What are drugs?
Drugs are chemical compounds and chemical reactions are the things that cause the effects
Three facts about drugs?
- They are specific compounds that act at specific sites in the body
- They resemble compounds that are normally found in the body or a pathogenic organism
- They can augment or block normal functions
Specified by generic name, same chemicals as trade drug so it has the exact same effect
Patents on drugs...?
Do expire so at that point other companies can begin to manufacture it -> This is where generic drugs come from
Made from plants (opium) and microbes (penicillin). Microbes are a big source of drugs because they're always fighting against each other and breaking down things
Man-made drugs. Ex. sulfa antibiotics, acetyl salicylic acid (aspirin), and ibuprofen
Using human DNA to purify and make purified drugs. Ex. Insulin used to be made of cow/pig insulin. now we take recombinant gene for insulin (human), input to new cell and have it process new insulin
How are drugs developed?
There are three methods then it must pass FDA standards. This is difficult because how do you figure out how they work?
3 main methods for identifying candidate compounds for drugs
Traditional uses, screens of large numbers in a disease model, and screens for safety
Scientists look at how the different drug/compounds has been used in the past in plants/foods by different cultures
Screens of large numbers of compounds for activity in a disease model...
You need a standardized system to test chemicals & reproduce part of the disease to test it on. The cheaper the assay is (mice, cells, etc) is the more tests you can do on all sort of chemicals.
Screens for safety
You move up from animal to animal (mice -> dog -> nonhuman primate -> human). Usually is they won't hurt animals the they won't hurt humans but sometimes they do
FDA only screens for prescription drugs, million of chemicals enter system unchecked. Safety degree is flexible but you want the safest drugs for the least severe things (ex. headaches) because you can definitely live with the illness
Depends on what you do with the drug. Manufacturer has to prove that the drug is effective. All drugs have effect so have to make it worth the risk b/c otherwise it's blocking them from taking a drug that can actually help
Different drugs can be used for non approved uses as long as it's prescribed, its perfectly legal and ethical
Easiest method, clear solution with drug dissolved into it, injected directly into bloodstream and compatible with blood
Cloudy drug, in liquid with drug particles in suspension. Has intentional and unintentional effects
Intentional effects of suspensions
Suspension being used to make a drug storage reservoir/"depots". In a depot drug won't immediately go to circulation and has to dissolve first. It will be injected into the muscle bed where particle aggregation will go off into blood vessel
Unintentional effects of suspensions
There is a warning on suspensions that if they are incompatible they would cause improper treatment that can lead to drug particles forming precipitates that would block arteries and also cause embolisms
Means a swallowed dose, must be absorbed from the stomach and/or intestine which is hard because of their environments
Has a pH 2, creates HCl which kills most things and might make drug unstable and ineffective. Kill nearly everything tat comes in so drug must be protected.
How are you going to protect a drug from the stomach and intestinal environment?
With enteric coatings
Wrapping a drug in a capsule and adding a coating so that the don't dissolve as easily and protect drug from stomach and vice versa
To get to target organ drugs must...
When given orally they must disintegrate, dissolve, and be absorbed across the gut wall to get to the target organ
Drugs must be able to dissolve. Packing drugs into a solution (as in 5 doses into one capsule to release gradually all day to achieve sustained release
Problems with sustained release?
Someone's stomach might be so strong that they dissolve the coating on drug and release all dose in the capsule at one-> potential overdose
For a drug to act, it must first get into the blood stream by crossing across cell layers. A measure of this is bioavailability
A measure of a drug being able to be absorbed into the bloodstream. The amount of drug absorbed
Trends in bioavailability?
Graphed on a concentration and time graph. The drug with the highest concentration at peak time has the highest bioavailability because it means that concentration is high because more of it was absorbed
Chemical equivalence and bioavailability
Bioavailability may be affected by the way drugs are prepared. Different component & casings affect bioavailability
How do you get two drugs with equivalent bioavailability? What does it mean?
It means that they have the same amount absorbed at any specific time. Probably means that they were prepared in the same way with same casings
Drug movement into, around, and out of the body (drug has to move around, in & out of barriers, cells, and organs
What barriers to drugs have to transit?
Drugs have to dissolve to move throughout the body. They have to pass barrier such as cell membrane and connections between cells
What characteristics make drugs more like or unlikely to pass these barriers?
A drug that can move through the phospholipid bilayer (lipid soluble) has access to all parts of the body and is easily absorbed.
What type of drug will have trouble crossing barriers?
A very charged/polar drug that doesn't dissolve well in oil but does dissolve in water
Two main ways drugs pass these barriers?
Drugs can move through the spaces between cells or drugs can move through cells
Passage between cells means what?
Drugs moving through the spaces between cells. This is tissue specific because of the connection between cells that differ in different tissues.
What affects passage between cells?
Drug sizes and spaces between molecules aren't always the same. Barriers are also different. Smaller molecules will pass easier than large molecule and it's especially hard/impossible to get into the brain this way
What are the 3 main types of barriers drugs will encounter?
Barriers in the brain, G.I. system, and the placenta
Called the blood brain barrier. Cells are tightly connected there's almost no space between cells and its designed to stop chemicals from getting inside. Exception is the chemosensory trigger zone
Chemosensory trigger zone
The palace in the blood brain barrier that purposefully lets molecules in to monitor for toxic things (thing is how a few drugs can get inside)
Connections between cells are much looser so it allow large molecules to pass. Most drugs will go through to placenta and make it into fetal circulation
Passage through cells means what?
Drugs that pass through cell layers by actually going through the cells themselves. Important if drug needs to cross the blood brain barrier to get into the CNS and affect brain. Has three important mechanism to do this
Thee mechanisms for drug to pass through cell?
Passive diffusion, facilitated diffusion, and active transport
Is the most common mechanism to get drug through cells. Main depending factor is whether it will dissolve in a lipid bilayer. It means drug moves down concentration gradient, no motor involved. The best you can get is a balance, movement will stop at equilibrium. 4 huge factors affect it
4 factors that affect passive diffusion & ability to pass and dissolve in lipid membrane
Lipid solubility, size, ionization, pH
Charged polar drugs are insoluble in lipid membranes so they won't cross. (Antidepressant must be lipid soluble to pass blood brain barrier to get into brain. If you don't want drug to affect brain make it lipid insoluble and it won't cross
When a lipid insoluble drug is carried through the membrane along a concentration gradient
How does facilitated diffusion work?
Recognition protein recognizes drug molecule and allows it to pass. Channels (ion channels etc.) allow molecule through by momentarily opening up for them, it's not motorized, does not create a concentration gradient so no burning of ATP, and drug molecules need protein carriers
How does it work?
The exact same way as facilitated diffusion expect that drug is transported through membrane against a concentration gradient. Also has recognition protein and in the process creates it's own concentration gradient
What is another important aspect of pharmacokinetics?
Absorption (moving between cells or through cells to get into target), distribution, and elimination are also important
Where the drug goes after absorption. Different drugs are distributes through different compartments in the body
3 common distributions
Plasma (some stay in the plasma), extracellular fluid (some are limited to the extra cellular fluid), and total fluid (some drugs go all over)
How would you measure the dilution of a drug after dosing and why would you measure it?
You take a sample blood draw after drug administration. If there's a lot of drug in sample it means that it stayed in blood stream (plasma), if there's not a lot it means it was absorbed into something else. You measure it to allow an estimation of how the drugs is distributed in the body
What is the volume of distribution?
The idea of where the drug is and how much dilution you need in volume to get the concentration you have. High concentration in sample means that no dilution happened. If sample is diluted it means you'll have low concentration
How are depots formed?
Drug not being evenly distributed and glomming onto a particular site. Can glom onto things like fat etc. Mean that at the moment it's not an active drug and it's all stored in one place. It can be done on purpose for extended release
How does a depot formation affect the volume of distribution?
You might take a sample and find no drug, it means it's all in a depot and not actually absorbed
What is a possible danger of a depot?
Something coming along and displacing the drug from the depot which would suddenly increase the drug concentration and it would all suddenly become active
Low volume of distribution
Means that you would get a concentrated sample, stayed in plasma, didn't go anywhere
Explain clearance in the simplest terms possible
Blood vessel has drug, filtered through a 'black box', drug molecules are expelled, and blood flow runs pure
What are the three types of elimination/clearance methods?
Metabolic clearance, First Pass Effects/Portal Circulation, and Excretion
When the drug is chemically altered to a different compound. Not physically removed from the body but instead becomes something else. Happens in the liver and can either active or inactivate some drugs. These drugs are mostly lipid soluble (?)
Active drugs and metabolic clearance
Most common. Active drugs meet enzyme, and the leave metabolites inactive and change. Drugs actions are over it's 'gone'
Inactive drugs and metabolic clearance
Sometimes drugs are inactive, will meet enzyme in liver, and it produces an active metabolite that then is the compound that produces the drug effect
Actual drugs you take is not the one that works until it's metabolized into something else by enzyme
Main drug/metabolite set up
Inactive drug + enzyme = active metabolite
Active drug + enzyme= inactive metabolite
Types of metabolic reactions
Oxidation and conjugation reaction (the reactions that cause it to turn into a metabolite either active or inactive). In most cases addition of either group can inactivated the drug which is the point, it makes the drug more polar and more likely to be excreted by liver later
Most common, drug goes to the cytochrome p-450 enzyme and is turned into metabolite by the addition of specifically an OH group
Instead of adding an OH group it adds on any other groups such as a sugar molecule. Linking something to drug to turn it into a metabolite.
What factors change metabolic activity and it's rate
Live metabolism rate can increase with the exposure to many compounds. Two main factors that affect it are the reduction of liver function and the induction of live enzymes
Reductions of liver function....
It reduces drug metabolism which causes higher levels of drugs because it's not being metabolized properly as planned so doses pile up as you take them
Explain liver function reduction in patient terms
Would affect neonates, patients with liver disease, and liver failure patients
Induction of liver enzymes
It increases drug metabolism because when the drug goes to the liver the liver notices and begins creating more more enzymes to metabolite the drugs and other drugs so lower blood levels of drug in general
First pass effects
Drugs that never reach the blood stream because they're dissolved in stomach before reaching the bloodstream. Drugs in this case are metabolized in other tissues such as the stomach. Would need to administer drug in non-oral ways
The kidney is most effective in excretion of small non-lipid soluble (as in polar and small) drug molecules. Many drugs are excreted either as unchanged or as metabolites by the kidney
Filtration and how does it work?
Drugs bound to proteins can't be excreted because proteins are too large. Only small molecules can get through the filter into the glomerulus. The filter is a siv which blood passes through but it keeps red blood cells and proteins from moving out. Filtered small drug particles go down tubule of the nephron and finally go to bladder then urine to wait to excretion
How does re-absorption happen and to what?
As filtration of small polar molecules is happening, the lipid soluble particles that have passed through the filter into the nephron will escape back into circulation because since they are lipid soluble they can't be held in by the cell barrier of the tubule. This makes it really hard to get rid of lipid soluble drugs since they'll keep escaping back into circulation. Water is also reabsorbed.
How does active transport play into this renal excretion process?
Some drugs are pumped into the urine through active transport. Moved straight into the glomerulus to go to bladder then urine
4 key points on elimination/clearance?
1) When drug taken orally it will either be metabolized quickly by liver or slowly by excretion
2) If lipid soluble it will become less soluble by becoming more polar as it's metabolize
3) If polar, it will either be concentrated or turned off from metabolism or gone by excretion
4) Some drugs are actively transported out
2 Main patterns kinetics of clearance follows?
Zero order kinetics (rare) and 1st order kinetics (common)
Zero order kinetics
Rare. Means drugs elimination goes at a constant rate (mg/hr). Results in a simple equation, and it means that method of elimination is going at a max all the time
Zero order graph
Drug concentration over time. Line is a straight linear graph which represents the constant rate drug is being eliminated at
1st order kinetics
Most common, has no "rate" of elimination. Rate of elimination is proportional to drug concentration. First order elimination. Rate of elimination varies with the dug concentration in the body. The more drug concentration there is the higher the rate will be because it sees a lot and wants to get rid of it all, the lower the concentration the slower rate will be because just a little so it can relax
1st order kinetics graph
Half of U shapes. Fast rate at beginning when drug concentration is biggest and low rate at end when drug concentration is lowest
Only way to quantify rate in 1st order. the amount of time it takes to get as half as you had of concentration. It becomes a constant as in every 30 minutes you get half of what you just had in concentration
What is the time to steady rate?
Steady rate is reached the rate of input is matched by the rate of clearance. Time to reach plateau is short if the doses are higher. Dose if set o match rate of clearance. You will always reach a plateau.
How long does it take to get rid of a drug?
It take about 4 half lifes. A drug that has a long half life is not removed from the body very fast It also takes 4 half lives to reach steady rate.
Compounding facts on dosing and reaching a steady rate
More slowly=steady dose faster and harder to get rid of. You can add a high dose to get to a steady rate faster then decrease it to maintain it steady and keep it going longer
How to the drugs work on the receptors?
Specific chemical structures on the drug molecule match those on the receptor and they interact
Explain Nicotinic acetylcholine receptors at the neuromuscular junction?
When an impulse goes to raise your arm, it releases acetylcholine and nicotinic receptors on the cell surface of the muscle causes it to happen. Nicotine itself will also activate this response
What is affinity?
The ability of a drug to want to bind to to irs receptors. Determines how long it will stay on receptor before it falls off again. And it makes no difference on the effectiveness of the drug
How does binding to receptors work?
involves affinity and you can ever bind more than 100% of receptors so it plateaus at around 100%
Describe a simple binding curve
Won't really be used because it's inaccurate. It's percent of receptors bound over drug concentration/ Goes upwards as a c shape. It holds no real comparison because many drugs may bind loose or tight or later in time so you don't see enough of it to compare
Describe a log scale binding curve
Accurate one. It's % receptors bound over log drug concentration. Lines to the left of the graph means high affinity and lines to the right mean low affinity. You can compare because you can see the differences over a long period of time in one graph
What is the Kd?
The concentration it takes to get to half of maximal binding (50%). If affinity to occupy receptors is high the the Kd will be off to the left. If affinity to bind is low it will have Kd off to the right
What does high affinity mean?
It means it's binding tightly and that it will have a low Kd because it can bind in low concentrations
What does low affinity mean?
It means it's binding loosely and that it will have a high Kd because it can only bind in high concentrations
2 different compounds going after the same receptor at the same time. Competition gets in the way of the original drug's purpose because it doesn't let it bind
Competitive binding cure compared to actual binding curve?
The drug on it's own might have a high affinity and a low Kd but with a competitor present not letting it bind, the curve shifts to the right & makes it seem as though the drug has low affinity and a high Kd
What does more specificity mean?
Means that the drug only interacts with a couple or just one receptor
What does low specificity mean?
That the drug can interact with many different receptors (not particularly a good thing)
How many responses do you get to a drug? How are specificity and responses related?
You want specificity and a response / more specificity= less response because its only interacting with a few select receptors
How do drugs enhance or block receptor activity?
Affinity has nothing to do with this. A drug binds to the receptor and three types of responses can happen. It can be an agonist, an antagonist, or a partial agonist
Also called activators. Have full efficacy, they activate responses at receptors. An agonist drug is a drug that when it gets to receptor it produces a response
Also called blocker. Drug that just sis on the receptors and occupies it and doesn't let anything else sit there and activate it. Can be useful because it can keep unwanted things from happening in the body
It will still do something when it sits on a receptor but unlike an agonist it will do less. Has unique ability to get a response but if its added when full agonists are present then it will decrease the efficacy and turn it down.
Describe a graded response curve
% response over log drug concentration. Measures responses that can be measure and assigned a number (like BP) these are graded responses
Describe a quantal response curve
% response over log drug concentration. Measure responses that either happen or don't. Yes or no responses (was patient cured? was patient pregnant? etc)/ 100% at this means all patients responded 'yes'
L/E -> (Lethal dose/concentration)/(effective dose/concentration)= Therapeutic index
You want a high therapeutic index (high ratio) because you want the lethal to be many more times higher than the effective to decreases chances of accidental overdose
Disclaimer about the dose response curve
It will not always line up with the dose response curve just because they're similar
Lower drug concentration reached with continuous use that gets the body used to it
Side effects (predictable vs unpedrictable)
predictable are unwanted but known effects of the drug. less predictable are allergies aka having a hypersensitive reaction