Messa George

How the medicine come into effect?

Blog Post created by Messa George on Jul 23, 2018

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The whole process on the drug going into the body and coming into effect covers widely. Generally speaking, the process involves three aspects: drug preparation, metabolic kinetics and pharmacokinetics. And the core process is the process of absorption, distribution, metabolism and elimination of drugs in the body which mainly relates with the dosage forms, routes of administration, mechanisms of action and metabolic characteristics of drugs. So let’s take step by step to learn how the medicine come into effect in chronological order.

 

Before absorption

 

Before the absorption of the body, the drug was delivered into the body like the digestive tract, mucosal skin to release its main components API. Specially, at this time, the API has not yet in the blood circulation or target organ which means the drug has not been yet absorbed. And the absorption time is mainly determined by the characteristics of the dosage form of the drug.

 

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Different dosage forms experience different processes. Oral solution does not need to disintegrate and granules do not need disintegration, so they just wait for be dissolute. In general, the preabsorption process of oral preparations ranges from fast to slow like this: Solution > suspension > powder > granule > capsule > tablet > pill.

 

Take the most common oral tablets as an example. The tablets are swallowed into the stomach, where dry solid tablets were split into smaller particles in a gastric acid environment which is the process known as "disintegration". The API then gradually dissolves from small particles into the digestive fluid which is known as "dissolution". The API in the digestive fluid is then absorbed into the blood circulation by digestive organs such as the small intestine.

 

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The rate of disintegration and dissolution is the most important indicator of the time required for tablets at this stage. The disintegration process is generally faster and can be completed in a few minutes. However, the dissolution rate is related to the solubility and other physicochemical properties of the drug itself which could be changed by changing pharmaceutical excipients or processing in the method of film, sugar coating and others to prolong or shorten the disintegration and dissolution. The process of dissolution is not as fast as good. And for certain irritants, we may want it to be released slowly in order to reduce the gastrointestinal irritation. Some preparation technologies such as coating, microencapsulation, inclusion, membrane controlled release, pellets and osmotic pumps can solve these problems.

 

Absorption

 

The absorption refers to the process of API entering the blood circulation through the drug delivery site. And the time of absorption mainly relates to the route of medication.

 

According to the route of administration, the rate of absorption is mainly like the following: Intravenous injection (no absorption process, direct circulation) > lung inhalation > intraperitoneal injection > sublingual > rectum > intramuscular injection > subcutaneous injection > oral administration > skin administration. Besides, oral administration has a "first-pass effect" which means that before the drug enters the blood circulation, it enters the liver from the hepatic portal vein. And then enters the blood circulation after the two-phase metabolism of the drug and enzyme. This process inactivates some API, but some pro-drugs are converted into active forms after metabolism in the liver. In addition, there is a reabsorption effect brought by "hepatointestinal circulation".

 

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Distribution

 

Then drug absorption will go into the "distribution" process which is the process of moving slowly from a blood-rich tissue (heart, liver, kidney, etc.) to the surrounding tissue. We may also call this "two-chamber model". This model refers that assuming that the drug is absorbed and distributed evenly to the "central chamber" immediately, and then slowly distributed to the "peripheral chamber" at a certain rate, the drug is absorbed, metabolized and excreted from the central chamber. And it adapted to most drugs.

 

When the blood or tissue concentration reaches the minimum effective concentration (MEC), it can simply be assumed that the drug effect begins at this time. In fact, the real production of drug effect requires the drug's "receptor" to combine with the drug by producing (or blocking) a series of biological signals to produce a pharmacological effect, which is related to the mechanism of the drug's action. A few nonspecific drugs act directly on a variety of physical and chemical factors whose mechanism of action is generally simple and rapid, such as osmotic pressure regulator (dehydration drug mannitol), acid and base regulator (anti-gastric acid drug aluminum hydroxide), heavy metal complexing agent, etc.

 

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However, most drugs are specific drug which produce pharmacological action by influencing enzyme activity like omeprazole, an antiulcer drug with proton pump enzyme inhibitor, cellular metabolism like uropyrimidine analogue, antitumor agent ,fluorouracil, biofilm function like sodium channel blocker, local anesthetic, lidocaine, active factors like DNA alkylating agent, anticancer drug, cyclophosphamide and receptor function like α / β receptor agonists, cardiopharmaceuticals, epinephrine, etc. Due to the great difference in the mechanism of action, there are many differences in the time of play. Even though the same type of drug, it can also affect the onset time and effect due to the physical and chemical properties such as lipid solubility affecting the membrane permeability and the binding capacity of the receptor such as spatial steric resistance, active group distribution and so on.

 

How long will the medicine take effect?

 

The time of medicine taking effect mainly depends on the pharmacokinetic characteristics of the drugs. In order to simplify the model, we here assuming that the drugs could be absorbed directly in an effective form and the dissociation of receptor and plasma albumin was accomplished in an instant. Besides, The metabolized product shall be inactive and directly eliminated. Many drugs do not exactly meet the above assuming, however it's just an ideal model. Many drugs undergo oxidation, reduction, hydrolysis, binding groups in vivo to form effective forms, or in a more active and weaker form. In other words, the unmetabolized drug and metabolites of drugs may all maintain activity. And some drugs even are excreted directly in its original form such as some of the sulfonamides drugs. Therefore, the variation of plasma concentration over time is determined by absorption, elimination of these two sets of differential equations. The absorbent portion has previously been mentioned, typically a two - compartment model. The following point is on elimination.

 

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Elimination

 

When the drug was first absorbed, the blood concentration was relatively high. At this time, due to the limited metabolic capacity of liver and kidney, the drug was eliminated in a constant amount of time which is called zero-order elimination kineics. Its kinetic equation is The concentration-time curve of the drug is which is a linear function. For different drugs, the constant Ke is different under different reaction conditions. As the drug is gradually eliminated, the blood concentration drops. And the drug is eliminated in a constant proportion per unit time. Its kinetic equation is. The concentration-time curve of the drug is which is an exponential function with an exponential term as negative. The clearance process of most drugs is in accordance with the first order kinetics. The first and zero levels of the image are shown as the following.

 

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There is a common concept called half-life means that the time it takes for drug concentration in blood to drop to half its current level. Because the first order kinetics is eliminated at constant ratio, the half-life is independent of the concentration of the drug. For example, the drug with a half-life of two hours whose current blood concentration of 100 units per hour will be reduced to 50 in 2 hours, 25 in next 2 hours and 12.5 in next 2 hours... The half - life of the drug that meets the first - level elimination is not related to the concentration , but is related to the biochemical nature of the drug and the physical condition of the patient. In other words, the time of the half-life period indicates whether the drug is long-effective or short-acting. For certain drug, different patients with different half-life period which can reflect the liver and kidney function of the patient. If the function is bad, the metabolism function is poor, the half-life period will become longer.

 

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How long will the effect last?

 

We can learn by simple calculations that for a single dose, after about five half-life periods, the drug concentration in the body will drop to about 3% of the original level which is totally eliminated. And for continuous administration or intravenous drip, after about five half-life periods, the blood concentration will gradually increase to be stabilized.


Due to such metabolic characteristics, different drug delivery protocols are generally adopted for different drugs and patients to maintain blood drug concentration within the therapeutic window. For drug with short half-life period, the interval of the sub - administration is shortened like 4 times a day. Or the patient is given a long - term intravenous drip to maintain the plasma concentration. For drug with long half-life period, it can be given at longer intervals such as once a day or even once a few days, once a few months. Of course, absorption can be delayed by different drug delivery routes or by slow-controlled release formulations. It may also reduce frequency in elderly patients or in patients with lower liver and kidney functions. There is also a method called "doubling first dose" to quickly reach the minimum effective concentration.

 

In fact, the question of how long the effect will last is little significance to patients, because most of the cases are divided to maintain the efficacy of medication. When the symptoms disappear, then it shall change the regimen or stop medication.

 

Key point: DMPK

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