Before you study the mechanism of action of drugs, I think it's important that you understand the concept of pharmacokinetics and pharmacodynamics. So this lecture is all about pharmacokinetics and the easiest way to remember what pharmacokinetics refers to is to think of it in terms of what the body does to a drug. So let's think about it.
When you either swallow a tablet or apply a cream on your skin, the first thing that takes place is absorption. So the drug has to absorb and once it gets absorbed either through your skin or through stomach, it gets into your bloodstream and then from there it gets distributed into the fluids outside and inside the cells. So once the drug gets distributed all over the body, the body starts metabolizing it, basically modifying the drug so that it's easy to excrete. This is done primarily by a liver, but it can also be done by other tissues. So for simplicity, drug passes through liver, gets biotransformed, and finally it gets eliminated.
So elimination is the last step. in which the drug and its metabolites get excreted primarily in bowel, urine, and feces. So now let's quickly recap what we learned about pharmacokinetics. Well, first, drug has to get absorbed.
Secondly, once it reaches systemic circulation, it gets distributed outside and inside the cells. Then it starts to get metabolized and liver plays important role in that. Finally, drug gets eliminated. Now, let's break down these steps and let's talk about them in a little bit more detail. There's many routes by which we can administer a drug, such as parenteral, topical, nasal, rectal, etc.
But unless the drug is given IV, it must cross cell membrane before it gets into systemic circulation. So absorption of drugs can happen in four different ways. First, through passive diffusion. Secondly, through facilitated diffusion.
Thirdly, through active transport. And finally, through endocytosis. So let's talk about passive diffusion first. Most drugs are absorbed by passive diffusion.
In passive diffusion, Drugs simply move from area of high concentration to area of lower concentration. So if it's a water-soluble molecule, it will easily move through a channel or a pore that's in the membrane. Now on the other hand, if it's lipid-soluble, it will just easily pass through a membrane without any help whatsoever. So now let's move on to facilitated diffusion.
So other drugs, especially larger molecules, will pass with the help of carrier proteins. Just like in passive diffusion, they also move from area of high concentration to area of low concentration. And the only difference is that they actually need a little bit of help from the carrier proteins that are in the membrane.
Let's move on to active transport. Some drugs are transported across membrane via active energy-dependent transport. Unlike passive and facilitated diffusion, energy for this process is derived from ATP.
When ATP undergoes hydrolysis to ATP, there is a high energy that comes from breaking of phosphate bond. Lastly, in endocytosis, drugs of very large size get transported via engulfment by cell membrane. Because of their large size, they wouldn't fit in a channel or a pocket of a carrier protein. You also need to remember that absorption is not exactly that straightforward.
It's a variable process depending on pH, surface area, and blood flow. And this also leads us to a concept of bioavailability. So let me ask you a question.
If you take a 100 mg oral tablet, how much of it gets actually absorbed in unchanged form? The answer is, it's not 100%. This is because...
Unlike drug given intravenously, oral medication gets metabolized in gut and in the liver and good portion of it gets cleared out before it reaches systemic circulation. The cool thing is that once we administer drug either orally or intravenously, we can then measure the plasma drug concentration over time. So a drug given IV would start at a concentration of 100% because it bypasses the whole absorption process.
However, a drug given orally would have to get absorbed first and then some of it would get eliminated before it even reaches systemic circulation. Therefore its curve would look a little different. Once we can graph this phenomenon we can then find areas under these curves also known as AUC.
AUC is really helpful in making comparisons between formulations and routes of administrations. So finally knowing all that bioavailability is simply AUC for the oral drug over AUC for the IV drug times 100. Once a drug gets absorbed it then gets distributed from circulation to the tissues. Distribution process is dependent on a few different factors such as lipophilicity. So highly lipophilic drug will dissolve through cell membrane much easier than the hydrophilic drug. Next we have blood flow.
Some organs such as brain receive more blood flow than for example skin. So if a drug can pass through blood-brain barrier It will accumulate much faster in the brain as opposed to in the skin. Next, we have capillary permeability. For instance, capillaries in the liver have lots of slit junctions through which large proteins can pass. On the other hand, in the brain, there are no slit junctions at all.
So it's more difficult for a drug to pass through. Next, we have binding to plasma proteins and tissues. So due to their chemical properties, some drugs will accumulate in some tissues more than the others. Also many drugs will bind to albumin which is a major drug binding protein that will significantly slow the distribution process. Finally we need to factor in the volume of distribution which is the theoretical volume that the drug would have to occupy in order to produce the concentration that's present in blood plasma.
So volume of distribution can be calculated by taking amount of drug in the body and dividing it by concentration of drug in blood plasma. So for example high molecular weight drugs tend to be extensively protein bound and don't pass through the capillaries as easy as smaller molecules, thus they have higher concentration in blood plasma and lower volume of distribution. Typically opposite is true for lower molecular weight drugs, especially the lipophilic ones which will distribute extensively into tissues and will result in larger volume of distribution.
So the bottom line is volume of distribution helps predict whether the drug will concentrate largely in the blood or in the tissue. This is really helpful in estimating drug dosing. For example, if drug has large volume of distribution, we would need to administer larger dose to achieve desired concentration. The last step in the pharmacokinetic process is elimination, which refers to clearing of a drug from the body mainly through hepatic, renal and biliary routes. So the total body clearance is simply the sum of individual clearance processes.
Most of drugs are eliminated by first order kinetics, which means that the amount of drug eliminated over time is directly proportional to the concentration of drug in the body. What this means is that, for example, starting with 1000 mg of a drug, the amount eliminated per each time period will be different, but the fraction will be constant. So in this example per each time period constant of 16% of a drug gets eliminated, however the milligram amount changes.
And if we were to collect these samples and plot them, the graph would produce a curve that looks something like this. Now there are few drugs such as aspirin that are eliminated by zero order kinetics, which means that the amount of drug eliminated is independent of drug concentration in the body. So the rate of elimination is constant. And if we were to take 1000 mg again as an example, this time, amount of drug eliminated is the same per each time period, which is 200 mg, but the fraction, the percentage is different.
And if we were to graph it, the zero order elimination would produce a straight line. Also the cool thing about these graphs is that if we can plot them, it's easy to determine half-life of a drug from them. So half-life is simply the time that is required to reduce drag concentration in plasma by a half.
This is important piece of information which along with volume of distribution, it can tell us a lot about duration of action of a drag. Half-life also helps us predict steady state concentrations. So when doses of a drug are repeatedly administered, a drug will accumulate in the body until the rate of administration equals the rate of elimination. This is what we call steady state. So if we were to graph it, when after each additional dose the peak and trough concentrations stayed the same, we know we reached steady state.
This is typically attained in about 4 to 5 half-lives. The reason why we are interested in steady state is because we want concentration of a drug high enough to be effective but not too high to be toxic. So the goal is to maintain steady state concentration within therapeutic range. Now there are situations such as life-threatening infections during which we can't waste time getting to steady state. So to compensate for accumulation time, large loading dose can be administered on treatment initiation.
to reach desired concentration more rapidly. Now, the most important route of elimination is through kidney, which excrete drugs into the urine. However, kidney can't efficiently get rid of lipid-soluble drugs, as they are passively reabsorbed. And that's where liver comes to the rescue, by transforming lipophilic drugs into water-soluble substances that are then easily removed by kidneys. Liver accomplishes that mainly through two metabolic reactions, called phase 1 and phase 2. Now let's talk about these reactions in more details.
So phase 1 reactions are all about making a drug more hydrophilic. These reactions involve introduction or unmasking of a polar functional group. So in phase 1 we are going to see oxidation, hydrolysis and reduction.
It's also important to remember that most of these reactions are catalyzed by cytochrome P450 enzymes. Now if metabolites from phase 1 are still too lipophilic, they can undergo conjugation reaction, which involves addition of a polar group. And this is what happens in phase 2. So in phase 2, we are going to see glutathione conjugation, acetylation, sulfation, and glucuronidation. These reactions produce polar conjugates, which cannot diffuse across membranes. Therefore they're easily eliminated from the body.
Now let's go back to cytochrome p450. This large family of enzymes is essential for the metabolism of drugs and although I wouldn't recommend anyone to memorize all of them there are few that are worth remembering because they catalyze vast majority of phase 1 reactions and these are the following CYP3A4N5 CYP2D6 CYP2C8N9 and CYP1A2 Many drug interactions arise from drugs ability to induce or inhibit these enzymes. Some of the important inducers include Benitoin, Carbamazepine, Rifampin, Alcohol with chronic use, Barbiturates, and St. John's Wort.
And a good mnemonic that you can use to remember these is P-Crubs. On the other hand some of the important inhibitors are grapefruit, protease inhibitors, azole antifungals, cimetidine, macrolides with exception of azithromycin, amiodarone, non-dihydropyridine calcium channel blockers such as diltiazem and verapamil. And again good mnemonic that you can use to remember these is G-PACMAN. And with that I wanted to thank you for watching and I hope you enjoyed this video.