Pharmacology - PHARMACOKINETICS (MADE EASY)

Summary

This lecture delves into the fundamentals of pharmacokinetics and pharmacodynamics, essential for understanding drug action. It explains the body's processes of drug absorption, distribution, metabolism, and elimination, highlighting different absorption methods and the impact of factors like lipophilicity and blood flow on distribution. The importance of bioavailability, volume of distribution, and drug half-life in dosing and maintaining therapeutic levels is discussed. The video also covers the liver's role in drug metabolism through phase 1 and 2 reactions, emphasizing the cytochrome P450 enzymes' significance in drug interactions.

Takeaways

• 💊 Pharmacokinetics is the study of what the body does to a drug, including absorption, distribution, metabolism, and elimination.
• 🧽 Absorption occurs through various methods such as passive diffusion, facilitated diffusion, active transport, and endocytosis, influenced by factors like pH, surface area, and blood flow.
• 📊 Bioavailability is the fraction of a drug that enters systemic circulation in its unchanged form, which is not always 100% due to gut and liver metabolism.
• 📈 The Area Under the Curve (AUC) helps in comparing different drug formulations and routes of administration, and is used to calculate bioavailability.
• 🚀 Distribution of a drug is affected by factors like lipophilicity, blood flow, capillary permeability, binding to plasma proteins, and the drug's volume of distribution.
• 🧪 Elimination of drugs primarily occurs through hepatic, renal, and biliary routes, with most drugs following first-order kinetics, while some follow zero-order kinetics.
• ⏳ Half-life is the time required for the drug concentration in plasma to be reduced by half, which helps in predicting the duration of drug action and steady-state concentrations.
• 💧 The kidney is the main route of drug elimination, but lipid-soluble drugs require liver metabolism to become water-soluble for efficient excretion.
• 🔬 Phase 1 and Phase 2 reactions in the liver are crucial for drug metabolism, with Phase 1 making drugs more hydrophilic and Phase 2 involving conjugation reactions.
• 🌀 Cytochrome P450 enzymes, particularly CYP 3A4, 2D6, 2C8, 9, and 1A2, play a significant role in drug metabolism and are involved in many drug interactions.
• 🚫 Drug interactions can occur due to the induction or inhibition of cytochrome P450 enzymes, with mnemonics like 'PCRABS' for inducers and 'GPACMAN' for inhibitors helping to remember them.

Q & A

What is pharmacokinetics and why is it important to understand before studying the mechanism of action of drugs?

Pharmacokinetics refers to what the body does to a drug, including absorption, distribution, metabolism, and elimination. It's important to understand because it helps in predicting how a drug behaves in the body, which is crucial for its efficacy and safety.

What are the four main processes involved in the pharmacokinetics of a drug?

The four main processes are absorption, distribution, metabolism, and elimination. These steps describe how a drug is taken into the body, spread throughout, modified, and finally removed.

How does absorption of a drug typically occur?

Absorption usually happens through passive diffusion, facilitated diffusion, active transport, or endocytosis, depending on the drug's properties and the route of administration.

What is meant by bioavailability and how is it affected by the route of administration?

Bioavailability refers to the extent and rate at which the active ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action. It is affected by the route of administration, with oral administration often having lower bioavailability due to first-pass metabolism in the liver.

How can the area under the curve (AUC) be used to compare different drug formulations or routes of administration?

The AUC represents the total exposure to the drug over time. By comparing the AUC for different formulations or routes, one can evaluate the relative bioavailability and effectiveness of the drug delivery methods.

What factors influence the distribution of a drug within the body?

Factors influencing drug distribution include lipophilicity, blood flow, capillary permeability, binding to plasma proteins and tissues, and the volume of distribution.

What is the significance of the volume of distribution in drug dosing?

The volume of distribution is a theoretical volume that indicates where the drug is likely to concentrate in the body. It helps in estimating drug dosing, as drugs with a large volume of distribution may require higher doses to achieve the desired therapeutic effect.

What are the two types of drug elimination kinetics and how do they differ?

The two types are first-order kinetics, where the amount of drug eliminated is proportional to its concentration, and zero-order kinetics, where the amount eliminated is constant regardless of concentration. The latter results in a straight-line graph when plotted over time.

How does the liver assist in the elimination of drugs, especially those that are lipid-soluble?

The liver assists by metabolizing lipophilic drugs into more water-soluble substances through phase 1 and phase 2 reactions. This makes them easier for the kidneys to excrete.

What are phase 1 and phase 2 reactions in drug metabolism, and what is their purpose?

Phase 1 reactions aim to make drugs more hydrophilic by introducing or unmasking a polar functional group, often involving oxidation, hydrolysis, or reduction. Phase 2 reactions involve conjugation, adding a polar group to make the drug more water-soluble and easily excretable.

Why are cytochrome P450 enzymes significant in drug metabolism, and which ones are commonly involved in phase 1 reactions?

Cytochrome P450 enzymes are significant because they catalyze the majority of phase 1 reactions, making drugs more water-soluble for elimination. The commonly involved enzymes are CYP 3A4/5, CYP 2D6, CYP 2C8/9, and CYP 1A2.

Outlines

00:00

💊 Understanding Pharmacokinetics and Drug Absorption

This paragraph introduces the fundamental concept of pharmacokinetics, which is the study of how the body processes drugs. It explains the process of drug absorption through various routes, such as swallowing a tablet or applying a cream, and how the drug enters the bloodstream. The paragraph details the steps of distribution, metabolism primarily by the liver, and elimination through bile, urine, and feces. It also discusses different absorption mechanisms including passive diffusion, facilitated diffusion, active transport, and endocytosis, and touches on the concept of bioavailability, emphasizing that not all of an oral dose is absorbed in its unchanged form.

05:04

📈 Measuring Drug Concentrations and Bioavailability

The second paragraph delves into how plasma drug concentrations are measured over time for both orally and intravenously administered drugs. It explains the difference in initial concentrations due to the absorption process and introduces the concept of the area under the curve (AUC) for comparing drug formulations and routes of administration. The paragraph defines bioavailability as the ratio of AUC for an oral drug to that of an IV drug, multiplied by 100. It also discusses factors affecting drug distribution, such as lipophilicity, blood flow, capillary permeability, binding to plasma proteins, and the volume of distribution, which helps predict drug dosing. The paragraph concludes with an explanation of drug elimination, primarily through hepatic, renal, and biliary routes, and introduces first-order and zero-order kinetics for drug elimination.

10:05

🛑 Drug Metabolism, Elimination, and Steady-State Concentrations

The final paragraph focuses on the elimination of drugs and the importance of understanding the body's metabolic processes. It discusses the kidney's role in excreting drugs and the liver's function in transforming lipid-soluble drugs into water-soluble substances for easier removal. The paragraph explains phase 1 and phase 2 metabolic reactions, highlighting the role of cytochrome P450 enzymes in drug metabolism. It also addresses drug interactions that can arise from the induction or inhibition of these enzymes. The concept of steady-state concentration is introduced, where the rate of drug administration equals the rate of elimination, typically achieved within 4 to 5 half-lives. The paragraph concludes by discussing the therapeutic range of drug concentrations and the use of loading doses to rapidly achieve desired drug levels in critical situations.

Keywords

💡Pharmacokinetics

Pharmacokinetics is the study of how the body processes a drug, including absorption, distribution, metabolism, and excretion. It is a key concept in the video, as it provides the framework for understanding what happens to a drug after it enters the body. For example, the script discusses how the body absorbs a drug through the skin or stomach, distributes it to cells, metabolizes it in the liver, and eliminates it through various pathways.

💡Absorption

Absorption refers to the process by which a drug enters the bloodstream from the site of administration. It is a critical step in pharmacokinetics, as it determines the amount of drug that becomes available for action. The script explains that absorption can occur through passive diffusion, facilitated diffusion, active transport, and endocytosis, and that it is influenced by factors such as pH, surface area, and blood flow.

💡Distribution

Distribution is the process by which a drug moves from the bloodstream to the tissues and cells throughout the body. It is essential for the drug to reach its target site of action. The script mentions that distribution is influenced by factors like lipophilicity, blood flow, capillary permeability, and binding to plasma proteins, which affect how a drug is spread throughout the body.

💡Metabolism

Metabolism in the context of pharmacokinetics refers to the chemical modifications that a drug undergoes to be more easily excreted. Primarily occurring in the liver, metabolism helps transform the drug into metabolites that are more water-soluble and can be eliminated from the body. The script highlights that metabolism is crucial for the body to clear drugs and their active metabolites.

💡Elimination

Elimination is the final step in the pharmacokinetic process, where the drug and its metabolites are removed from the body. The script explains that elimination primarily occurs through bile, urine, and feces, and it is a key factor in determining the duration of a drug's effect and its potential for toxicity.

💡Bioavailability

Bioavailability is the proportion of an administered drug that enters the bloodstream in its active form. The script points out that not all of a drug taken orally is absorbed unchanged due to metabolism in the gut and liver, which affects the drug's bioavailability. It is a critical concept for comparing different drug formulations and routes of administration.

💡Volume of Distribution

Volume of Distribution is a theoretical volume that represents the space in which a drug appears to be dissolved within the body. It helps predict whether a drug will concentrate in the blood or tissues. The script uses this concept to explain how drugs with different molecular weights and binding affinities distribute in the body, which is important for dosing and maintaining therapeutic drug levels.

💡Half-Life

Half-life is the time required for the concentration of a drug in the body to decrease by half. It is an important parameter for understanding the duration of a drug's action and for calculating the time to reach steady-state concentrations. The script mentions that half-life, along with volume of distribution, can indicate how long a drug remains effective in the body.

💡Steady State

Steady State is the condition where the rate of drug administration equals the rate of elimination, resulting in constant drug concentrations in the body. The script explains that this state is typically reached within 4 to 5 half-lives and is important for maintaining drug concentrations within a therapeutic range for effective treatment without toxicity.

💡Cytochrome P450

Cytochrome P450 is a large family of enzymes that play a crucial role in the metabolism of drugs, particularly in phase 1 reactions. The script identifies specific enzymes, such as CYP 3A4 and 2D6, that are significant for drug metabolism. Understanding these enzymes is important for predicting drug interactions and the body's ability to process certain medications.

💡Drug Interactions

Drug interactions occur when one drug affects the activity of another, which can be due to the induction or inhibition of enzymes like the cytochrome P450 family. The script provides examples of inducers and inhibitors, such as Phenytoin and grapefruit, respectively, that can significantly alter drug metabolism and effectiveness. This concept is important for safe and effective medication use.

Highlights

Pharmacokinetics is the study of what the body does to a drug, including absorption, distribution, metabolism, and elimination.

Absorption is the first step in pharmacokinetics, where the drug enters the bloodstream through the skin or stomach.

Drugs are distributed into fluids outside and inside cells after absorption.

Metabolism involves the body modifying the drug for easy excretion, primarily by the liver.

Elimination is the final step where the drug and its metabolites are excreted through bile, urine, and feces.

Different routes of drug administration require the drug to cross membranes before entering systemic circulation.

Passive diffusion is the most common method of drug absorption, moving from high to low concentration without assistance.

Facilitated diffusion involves carrier proteins to help larger molecules move across membranes.

Active transport requires energy from ATP for drug molecules to cross membranes against concentration gradients.

Endocytosis allows very large drugs to be transported via cell membrane engulfment due to their size.

Bioavailability is the amount of drug absorbed in unchanged form after oral administration.

Plasma drug concentration over time can be measured for both oral and intravenous drug administration.

AUC (Area Under the Curve) is used to compare different drug formulations and routes of administration.

Bioavailability is calculated as the ratio of AUC for oral drug to AUC for IV drug, multiplied by 100.

Drug distribution is influenced by factors like lipophilicity, blood flow, capillary permeability, and plasma protein binding.

Volume of distribution is a theoretical volume indicating where the drug is concentrated in the body.

Elimination of drugs primarily occurs through hepatic, renal, and biliary routes.

First-order kinetics describes drug elimination where the amount eliminated is proportional to the drug concentration.

Zero-order kinetics means the drug elimination rate is constant, regardless of drug concentration.

Half-life is the time required for the drug concentration in plasma to reduce by half.

Steady-state concentration is achieved when the rate of drug administration equals the rate of elimination.

Loading doses can be administered to rapidly reach desired drug concentrations in urgent situations.

The liver plays a crucial role in drug elimination by transforming lipophilic drugs into water-soluble substances.

Phase 1 and Phase 2 metabolic reactions in the liver make drugs more hydrophilic for easy elimination.

Cytochrome P450 enzymes are essential for drug metabolism, with certain enzymes catalyzing the majority of Phase 1 reactions.

Drug interactions can occur due to the induction or inhibition of cytochrome P450 enzymes by other drugs.

Transcripts

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

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 drug and its metabolites get excreted

primarily in bile 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 some 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 a 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 ADP 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 milligram oral tablet how much of it gets actually

absorbed in unchanged form the answer is it's not a 100 percent 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 percent

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 it's 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

administration so finally knowing all that bioavailability is simply AUC for

the oral drug over AUC for the IV drug times 100 once the 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 some 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 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 a 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 route 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 milligrams 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 percent 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 milligrams again as an

example this time amount of drug eliminated is the same per each time

period which is 200 milligrams 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 a half-life is simply the

time that is required to reduce drug concentration in plasma by a half this is

important piece of information which along with the volume of distribution it

can tell us a lot about duration of action of a drug 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 stay 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 a kidney can't efficiently get rid

of lipid soluble drugs as there a passively reabsorbed and that's where

the 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 CYP 3A4 and 5 CYP 2D6 CYP 2C8 and 9

and CYP 1A2 many drug interactions arise from drug's ability to induce or

inhibit these enzymes some of the important inducers include Phenytoin

Carbamazepine Rifampin alcohol with chronic use barbiturates and St. John's Wort

and good mnemonic that you can use to remember these is

"PCRABS" on the other hand some of the important inhibitors are grapefruit

protease inhibitors azole antifungals Cimetidine macrolides

with exception of Azithromycin Amiodarone nondihydropyridine calcium

channel blockers such as Diltiazem and Verapamil and again good mnemonic that

you can use to remember these is "GPACMAN" and with that I wanted to thank

you for watching and I hope you enjoyed this video