2060 WEEK 3

Lesson 1. Drug Metabolism 

Foreign substances in including med, are metabolized in the body through the same enzymatic pathways and transport systems that handle nutrients from food. Many of these drugs are hydrophilic and accumulate in the body if not properly eliminated which could lead to toxicity. 

Metabolism plays a role into transforming hydrophobic substances into hydrophilic forms to make them easier to excrete (urine -> bile) 

Drug metabolism: a process through which drugs are altered through enzymes (liver) to change its chemical structure also called biotransformation 

*many tissues can metabolize drugs but the liver does it the most 

These enzymes break down potentially harmful exogenous toxins in our foods and conf=vert them into safer forms. They also help create important endogenous molecules that are needed  to maintain proper function. 

Drug metabolism has several important therapeutic consequences that can influence a drugs affects on the body; 

1. Increase water solubility - this is done because most drug are metabolized in water soluble forms in order to excrete from the body from the kindeys.  

2. Inactive drugs – metabolism neutralizes a drug preventing harmful effects 

3. Increase drug effectiveness – for some drugs, metabolism enhances the therapeutic action of a drug making it more effective (codeine metabolizes into morphine -> more potent) 

4. Activate prodrugs – some medications are administered in inactive forms (prodrugs) and will only be active after being metabolized (clopidogrel->anti platelet prodrug that is activated in the liver because of metabolism) 

5. Increase drug toxicity – drugs that are metabolized can produce metabolites that can lead to more harmful side effects than the original drug or to OD (acetaminophen is converted into a metabolite that is very toxic to the liver) 

In most clinical situations, the drug conc is much lower than the body's ability to metabolize it meaning the body can efficiently clear the drug following the first order of kinetics. 

First order of kinetics: the rate at which the drug us metabolized is directly proportional to the conc of the free drug in the body. -> as the conc of drug increases, the body metabolizes a larger amount of the drug per unit of time, as the conc decreases the amount of drug metabolized also decreases 

For this to be true, there must be more enzymes than drugs available to control the amount metabolized and not overwhelm the enzymes. 

The drug decreases quick at first and as the drug conc decreases it slows down. This is because the body metabolizes a constant fraction where it depends on the drug conc 

Zero-Order Kinetics: the bodys enzymes become saturated and overwhelmed, the body metabolizes a constant amount of drug over time regardless of the drug conc. This means the rate of metabolism doesn’t take the drug conc into consideration, a fixed amount of drug is metabolized per unit of time. 

The drug conc decreases in a linear constant manner over time, no matter how much drug is present it eliminates the same amount of drug conc per unit of time. 

This is because when there is more amount of drugs than enzymes only a fixed amount of drugs can be metabolized because there is only a certain amount of enzymes for metabolism. 

Ex. Ethanol (alcohol) when someone's drinks alcohol the body can only metabolize it at a constant rate because the liver enzymes become saturated, no matter how much alcohol is in the blood.  

First-Pass Metabolism of Drugs: oral (enteral route) medication must pass through the digestive system where it may be metabolized before reaching the rest of the body. This is called first pass metabolism; when a drug is absorbed through GI tract and transported to the liver via the hepatic portal. 

First pass can happen in other areas in the body; 

1. Hepatocytes in the liver-> enzymes in the liver modify drugs before they enter the blood stream and before they are excreted into bile. 

2. Intestinal enterocytes -> drugs are absorbed in the sm intestine by cells called enterocytes and undergo metabolism before reaching the live/circ system 

3. Stomach -> the stomach may contribute ti breakdown of drugs that undergo acidic/chemical changes in the stomachs acidic environment 

4. Intestinal Bacteria -> gut bacteria can alter and metabolize drugs that are complex or pass through the intestine before it reaches the blood stream. 

First pass reduces the amount of the starting drug (parent drug) that reaches the circ system -> only a fraction of the original does is available to work on the body. This is why drugs that undergo significant first pass may need higher oral doses to work on the body or another route (paranteral/sublingual) to bypass first pass. 

Lesson 2. Phase I and II of Metabolism 

The biotransformation of a drug can be broken down into two main categories; 

Phase I Metabolism: reactions that add or expose functional groups that make the drug molecule more polar (water-soluble) This can be done by adding a hydroxyl group (-OH) or an amine group (-NH₂) to help the body eliminate the drug easily. 

-> most common reaction is adding one atom of oxygen (O) to a drug, this is called oxidation, or gaining electrons by adding a hydrogen (reduction), and breaking the chemical bond using water (hydrolysis) 

Phase II Metabolism: different enzymes add larger chemical groups (glucuronic acid [a sugar], sulfate[ –SO₄] or glutathione [-GSH]) to drugs or metabolites by conjugation -> making the drug even more polar. 

Some drugs will undergo phase I+II after another and other drugs might only go through phase I or only phase II. 

Cytochrome P-450 Metabolizing Enzymes: large family enzymes that are the main type of phase I meta enzymes. Often results in a formation of a metabolite (more easily excreted from the body), found mainly in the smooth endoplasmic reticulum (ER) which is a major site for many of the cells metabolic preocesses. 

*nomenclature – there are 18 families of CYP enzymes with sub families based on sequence similarity and different isozymes (slight diff versions of enzymes) 

CYP is expressed by diff cells type (enterocytes of sm intestine, tubule cells of kidney, pulmonary cells of lungs, hepatocytes of liver) This enzyme specifically metabolizes the largest fraction (50%) of prescribed drugs.  

Phase II Metabolizing Enzymes: These enzymes in phase II metabolism add various types of side groups that make the drug more polar and therefore soluble to allow for excretion.  

Hepatocytes express most phase II enzymes and there can be variability in the expression levels of different enzymes depending on factors like genetics, age sex, etc.  

*not all phase II enzymes are expressed in high lvls in all cells that can metabolize drugs (sulfotransferases [add –SO₂ ] are low in hepatocytes but high in enterocytes) 

Phase II Enzymes:   

1. UDP-glucuronosyltransferases (UGTs) - catalyze the transfer of glucuronic acid (sugar) to a drug -> more polar 

   2. Sulfotransferases (SULTs) - catalyze the transfer of a sulfate group (-SO4) to drug ->more polar 

   3. Glutathione S Transferases (GSTs) - catalyzes transfer of glutathione molecule (-GSH) to drug -> makes metabolite less toxic 

   4. N-acetyltransferases (NATs) - catalyze the transfer of an acetyl group from the acetyl CoA to a drug 

   5. Thiopurine Methyltransferase - Catalyze the transfer of a methyl group (-CH₃) to a drug  

      1. Theres only one human TPMT enzyme 

Factors That Effect Metabolism 

1. Age: takes babies one year to have reasonable amount of drug metabolizing enzymes, after they are 2 years old they have the same amount as adults do. 

2. Drug interactions: 

   1. Enzyme induction: CYP isozymes are susceptible to induction->(process where a cell makes an enzyme in response to drugs/chemicals) but this can have consequences in the form of increased drug metabolism which can cause; low drug plasma conc., low drug activity if metabolite is inactive, high drug activity if metabolite is active 

   2. Enzyme Inhibition: some drugs/natural compounds can inhibit CYPs this can cause; higher plasma drug conc., higher effects of drugs, higher risk of drug toxicity 

3. Disease state: diseases that affect organs that express drug metabolizing enzymes can cause reduced drug metabolism over all (liver, kidney, bowels/GI system) 

4. Genetic Polymorphisms -> a variation in the DNA sequence among individuals: a change in the enzymes DNA sequence can affect how many enzymes are expressed and how efficiently they work 

   • There are some variations in the CYP2D6 enzymes that results in certain people have ultra-rapid metabolizers, intermediate metabolizers (normal), and poor metabolizers (rare) 

     • Ultra-rapid metabolizer population is more at risk for drug toxicity as certain metabolites that are metabolized too fast can cause higher levels of the more potent drug resulting in overdose (ex. codeine->morphine) 

      

      

Lesson 3. Renal Excretion 

Drugs and their metabolites are mainly excreted through the kidneys in urine -> can also be excreted through bile, exhaled air, saliva, and breast milk. 

Filtration of drugs: regardless of the route all drugs in the blood WILL be processed through the kidneys. Not all drugs can filter into the nephrons, particularly if they are bound to proteins, small free drugs have no problem going through the barriers to filtration 

The three barriers to filtration: 

1. Size of the glomerular pores/spaces in b/w endothelial cells 

2. Size/space in b/w the matrix of the basal lamina and overall negative charge of the sugars in the matrix 

3. Size of slit spaces in b/w podocytes 

Therefore a drug/chemical must be small enough to get through the small spaces of the podocytes fingers that wrap around the glomerulus (capillary), not overall negative to get through the negative basal lamina underneath that binds the podocytes and keeps the structure of the capillary, and lastly small enough to get through the pores of the actual capillary. 

What CAN pass the barriers: water (H2O), CO2, O2, free drugs (as long as it isn't too big/too negative), Na+, K+ AND Cl- (Cl- is so tiny that it doesn’t get repelled by the basal lamina), glucose and amino acids (tiny molecules) 

What CANNOT become filtrate: proteins (too large or too negative), red/white blood cells (too big) 

The Glomerular Filtration Rate (GFR) - the quantity of fluid and solutes dissolved in the water filtered per unit time 

Many drugs can be filtered into the capsular space of a nephron due to the pressures that move large amounts of fluid into the nephron 

Normal young adults GFR= 180L/day or 125mL/min 

Individuals that have decreased renal function (with lower GFR) will have trouble effectively excreting drugs from the blood 

Tubule Transport 

Tubule Secretions of Drugs: Drugs can be selectively secreted into the nephron tubules as the blood travels in the capillaries surrounding the tubules. 

• Anion Secretion – neg charged compounds (organic anions OA-) can be selectively secreted in the tubule lumen. This is done due to uptake transporters the basolateral membrane (ex. Organic anion transporters [OATs]) These transporters don’t require ATP to function and use the conc gradient of other substances to drive the transport. 

This example shows an OAT exchanging a dicarboxylate (DC-) for an OA- uptake transporter mechanism at the basolateral membrane. (DCs are a common metabolite found in the blood). The organic anion needs exit out of the apical using efflux transporters. There two different mechanisms this can happen with.  

1. Another OAT exchanger (DC for OA) which allows DC to be exchanged at the basolateral membrane 

2. A primary active transporter (MRP2) or multidrug resistant-associated protein 2 -> this is a common efflux transporter that requires ATP to push the drug across the membrane 

• Cation Secretion – pos charged compounds (OC+) are also transported across the basolateral membrane using organic cation transporters (OCT). These uptake transporters move pos charged drugs by themselves into the tubule cells from capillaries 

This example shows the uptake transporter moving the OC+ across the basolateral membrane. The OC+ needs to exit the apical membrane using efflux transporters and there are two types available to OC+s 

1. P-glycoprotein (P-gp) which is a primary active transporter that requires ATP to pump the OC+ across the membrane (there are also protein carrier exchangers that do not require ATP) 

2. Multidrug and Toxin Extrusion (MATE) transporters can exchange hydrogen (H+) for an OC+ 

   1. This is assisted with the Na+/H+ exchanger that takes Na+ from the tubule and exchanges it for H+ in the membrane which is promptly put back into the membrane by the MATE transporter 

Drug Reabsorption:  

Recall: water is reabsorbed and many solutes are reabsorbed within the proximal convoluted tubule, this causes the distal tubule conc to exceed the conc in the surrounding blood making reabsorption possible. 

However, the pH of the filtrate can change throughout the nephron tubules which affects whether a drug can become ionized or stay neutral -> RECALL: ionized drugs have a harder time crossing cell membranes which can stop them from becoming reabsorbed. 

Therefore, if there's an increase in drug conc in the tubule and it remains neutral, it can become reabsorbed. 

Most organic substances are either weak acids or bases which can become ionized or stay neutral based on their environment which allows them to be passively reabsorbed in their neutral forms. 

Weak acids stay neutral in acidic environments (more H+ ions) -> can be reabsorbed 

Weak bases stay neutral in basic environments (less H+ ions) -> can be reabsorbed 

Renal function:  

kidney function decreases with age and drugs need to be adjusted to account for this decrease in function. 

Kidney function can also be affected by disease, chronic kidney disease is a progressive disease that can result in complete kidney failure. Measuring the GFR can indicate if there are enough functional nephrons filtering (secreting and reabsorbing drugs) -> the lower the GFR the lower the function of the kidney 

GFR Values 

Lesson 4. Drug Excretion – Biliary/Other 

Biliary Excretion 

Drugs are also excreted through bile, usually larger drugs. Amphithic drugs (drugs that have both polar groups and lipophilic groups), or drugs that have glucuronic acid added to them. 

This is done by the liver which produces and secretes bile containing bile salts which is important for lipid digestion and drug metabolization. 

Bile is stored in the gallbladder that will be stimulated to excrete the bile solution when food enters the sm intestine. 

Bile is excreted into the duodenum and any metabolized drugs that aren't reabsorbed in the intestine back into the portal vein are excreted in feces. 

Both phase I and II occurs in the main cell type of the liver, hepatocytes, they express many CYP family members with enzymes that add side groups to compound like UDP-glucosyltransferases and methyl transferases.  

The liver also created albumin which is the main plasma protein that binds drugs in the blood.  

It also has immune cells located in the tissue of the liver that helps identify and destroy foreign cells. 

Blood Supply To Liver: Liver receives blood from two main vessels (hepatic artery and portal vein) Within the liver the blood combines together and mixes in the leaky blood vessels called the sinusoids (leaky). This allows almost everything in the blood to leave 

 the vessels and interact with the cell membrane of the hepatocytes. These cell membranes have many transporter proteins on their cell membranes allowing for items to be transported into the cells. Biotransformation of the drugs occur within the hepatocytes (due to phase II and II enzyme presence) where they will be secreted back into the blood by being distributed into the sinusoids and then collected into the central vein which will distribute the modified drug blood to the body. 

The membrane beside the sinusoidal capillary is called the sinusoidal membrane and the membrane beside the bile canaliculi is called the canalicular membrane. 

The protein carrier that moves bile salts across the canalicular membrane needs ATP to pump against the conc into the bile solution. The bile salts that are reabsorbed from the intestine are able to enter the hepatocytes through the sinusoidal membrane by a transporter. This is a NA+ dependent co-transporter that doesn’t need ATP because it is powered by the conc gradient for Na+. 

Drugs that are moving through the sinusoids (capillary) of the liver are exposed to the hepatocyte membrane where there are many protein carriers.  

Some among them are (Uptake transporters) OATs and OCTs that move organic cations and anions (drugs and metabolites) into the hepatocytes. 

Some efflux transporters include MRP2 and P-gp transporters on the canicular membrane that move OA-, and OC+ (P-gps move OC+ and amphipathic drugs into bile. These transporters require ATP to function (primary active transporters [goes against conc.]) 

Another efflux transporter on the sinusoidal membrane is the MRP1/3  which release biotransformed drugs back into the circulation for redistribution to the circulation -> this making the drugs/metabolites more hydrophilic making it easier for excretion by kidneys 

Pulmonary Drug Excretion 

This type of excretion is for drugs that are usually gaseous and/or highly volatile (substance that is easily evaporated) 

Drugs that are absorbed through the lungs are usually excreted in the lungs and arent reliant on drug metabolism (don’t need to be metabolized first) 

Factors Affecting Pulmonary Excretion:  

• RR- the faster the RR the more drug will be excreted, its better to slow down the RR however to increase drug absorption 

• CO – a larger CO is due to how well the heart pumps blood around the body to lungs, the more blood delivered the better the rate of excretion 

• Solubility of Drugs in Blood – the more soluble the drug the higher the pulmonary excretion, drugs with low solubility have lower excretion 

Breast Milk Drug Excretion 

Some drugs can be excreted in breast milk and will therefore be exposed to the breast fed infant. 

This is considered when prescribing drugs to mothers who will be breast feeding 

Breast milk has a lower pH than the mothers blood plasma and a higher lipid content than the blood of the mother, this influences what drugs can be excreted in breast milk. 

Factors Affecting Drug Excretion In Breast Milk 

• Lipophilic Drugs – Drugs that are lipophilic move more easily throgh the cell membranes of the mammary glands -> into breast milk 

• Low Molecular Weight – smaller drugs move  more easily across the epithelial cell membranes from the mothers blood to the breast milk 

• Low protein binding – Free drugs are more likely to be secreted into breast milk 

Drugs can also be transported from the blood across the epithelial cells of the mammary glands by efflux transporters like the Breast Cancer Resistance Protein (BCRP) which typically effluxes vitamins into breast milk but also drugs and metabolites. 

Also drugs that are weak bases become ionized and trapped in the milks acidic environment resulting in milk excretion. 

Lesson 5. Clinical Measurements of Pharmacokinetics 

Recall: the higher the conc of drug in the blood, the greater the effect will be. 

Recall: Bioavailability- how much drug is absorbed and how much made it to circulation 

Recall: Volume of Distribution – the drugs ability to get to its target tissue while being impacted by the other places it goes in the body 

Clinical pharmacokinetics are linked to the processes of absorption and distribution. 

Metabolism and excretion results in the elimination of drugs and their effects on the body, impacting the possible toxcicty to the body. 

Clearance: the fundamental pharmacokinetic parameter related to metabolism and excretion that determines how a drug will behave in the body. 

• The volume of plasma from which a drug is completely removed per unit of time – total drug clearance is important because it determines the dosage rate required to maintain a certain blood conc of the drug. 

  • Dosing rate = plasma conc(CL) 

• In order to determine the total clearance of a drug, we must combine all the ways the body removes a drug from the plasma 

  • CL total = CLrenal + CLhepatic + CLother 

Clearance is impacted by how much blood flow each organ receives (kidney or liver) 

Half-Life: the time it takes for the conc of the drug in the plasma to reduce by half its conc or by 50% 

This values will directly impact dosing intervals and help predict how long a drug will stay active in the body. 

• Half life is related to the volume of distribution per clearance 

  • T1/2 = 0.693(Vd/CL) 

The larger the volume of distribution, the longer the half-life but the lower the clearance. (^Vd,^T1/2, 🔽 CL) 

Fore repeated dosing, knowing the half life allows for a steady state and knowing how long it takes for drug levels to decline once we stop giving it. 

• Recall: formula for Vd = total amount of drug in body/plasma conc of drug 

The Rate of Elimination: the rate of elimination is the amount of drug removed from the body by measuring the conc of drug that remains in the blood 

• Because multiple organs can clear drugs from the plasma, the rate of elimination takes all methods into account 

  • Rate of Elimination = CL total(Plasma conc) 

• The rate of elimination is a culmination of all clearance processes, but while some drugs are onlt cleared by the liver, other drugs are cleared by the liver AND kidney 

By measuring the amount of drug conc that still remains in the blood we can observe the rate at which the blood is eliminated from the body. (3mg/hr or 9mg/hr) 

Recall: First Order Kinetics - the rate at which the drug us metabolized is directly proportional to the conc of the free drug in the body. 

Zero Order Kinetics - the body's enzymes become saturated and overwhelmed, the body metabolizes a constant amount of drug over time regardless of the drug conc. 

Route of Administration & Elimination 

For routes that require absorption first, theres an increase in drug conc during the absorption phase which is followed by a decline in the elimination phase. 

Oral – when a drug is given orally the rate of absorption is greater than the rate of elimination, as elimination begins to occur, it becomes equal to the rate of absorption which is the max conc or peak of drug in the plasma. Over time the rate of elimination will increase over the rate of absorption due to the decrease in drug conc 

IV Administration – the drug given via IV is constant and there's is no absorption that occurs due to its direct access to the circulation. This means the drug conc will rise and will be metabolized by vital organs which will also begin the elimination process. This will cause the blood conc to stabilize and become equivalent to the rate of elimination. When the IV administration stops, the drug conc will decrease until its fully eliminated from the body. 

IV Bolus – recall that an IV bolus is a rapid injection of a drug directly into the body which means the drug conc is at its highest point when it is injected. It also does not go through absorption and instead distributes throughout the body which reduces its drug conc and like regular IV admin, is metabolized and excreted which further decreases it drug conc. Recall that the rate of elimination relies on the drug conc, meaning the greater the drug conc, the greater the elimination 

Repeated Dosing: most prescriptions require multiple dosing which results in accumulation of drugs in the body until stabilization has occurred; this is called steady state.  Drugs taken orally or as IV bolus, the conc fluctuates, the high level is the peak and the low level is the trough. 

The goal of drug therapy is for the fluctuations at steady state to be within the therapeutic range. 

Time of Dosing: When the same dose of drug is giving repeatedly, it takes 5 half-lives to reach steady state. 

After the first dose the drug will stay in the system at the same time the second dose is administered, and the drug conc will rise and fall as other doses are given at specific times. 

Steady state occurs when the rate of drug input equals the rate of drug output (elimination) 

It will take the same amount of time for different doses of the same drug to reach steady state, the higher dose will just have a higher steady state conc than the lower dose 

Loading dose: are large doses that are given at first to get a patient to steady state faster if the half lives are longer. These large doses are followed up by smaller doses to maintain the drug conc at steady state. (Red line above) 

Assuming bioavailability is 100%, loading dose =(target drug plasma conc)(Vd) 

Decline From Steady State – it takes 5 half lives for a drug to be mostly eliminated from the body and 9 half lives for every molecule to be eliminated from the body 

^this is important for patients that are experiencing allergic reactions 

Comparing Dosing and Half-Life: drugs that are formulated differently (Vd, CL) will have different half lives that will affect the dosing. 

A drug with a shorter half life will require more frequent dosing that a drug with a longer half life. This is because the drug with the longer half life will be able to stay in the therapeutic range for longer. This is because shorter half life means faster elimination and repeated dosing maintains the drug in its therapeutic window. 

• Drugs absorbed from hepatic portal vein from sm intestine carry them directly to liver for first pass metabolism 

• Liver gets blood from hepatic portal vein (nutrient and drug rich blood from GI system) and hepatic artery (O2 rich blood) 

• After metabolism, drugs/metabolites may enter circulation by hepatic central vein or be excreted into the bile duct which leaves the liver via the common hepatic duct 

• Bile is released into sm intestine via gallbladder, if it is reabsorbed back into hepatic vein it is called enterohepatic recycling, if not reabsorbed it is excreted into feces. 

This shows that the rate of elimination is not constant for first order kinetics because the less drug conc the less amount needed to eliminate, this is shown as a constant exponential decline 

This shows the rate of elimination IS constant because this drug has saturated all the enzymes causing a linear fixed amount of the drug to be eliminated at a fixed linear rate 

Three ways to reduce drug fluctuations: 

• Use continuous IV infusion -> allows for constant drug lvls (not feasible) 

• Use depot preparations -> releasing drugs at slow/constant state minimizes peaks and troughs 

• Change the dosing interval -> giving the same dose multiple times a day reduces the size peaks and troughs