell to bind to these receptors. Concept of 2 nd messengers: G proteins are transmembrane proteins that are connected to specific receptors which will react with endogenous hormone substances inside drugs. G proteins might immediately mediate hormonal activity or instead they might transfer the signal from the drug receptor complex to another enzyme called 2 nd messenger that in turn will mediate some hormonal activity. The pathway the G protein takes depends of the existence of the 2 nd messenger inside the cell. Examples on 2 nd messengers: 1. In slide no. 25: The stimulation of Adenylyl cyclase will stimulate ATP to be converted to camp then camp will mediate the hormonal activity as a response to the drug. The G protein here is "Adenylyl cyclase" and the 2 nd messenger is the "camp".
2. Diacylglycerol 3. Inositol trisphosphate 4. Calcium ( plays a major role as 2 nd messenger to many drugs) An experiment to prove that a particular 2 nd messenger mediates a response/effect for a specific drug or hormone: 1. Isolate the cell that will interact with the drug (from the target organ or tissue) in a dish. 2. Isolate other cellines with different 2 nd messengers. 3. Treat all cellines with the drug. 4. Observe the response for all cells. The response will be obvious and easily recognized (the drug will interact with the receptors and cause an increase in other substance such as hormones; e.g. TRH.) 5. The final response for the drug will be different in those cellines that have different 2 nd messengers. While if other cells are found with the same response as the interacting cells, then they will contain the same 2 nd messenger. Relationship between drug response and drug dose: Graded dose-response curves are used to test and evaluate particular responses to a specific dose drugs in isolated organs. Quantal dose-response curves are used to measure responses versus doses in individuals.
Graded dose-response curves: To be able to draw a Graded dose-response curve the organ is taken out and put in an organ bath (note: the organ bath contains fluid resembling our internal environment) then treated with a specific drug and after that the response (e.g. contraction in the intestine or increase in heart beats; depends on the organ and drug being used) will be measured using a physiological recorder. The dose must be known and it must be treated with a control, a placebo as an example (a placebo is a drug that contains all ingredients of the formula except for the active form). The curve : Vmax Response (%) Dose (mg) If we use log dose the curve will have a sigmoidal shape: V max Response (%) Log dose (mg)
As the dose increases the response will increase until a point is reached where the response won't increase with the increase of dose. That point resembles the maximum response/intrinsic activity, (Vmax). At that point, saturation of the drug will be reached, which means that there are no more free receptors available for the drug to increase the response. Vmax is the efficacy of the drug. Before the drug is synthesized, the concentration at which the response is "Vmax" at the site of action must be known. The less the concentration is, the better the drug will be. ED50 (from concentration versus time chart) is the dose that produces 50% of the response / effect. Here ED is used to evaluate the safety of the drug. Check slide no. 28. Also when reporting a negative response (not a good response/ side effects), as the dose increase, the response will increase until we reach the most sever response which is death (of course we don't reach this point in humans; we report it in animals and predict it in humans according to the results gotten from animals.) LD50 is the dose that produces 50% of the death response. Quantal dose-response curves: To be able to draw a quantal dose-response curve the response of the drug versus the dose must be studied on individuals and different populations due to individual variations. The curve: # Pt s Dose (mg)
From studying the curve: a. Some individuals will respond at low doses without any side effects. b. Most individuals will respond at a particular dose. c. Some will not respond at all. d. Some will not respond and suffer side effects or death at normal/therapeutic doses. The point of this curve is to know the particular dose at which most individuals respond without side effects or at least with very small side effects. This particular dose is the normal therapeutic dose. In summary: side effects and responses differ between individuals. For example; there are some individuals that respond to a drug at a low dose with no bad side effects while others don't respond at any dose. Also, some individuals show side effects at therapeutic doses. In slide no. 31: ED is drawn on the effect curve while LD is drawn on the side effect curve. The more the two curves are away from each other the better the drug will be. We also notice that LD50 is not that much far away from Vmax while death is far away from Vmax. The dose that produces Vmax and the dose that produces side effects must be known for the sake of safety. For the drug to be safe and effective, the dose that causes death must be far from the dose that produces Vmax. Note: Effective doses are not given as a specific number but as a range.
Potency : It is a comparison between two drugs within the same group (such as steroids.) It compares the strength or activity of two drugs that produce the same effect and has the same efficacy. The doses of the two drugs (A and B for example) are compared, and if a dose of A less than a dose of B gives the same effect as B then A is a better drug. In summary: the drug that can give us the same response or activity but with a less dose is the better one. The stronger drug is said to be more potent. The more potent drug reaches V max at a lower dose with fewer side effects. In Summary: The more potent drug is given in a lower dose to the patient. Potency is not important when manufacturing the drug but it is important when treating the patient. Affinity of the drug : It is a Measurement of the strength of the binding or attraction between the receptors and the drug. In other words, it is the ability of the drug to form a stable complex with the receptors. The drugs which have a high/good affinity enter the circulation, reach, and bind quickly to the receptors. Comparison between the affinities of two drugs is done between drugs in the same group (same response or efficacy).
According to the affinity agonists are classified into: 1. Weak agonists. 2. Strong agonists. 3. Full agonists. Evaluation of drug safety: Is determined by : 1. Therapeutic index: the larger it is, the safer the drug. 2. Margin of safety. 3. Protective index (PI): The higher it is, the safer the drug. Notes: a. Sometimes drugs with low therapeutic index or that cause side effects way much before reaching v max or has high death rates are used due to lack of other alternatives or treatments b. Anticancerous drugs are an example on drugs used with many side effects and low therapeutic index. In some of these drugs side effects, such as vomiting and nausea, are considered as a sign on efficacy of the drug. c. Digoxin is another example on drugs with low TI. It has a TI of 2 and is used to treat patients with heart failures. Therapeutic index (TI): It is defined as = LD50 / ED50 For example; If TI= 1 then that means that the dose that causes the death of 50% of patients is the same dose that prodices response in 50% of the patients. The therapeutic index is a measurement for the safety of the drug. But it is very accurate.
The larger the index is, the safer the drug will be. Margin of safety: ( the doctor explained it more in the following lecture) It correlates the lethal dose that produces death in 1% of the individuals which means that at this dose the drug is affective in 99% of the individuals. The Larger the value, the better and safer the drug. Margin of safety is better than therapeutic index in determining the safety of drugs. Protective index (PI): It is the ratio between the dose that produces side effects and the dose that produces desired/wanted effects. PI = ED50 producing side effects / ED50 producing desired effect PI of 1 means that the dose which produces the desired effect in 50% of pt s still produces side effects in 50% of them. The higher the dose that produces side effects is, the safer the drug. The larger the index is, the safer the drug. It is the best measurement for drug safety because most drugs produce side effects in doses lower than those that produce death ( as you could see ED is used in calculating PI)
In slide no. 37 : There is a comparison between two drugs, A and B. Drug B is safer because it has a higher therapeutic index. In slide no. 39: ( He asked us true or false questions) Drug A is more potent than drug C because A gives Vmax at a lower dose. Drug A has similar efficacy as drug B. Drug D has similar efficacy to drug A. We cannot compare potency of C with potency of D due to the differences in action and response demonstrated by the differences in their curves. The potency cannot be compared to drugs of different classes but efficacy can. Done Please refer to the slides and sorry for any mistakes. Written by: Nada "Zaid Al Kaylani"