Pharmacology Notes Lecture 1

Pharmacology Notes Lecture 1: • Pharmacology is a branch of science concerned with drugs and their actions while a pharmacologist is a scientist concerned with pharmacology. Hippocrates demonstrated the risk vs reward for drug treatment, while Paracelsus showed that dose determines the effect of the drug while Erlich showed that drugs bind to molecular targets. • A safe and effective drug is made when there is a balance between pharmacodynamics (way drug interacts with the body- effect on body) and pharmacokinetics (how body reacts to drug- getting in and out). These two fields are interconnected. For pharmacodynamics relates to the target, where we must understand the target causing the problem. The drug must be able to bind to the target region, must be an effective concentration, must have an effect on the region and it must be selective so it doesn’t impact on other systems. Pharmacokinetics involves how the drug gets there (drug must be absorbed, distributed and reach an effective concentration) and how the drug leaves (drug is metabolised and excreted). The body will try to remove the drug out of the body and need to make sure it is kept in, so the drug is not metabolised readily. • A drug is a chemical that affects the physiological function in a specific way. It can be found present in the body which is used for cellular communication (hormones, neurotransmitters and second messengers) or they can be antibodies and genes. An example includes adrenaline which is from the adrenal gland and can help treat anaphylactic shock. Drugs can also not normally be found in the body and be synthetic or naturally occurring. It can be a therapeutic agent but can also become a poison so dose and context of substances is important for effect and toxicity. • Most marketed drugs have both a trade name and a generic name, such as Panadol (paracetamol), Ventolin (salbutamol) and Prozac- antidepressant (fluoxetine). We can also use the drug family names to help identify drugs such as selective serotonin reuptake inhibitor (SSRIs). • Pharmacodynamics is involved with site of action & selectivity (where) and potency & efficiency (how much) while pharmacokinetics is involved with potency & efficiency (how much) as well as absorption & elimination (how often). • The way the body deals with drugs is through ADME (absorption, digestion, metabolism and excretion). • An agonist drug is one that elicits a response while an antagonist is one that blocks a pathway. Workshop 1: • In order to identify an abnormal process in disease, we need to understand how systems work under normal homeostatic conditions. From there we can work out how dysfunction causes disease. Once abnormal processes are identified, we can treat diseases by ‘fixing’ or ‘changing’ the disease state back to the normal. We can design and use drugs to target these mechanisms. • A good scientific method encompasses the following: Ask a good question (hypothesis), design a rational experimental protocol, execute the protocol in a technically competent manner, measure responses accurately, analyse the collected data, interpret the results in light of hypothesis, communicate findings in a concise and logical fashion, modify preconceptions and then ask a better question. • The layers of complexity in organisms goes from molecules to cells to tissues to organs to simple organisms to complex organisms. • An example of defining a problem is when we look at an issue such as high blood pressure, we would need to find a drug that decreases blood pressures but we need to look at the other layers of complexity to make a good drug. At a tissue level the problems could include there is too much contraction of blood vessels, too much cardiac or nerve activity, thus some responses to these issues are to inhibit transmitter release from nerves, decrease hormone production, relax blood vessels and reduce cardiac contraction and rate. At a cellular level, we can have the problem of too much activation of receptors, too many ion channels opening or too much hormone/transmitter production. To combat this we may produce a drug that inhibits Ca2+ entry or blocks receptors for hormones/transmitters coupled to ion channels. At a molecular level we could have the problem of too much Ca2+ or too many signalling molecules increasing the concentration of Ca2+, thus we need to find a drug that inhibits Ca2+ entry. • Drug discovery requires assessment at all levels. At a molecular level we need to test if molecular approaches can be used to define drug targets and mechanisms. At a cellular level we need to test if the drug target and its mechanism can be characterised at the cellular level in health and disease. At a tissue level we need to see if the drug can be tested on an isolated organ or tissue in health and disease. • The process of in vitro drug testing is when the drug test takes place in a test tube, culture dish or anywhere outside a living organism while in vivo drug testing is a drug test taking place inside a living organism. This includes where we use a relevant animal disease model while with humans we do highly ethical and highly controlled clinical trials where we try our best to ensure that it is safe. If we want to assess how a tissue responds to in vitro experiments we need to mimic physiological conditions such as the organ bath experiment where the tissue is suspended in solution with similar physiological conditions that mimic the body. • Some factors that we need to consider to mimic physiological conditions include temperature, pH, O2:CO2, energy source and salt concentrations. This is seen in the organ bath experiment where we submerge the tissue in a physiological solution with a heating jacket maintaining body temperature and an O2:CO2 inlet. With in-vitro experiments, the parameter depends on the tissue where the type of tissue will have varying rates of contraction, force of contraction, length of contraction and lumen areas. • The guinea pig ileum has longitudinal and circular smooth muscles, blood vessels, autonomic ganglia and nerve fibres. It may contract or relax in response to drugs that may act: directly on the smooth muscle through an action on receptors located on the muscle cell membranes or act indirectly through the release of neurotransmitters or local hormones acting on receptors of muscle cells. To measure length change in the ileum from contraction, we keep the tissue at a constant tension and measure the change in length through using an isotonic transducer (constant tension). The peaks we see in the graph indicate reductions in the length of the tissue as a result of the drug addition. • When making stock solutions, we need to weigh out drugs to dissolve in appropriate volumes. A 1M solution is easy to calculate but far more concentrated than required for drug responses. To make this solution requires many grams of compound (expensive) and it could lose stability. So we prefer to weigh out small quantities (mg) of drugs such that they are cheaper but sometimes weighing accuracy is an issue in very small amounts. A stock solution of 10-2M can be made easily as this is in the mg/mL range. Often the concentration of the drug stock is much more concentrated than what we want to test, thus we need to dilute. • The dilution factor is the initial concentration over the final concentration. The dilution factor can be used to determine the volume of stock solution (10-2M) to be added to a known volume to achieve the desired final concentration (10-10M). This is called a simple dilution. This dilution factor is 100,000,000, we are making the concentration that much more dilute and thus we need to perform a 1 in 100,000,000 dilution. For this experiment, 25 ml of solution is required to completely cover the tissue in the organ bath that is 25,000μL of solution. This results in an addition of 0.25nl of the stock solution which is infinitesimally small. Thus we use a practical alternative to make less concentrated stocks, so that we can add volumes that pipettes can measurably reliably via serial dilutions. This is when we dilute the stock solution in a step wise manner, by factors of 10. To determine how much stock we add to the bath volume, we can keep the drug additions small relative to the bath volume but large enough to be accurate or we divide the bath volume by the dilution factor. We then look at a concentration-response curve to measure the changes from baseline to determine the response. • When changing the solution in the organ bath, the tissue will “sag” and which may interfere with measurement of response to drug (might look like contraction when sagging) thus we can avoid this by using increasing concentration of drug without draining and refilling the organ bath, we do this by adding cumulative concentrations such that there is less noise around the results and wear and tear on the tissue. • Pharmacologists like to test drugs at a range of concentrations at half-log units. Half log units end up being evenly spaced on a concentration-response graph using a log scale for concentration. It’s necessary to change to more concentrated stock solutions for higher concentrations of acetylcholine to avoid adding large volumes to the bath. • When plotting concentration-response curve data, we have a y axis of % maximum response against the log of the concentration of the drug. The graph will take a sigmoidal shape whereby the threshold is where the response to the drug begins and it then plateaus at the maximum due to physical restrictions or saturated receptors.

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