Lesson 1 Flashcards
Explain the definition of pharmacokinetics and pharmacodynamics, What is ADME? what does it change if a drug is lipophilic o non lipophilic?
In pharmacology there are two main aspects, the first one pharmacodynamics which describes the interaction between a drug and its target, so it explains the mechanism of action of the drug, the second aspect is pharmacokinetics and it’s about the movement of the drug in our body, so all the processes that the drugs undergo to be absorbed, distributed, metabolised and eliminated.
In pharmacokinetics we use the acronym ADME (absorption, distribution, metabolism and excretion). Infact, unless we inject the drug in our body, we need to absorb the drug in the bloodstream. That means that it is very important that the drug is lipophilic to use passive transportation and cross the membranes faster. if we have non-lipophilic molecules they can still be used as drugs but in this case they need to be either very small to use the paracellular transport, meaning the transfer of substances across an epithelium by passing through the intercellular space between the cells not through them. if the molecules are normal sized they can be transported with an active transportation mechanism.
Most drugs are lipophilic by nature and that means that they will follow the Fick’s law that considers not only the characteristics of the drug but also its surroundings: like the difference in concentration between the two areas, the partition coefficient, this depends on weather in oil-water solution a drug distributes itself more in the oil or water, the more it is distributed in the oil the more lipophilic it is. Also if the area of absorption is small the flux will be lower, for example when using enteral ways of administration there is great absorption in the intestine where the area dedicated to this process is very large. The law also considers the thickness of the membrane: the thicker the membrane the slowest the flux is.
what is the half life of a drug? describe the correlation between plasma concentration and time.
t1/2, also called half-life, is the time it takes for the plasma concentration (Cp ) of a drug to be reduced by 50%. Half life is independent form the starting concentration of the drug, and this is very important because it can be used to choose the dosage of the drug and how many times do we have to administer the drug in a specific timeframe, basically It enables one to predict the time course of Cp after a bolus of drug is given. This graphic correlates plasma concentration and time. It describes the effect of the drug and its duration. Initially, the blood drug concentration after administration is zero. We have to wait for some time, called Lag period, so that the drug produces an effect reaching a certain concentration in the cell, this concentration is called MEC desired. MEC desired means “minimum effective concentration” and it is the concentration at which the drug starts having an effect. The duration of the drug’s effect reflects the length of time the drug level is above this value. After reaching the MEC line the drug concentration increases producing the peak effect and then decreases. The intensity of a drug’s effect is related to how high its concentration is in comparison to the MEC line. In this graph we can already understand that it is not an endovenous administration otherwise the peak would happen immediately without the lag period. After the peak we notice two types of decrease: the first drop is due to its distribution, because the drug leaves the blood stream in order to interact with the target organ, the second part is related to excretion which is acted by the liver and the kidneys. in fact there are two speeds in the graph at which elimination happens.
what is therapeutic window? how can we change the ADME of a drug?
t1/2, also called half-life, is the time it takes for the plasma concentration (Cp ) of a drug to be reduced by 50%. Half life is independent form the starting concentration of the drug, and this is very important because it can be used to choose the dosage of the drug and how many times do we have to administer the drug in a specific timeframe, basically It enables one to predict the time course of Cp after a bolus of drug is given. This graphic correlates plasma concentration and time. It describes the effect of the drug and its duration. Initially, the blood drug concentration after administration is zero. We have to wait for some time, called Lag period, so that the drug produces an effect reaching a certain concentration in the cell, this concentration is called MEC desired. MEC desired means “minimum effective concentration” and it is the concentration at which the drug starts having an effect. The duration of the drug’s effect reflects the length of time the drug level is above this value. After reaching the MEC line the drug concentration increases producing the peak effect and then decreases. The intensity of a drug’s effect is related to how high its concentration is in comparison to the MEC line. In this graph we can already understand that it is not an endovenous administration otherwise the peak would happen immediately without the lag period. After the peak we notice two types of decrease: the first drop is due to its distribution, because the drug leaves the blood stream in order to interact with the target organ, the second part is related to excretion which is acted by the liver and the kidneys. in fact there are two speeds in the graph at which elimination happens.
Speak about pharmacodynamics and the type of receptors you know.
Pharmacodynamics describes the interaction between a drug and its targets like enzymes, receptors and carriers. when we speak about receptors we have to keep in mind that each receptor has a specific structure. Receptors are classified as:
- Ligand-gated ion channels (ionotropic receptors): the ligand is capable of opening the channel and the response of the cell is very fast, but it also ends quickly (milliseconds).
- G protein-couple receptors (metabotropic): cellular response is slower but it can last longer.
- Kinase-linked receptors: the response takes hours.
- Nuclear receptors (also called transcription factors modulated by ligands). They interact with DNA in order to modulate gene transcription.
What are agonists and antagonists? How are they classified based on the way they bind and act on the receptor?
Also, it is important to know about the different drugs that interacts with these receptors as agonist or antagonists. The difference between agonists and antagonists depends on the effect produced by binding with the receptor. Only agonists are able to induce a response and they mime the endogenous ligand. Antagonists are also able to bind receptors, but they can’t induce a response .
In the enzyme we find to main sites, the orthosteric site and the allosteric site, the orthosteric site is the binding site for the endogenous ligand, while the allosteric site is a site which is able to have an effect on the orthosteric site. now an allosteric agonist also called allosteric modulator would simply activate the effects of the allosteric binding site which, depending on if it’s a positive allosteric site or a negative allosteric site, will either increase or decease the primary effect at the orthosteric site. Positive allosteric modulators work in a variety of ways to increase the primary activity of the receptor but they have no effect on their own. Some modulators are able to trigger responses themselves instead of just enhancing them. (Ex: Neuropeptides and benzodiazepines ).
Some antagonists are able to bind to the orthosteric site, these are called competitive antagonists because they compete for the same site as the endogenous ligand, a reversible competitive antagonist instead is able to displace the endogenous ligand but we would be able to restore the original effect by increasing the dosage of the agonist. However if we are dealing with an irreversible antagonist, it will be able to bind to the orthosteric site and never detach. So even if we increase the dosage of the endogenous ligand we have no change in the effect which will be necessarily reduced.
We also have non-competitive antagonists, they bind to an allosteric site instead of the orthosteric one to prevent activation of the receptor. they can also be reversible (when detachable) and irreversible (when they cannot be detached form the site).
what are partial agonists? what about inverse and biased agonists?
Going back to agonists, a partial agonist is an **agonists that despite its ability to bind to all the receptors present in the tissue cannot produce a response that is similar to the full agonist which is the only one able to produce the maximum effect. partial agonist have a very important feature that can be used in specific situations, they are also called dualists. the lower the concentration of the endogenous ligand is the more they act as agonists (without being as efficient as full agonists) This aspect is really useful in treating some diseases like schizophrenia in which there are some areas with an excess of dopamine and other with a lack of dopamine.
Inverse agonists instead are able to induce an effect which is opposite to the one produced by agonists. What can we use to explain the existence of inverse agonists? we have hypothesised that some receptors can trigger the response in the cell even when they are not tied to the ligand, this effect is called constitutive activity of the receptor, so the population of receptors is constituted by two different receptors: the one that are at rest and one that have constitutive activity. Agonists have a high preference for receptors in their activated state, whereas pure antagonists bind to both receptors at rest and activated ones with no preference. In contrast, inverse agonists have a high preference for the ones in resting state and so they are able to shut down the constitutive response.
In the end, biased agonists (functional selective agonists) are compounds able to selectively activate one pathway instead of the other. The only example that we have is about G coupled receptors which are able to trigger cellular response in two ways (double activity). These receptors can activate two different signalling cascades:
- Directly linked to G proteins (Gi, Gs, Gq)
- Beta arresting pathway
The pathways are involved in triggering different responses. They are able to induce therapeutic (positive) effects but also side effects. For this reason, many research studies attempt to find biased agonists in order to avoid side effects. For example, opioids: morphine, besides controlling pain,(analgesic effect) is also able to reduce breath rhythm and induce respiratory depression. In this context biased agonists would be very useful to avoid side effects.
So drugs acting on receptors may be agonists like full agonists, partial agonists, biased agonist and inverse agonists, and allosteric modulators, these last ones are safer drugs because they do not have an effect per se but they need a endogenous ligand
