Lecture 10 - Absorption

CHE-30010 Lecture 10 - Natalie 12/02/2021 Absorption If a drug/poison is injected intravenously, the peak plasma concentration is reached almost immediately. Substances that are smoked or inhaled are also quickly introduced into the bloodstream because of the rich blood supply in the alveoli – based on the technique of the person. In many instances the drug/poison will be swallowed. The substances then needs to enter the bloodstream from the GI tract, so has a slower peak time. Drugs are absorbed through gastric membranes and delivered to the liver via the hepatic portal vein (injected/smoked drugs avoid this). The liver processes the drug and passes it into the general circulation (first pass metabolism). Many drugs are significantly metabolised at this stage. Some toxic substances can be converted into non-toxic metabolites during first pass metabolism so never have the opportunity to become dangerous. If the dose is high enough, the liver becomes overwhelmed and the enzymes in the liver become saturated, so they aren’t fully detoxified and pass unchanged into the circulation and have a toxic effect. A big factor is the acidity and polarity of the drug. Stomach – may or not be broken down by the acidic conditions. If intact, but has acidic and basic groups, the low pH ensures these groups are protonated, so basic substances become charged. GI tract is aqueous so polar charged molecules dissolve best, to be absorbed it has to pass through the membranes. Too polar drugs won’t cross the membranes unless active transport is involved. Non-polar drugs that don’t dissolve in the aqueous environment will not disperse enough to reach the membrane to dissolve across. Small intestine – pH increases, so charged species will become ionised the further down the GI tract so can be absorbed later in the process. Acids and bases Helps to understand why the changes in pH in the GI tract are important for absorption. All acids and bases live in equilibrium of being a combined species and separate entities. Bases – left would be in the stomach and on the right is in high pH environments. CHE-30010 Lecture 10 - Natalie 12/02/2021 Ka = acid dissociation constant, quantifies how strong an acid/base is. Large values so natural logarithms are used to simplify comparison. pKa = - log(ka) and log[H+] = pH Tells us that for a monoprotic acid/base, a change in pKa and pH of one unit, results in a 10:1 mixture of neutral: ionised species in the mixture. pKa of 5 in a neutral environment of pH 7 (blood), the difference is 2, so there is 100 x more neutral species than the ionised species. Relatively small changes in acidity of the environment can have a big effect on whether a species is suitable for absorption. Therefore, neutral and non-polar drug molecules can pass more easily through lipid membranes, but we need a trade-off of solubility in order for them to be absorbed. Basic amines are almost completely protonated at low pH (start of the GI tract). To pass through the lipid membrane (which would be difficult), the very low levels of neutral amine present need to be rapidly transported across. This is achieved by a huge surface area in the small intestine (microvilli) and active transport mechanisms, so the equilibrium is shifted and more ionised species goes to the neutral species, so more passes through and so on. Bioavailability The amount of the drug that is available after oral ingestion, divided by the amount that would be available after IV injection, usually expressed as a percentage. 𝐹= 𝑎𝑚𝑜𝑢𝑛𝑡 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑙𝑜𝑜𝑑𝑠𝑡𝑟𝑒𝑎𝑚 𝑋 100 𝑎𝑚𝑜𝑢𝑛𝑡 𝑖𝑛 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 Tells us how much of the drug dose would be absorbed and end up in the bloodstream for distribution and have the desired effect. CHE-30010 Lecture 10 - Natalie 12/02/2021 This can make a large difference on how the drug effects a person – morphine has a very high first pass metabolism, so a bioavailability between 20-30%. Heroin generally gives greater bioavailable morphine – nearly all oral heroin is converted into morphine, dependent on previous drug use. Heroin is a prodrug of morphine. Deacetylated into morphine, so the effects felt are from morphine and the bioavailability of each explains this. Alcohol groups in morphine are more polar than the ester groups in heroin, so is too polar and is not easily absorbed into the body and has difficulty crossing the blood-brain barrier to exert its effects. Quickly metabolised further so deactivates it and allows a quicker excretion. Ester groups in heroin makes it less polar and removes these issues with absorption so quickly enters the bloodstream to be distributed through the body and can enter the bloodbrain barrier. It is here converted into morphine, so has a more concentrated effect than morphine as it is more bioavailable as heroin and gets the morphine to where it needs to be to exert its effect more effectively.