Biopharmaceutics Flashcards
What is biopharmaceutics?
The relationship between the physical and chemical properties of a drug in a dose form and the pharmacologic response after administration
What is biopharmaceutics dependent on?
- chemical nature
- physical state
- type of dosage form
- presence/ absence of excipients
- pharmaceutical process (type of granulation, tablet press, pressure applied to the tablet, friability, dissolution- all of these factors affect bioavailability)
What is the definition of pharmacokinetics?
Study and characterization of the time course of drug absorption, distribution, metabolism, and excretion.. The relationship of these process to the intensity and time course of the therapeutic and adverse effects of drugs. Also RELEASE of the drug (ie. from a solid dosage form)- part of absorption process
What is the definition of bioavailability?
Rate and extent (amount) to which a drug is absorbed from a drug product into the body or to the site of action
What is the definition of clinical pharmaceutics?
Is the application of pharmocokinetic methods in drug therapy. It involves a multidisciplinary approach to individually optimized dosing strategies based on the patient’s disease state and patient-specific considerations. (T1/2 varies from patient to patient - we assume that the patient is within 95% percentile of thousands pf patients but chances are they are not)
What is the definition of pharmacodynamics?
Refers to the relationship between drug concentration at the site of action (receptor) and pharmacologic response
What is the 4 factors that contributes to biopharmaceutics?
Absorption
Distribution
Metabolism
Excretion
What affects drug absorption?
- transport processes, pH, lipophilicity, particle size, first pass effect– drug dissolution rate also affects drug absorption
What affects drug distribution?
- body fluid compartments, tissue distribution, protein binding
What happens to the drug is it is protein bound?
- it is pharmacologically inactive (the drug is overtaken and is engulfed by a protein)
What are the different things that contribute to drug metabolism?
- phase 1 and phase 2 reactions, michaelis-menton (phenytoin- kinetics are non-linear), genetics, age, disease states, drug interactions
What are the different ways that drugs are excreted?
- renal clearance (filtration, secretion, reabsorption), enterohepatic circulation, biliary clearance
What is the definition of bioequivalence?
methodology of measuring (experimental design, statistical considerations). relative and absolute bioavailability
High molecular weight cannot be given in what route?
Orally
What is the onset of action of inhalation devices?
- rapid onset
IV drugs are suitable for what medications?
- Suitable for large volumes and for irritating substances or complex mixtures, when diluted
- Its valuable for emergency use
- Permits drug titration
- Usually required for high molecular weight protein and peptide drugs
- Not suitable for oily solutions or poorly soluble solutions
What is the absorption pattern of subcutaneous injection?
- prompt, from aqueous solution
- slow and sustained, from repository preparations
Subcutaneous injection is suitable for what medications?
- suitable for some poorly soluble suspensions and for installation of slow release implants
- not suitable for large volumes
- possible pain or necrosis from irritating substances
What is the absorption pattern of intramuscular injections?
- prompt, from aqueous solution
- slow and sustained, from repository preparations
Intramuscular injection is suitable for what medications?
- suitable for moderate volumes, only vehicles, and some irritating substances
- appropriate for self-administration
What is the bioavailability like for oral medications?
- potentially erratic and incomplete
Are ionized drugs able to cross over into the absorption site?
NO - they may require transport proteins to cross
Can hydrophilic drugs pass into the lipid bilayer?
- aquaporins allow water and inorganic ion passage - the majority of drugs are TOO LARGE to fit through.
What is diffusion characteristic of?
- characteristic of particle size, concentration, high to low concentration - its a physical and a chemical event —- it is either a passive or an energy requiring process (only active TRANSPORT)
How do we know if a substance if using a transport system of diffusion?
- Active transport mechanisms: require ATP
Diffusion: related concentration
What is the function of the liver?
- detoxification and drug metabolism
Where do SL preparations enter the body first?
- enter the coronary arteries first, bypass 1st pass metabolism
Tablet disintegration and dissolution occur in the ____ where the pH is LOW (during fasting, pH=higher)
stomach
What is the purpose of making the tablet enteric coated?
- ensures that it comes out in the intestinal; ;after (at a higher pH)
What is the dissolution rate of tablets?
- very limited and slow
How do drugs move into the microvilli?
- there is no flow at the surface of the microvilli
- must diffuse to the surface (takes time)
- there are millions of microvilli for absorption (they are high and project quite a bit of SA)
- concentration is the limiting factor on how much drug is absorbed (if not absorbed, it is excreted)
Only _____ drug can be in solution
ionized
The portal vein drains into the liver - this is called the ______
first pass effect
What preparation should you give the drug as if it is highly excreted via first pass?
- formulate as a rectal preparation – the vessels supplying the rectum goes into the IVC into the vasculature - the inner area goes to the inferior mesenteric vein to the portal system
For severe vomiting, how should drugs be dosed?
- rectal administration is better- bypasses the portal vein feeding into the IVC
What is the pH value of the stomach?
1-3
What is the pH value of the duodenum?
5-7
What is the pH value of the colon?
7-8
Distribution of a drug across the gut depends on what?
pka, lipid solubility, pH in solution
If the drug is mostly ionized, it will stay in the _____
If the drug is mostly unionized, it will stay in the _____
BLOOD
TISSUE
______ are the main line for uptake
Transporters
What is the nutrient content in the portal vein?
- the portal vein has a lot of nutrients in it but no oxygen - requires mixing with the hepatic artery to get oxygen that will allow the liver cells to survive
What are the 2 blood vessels that feed into the sinusoids? Where do these sinusoids lead to?
- the hepatic portal vein and the hepatic artery – the sinusoids dump into the central vein leading into the IVC and the heart
The hepatocytes are bathes on each side by ____
blood
Nutrients come into the sinusoids from the blood flow and is eliminated into the ____
bile (when they mix together there is oxygen delivery down the sinusoids into the central vein)
You can reverse a ______, but not a cirrhotic liver with diet and exercise
fatty liver
How many different zones are there on the liver?
3
How is the liver able to regenerate?
- the cells closest to the central vein undergo apoptosis and slough off
- new hepatocytes regenerate in zone 1 and push everything out (zone 1 becomes zone 2, 2 becomes 3 - still hepatocytes but the size, enzymes and function will differ
What happens to a large liver when it is transplanted into a small cavity?
- when transplanting a large organ into a small one, the cells in zone 3 are going through apoptosis. The sinusoids are being shrunk down to fit into the cavity
- the regeneration occurs in zone 1 - old zone 1 becomes zone 2, etc
Zone ___ cells have the highest uptake of drugs (zone 3 has the lowest uptake)
1
The endothelium of the liver is not intact and has _____. Small openings allow plasma proteins through (everything in the sinusoids minus RBC’s- space of disse is 2 micron)
fenistrations
The ____ with the holes in them buffer the flow between the hepatocytes and the red blood cells. Only plasma proteins and things that are soluble in the blood will pass through these holes in the membrane
sinusoids
Why is it so hard for a drug, even if it is lipophilic, to cross the membrane solely by diffusion?
Due to the fluid mosaic model of the cell- the membrane of the cell is not rigid, it flows. There are many proteins, glycolipids, oligosaccharide side chains, etc which makes it harder for the drug to get though and difficult to find a direct lipophilic area for drug diffusion (therefore the drug is mostly taken up by transporters)
What happens if you do not remove bile from inside of a cell?
- the bile salts act as a soap and solubilize the intracellular contents - albumin becomes glycosilated
What is the process of the drug being taken into the cell by transporters?
Drug transporters act as gatekeepers - drug goes through uptake transporters and goes into the cell where it undergoes metabolism by CYP450 (phase 1) or UGTs (phase 2). The metabolite goes through efflux transporters out of the cell
What different things do drug transporters control?
- control intracellular drug concentrations and access to drug metabolizing enzymes
- controls systemic drug concentrations - absorption and excretion
- controls drug concentrations at the site of action
What is the specificity like of enzymes?
- enzymes are proteins that catalyze specific reactions, but very slight structural changes to the substrate molecules often abolish or dramatically decrease activity
- VERY SPECIFIC
What is the specificity of transporters?
- transporters are proteins that can recognize many different substrates, sometimes form structurally unrelated classes
What are SLC transporters generally used for?
- responsible for the uptake of molecules into the cell
Where are most SLC transporters located?
- most SLC transporters are located in the cell membrane, although there are some members located in the mitochondria and other intracellular organelles
What are the different SL uptake transporters?
OATs (organic anion transporters) OATPs OCTs (organic cation transporters) PEPTs (peptide transporters) MATEs (multidrug and toxin extrusion protein)
What are the ABC efflux transporters?
P-gp (ABCB1) (binds hundreds of different PRO)
BCRP (ABCG2 (breast cancer resistant protein)
MRPs (multi-drug resistant protein)
BSEP (bile salt extrusion protein)
What does ABC transporters stand for?
ATP binding casette
What are ABC transporters responsible for?
efflux of molecules from the cell
ABC transporters are _____ proteins that use ATP hydrolysis as an energy source to translocate substrates across the membrane
transmembrane
Are ABC transporters typically quite large?
yes, they are
Why is there drug interactions in different parts of the body than where the drug is designed to have action?
- because every organ has transporters, and different organs can have the same transporter - they are NOT specific
What is the OAT1 transporter typically responsible for?
responsible for elimination of many drugs by transporting them into urine
Active transporters are inhibited _______ by substances that interfere with cell respiration
non-competitively
If you drop the temperature of the cell, what will happen to the processes of diffusion and active transport?
- diffusion will not be altered so much by dropping the temperature
- active tranport mechanisms are stopped- energy production is stopped when the temperature is dropped
What does the volume have to do on the rate of emptying on gastric cells?
- the larger that starting volume the greater the initial rate of emptying. After this initial period the rate slows
What does the osmotic pressure have to do on the emptying of the stomach?
- increase at lower concentrations, decrease at higher concentrations
What does the physical state of the meal have to do on the emptying on the stomach?
- solutions and suspensions empty more rapidly than chunks
What does the addition of acids have to do on the rate of stomach emptying?
they reduce the rate of emptying
What does the addition of an alkali have to do on the rate of stomach emptying?
they increase the rate of stomach emptying
What effect do anticholinergics have on the rate of stomach emptying?
decrease
Narcotic effect on stomach emptying
decrease
Metoclopromide effect on stomach emptying
increase
Ethanol effect on stomach emptying
reduction
What effect do bile salts have to do on the rate of stomach emptying?
- reduces the rate
What could happen if you take coke/coffee with medication instead of water?
- you can change the pH of the stomach, thereby affecting the transporters
What are the drug related factors that are affecting dissolution?
- Solubility
- Solvation
- Crystallization
- Particle size
- Complexation
What is the double peak phenomena?
- it is caused when you are eating a meal/snack
- when you eat something, it diverts blood to the GI so that it can carry the nutrients away- you have an increased drug uptake
