1 - Absorption Flashcards
What is biopharmaceutics?
Relationship btwn physical and chemical properties of a drug in a dosage form and the pharmacologic response after administration
What is biopharmaceutics dependent on?
- Chemical nature (ex: salt, ester)
- Physical state (ex: liquid, solid, particle)
- Type of dosage form (ex: tablet, injectable, inhalation)
- Presence/absence of excipients
- Pharmaceutical process (ex: type of granulation, tablet press, friability)
What is friability?
Ability to withstand degradation
What is pharmacokinetics?
- Study and characterization of time course of drug absorption, distribution, metabolism, excretion, and release
- The relationship of these processes to the intensity and time course of the therapeutic and adverse effects of drugs
What is bioavailability?
Rate and extent to which a drug is absorbed from a drug product into the body or to the site of action
What is pharmacodynamics?
The relationship between drug concentration at the site of action and pharmacologic response
What are some factors that affect absorption?
- Transport processes
- pH
- Lipophilicity
- Particle size
- First-pass effect
What happens if a drug is protein bound?
Pharmacologically inactive
____ is the largest route of excretion
Renal clearance
____ MW drugs cannot be given orally because _____
- High
- Have immediate availability in the body, so increased risk of adverse effects
Which dosage form is the safest to give and why?
Transdermal because it can be easily removed
Which route of administration is used for emergencies?
Intravenous
What are disadvantages to intravenous drugs?
- Increased risk of adverse effects
- Must inject solutions slowly
- Not suitable for oily solutions or poorly soluble substances
Which route of administration is suitable for some poorly soluble suspensions?
Subcutaneous
Which route of administration is suitable for instillation of slow release implants?
Subcutaneous
What are disadvantages to subcutaneous drugs?
- Not suitable for large volumes
- Possible pain or necrosis from irritating substances
What is the absorption pattern for subcutaneous drugs?
- Prompt from aqueous solutions
- Slow and sustained from repository preparations
What is the absorption for intramuscular drugs?
- Prompt from aqueous solutions
- Slow and sustained from repository preparations
Which type of intramuscular drugs are suitable for self-administration?
Repository preparations b/c slow and sustained release
What are disadvantages to oral drugs?
- Requires px compliance
- Bioavailability potentially erratic and incomplete
What is plotted on a log dose effect curve and what is the shape of the data?
- % max response vs % effective dose
- Shape is sigmoidal
How do hydrophilic drugs cross the lipid bilayer?
- Channels (limit MW)
- Transport proteins (*main way drugs cross)
What is the problem w/ lipophilic drugs and the lipid bilayer? How is this overcome?
- Lipophilic drugs can easily cross the lipid bilayer, but don’t want to cross into blood
- Drug binds to albumin b/c drug has higher affinity for albumin than bilayer
How is the affinity of drugs for albumin increased?
Albumin proteins bump up against the lipid bilayer which increases the affinity
How is a drug transferred from albumin to a transporter?
- Drug can jump in the free form or as a protein-bound drug
- Ionic interaction b/c albumin and transport protein, so if charges line up correctly, binding site of albumin changes, causing affinity for drug to albumin to decrease a lot, making affinity for transport protein greater than for albumin
Where does a transport protein take a drug?
Into tissue
Which process/compound is responsible for side effects of drugs and why?
Transporters because they are present in tissues where you don’t want the drug to go
Which compounds are not able to cross to the absorption site? How is this overcome?
- Ionized compounds
- Require a transport protein to cross
How do sublingual preparations avoid first pass metabolism?
Enter coronary arteries first
Where do disintegration and dissolution occur?
In the stomach where pH is low
For liquids, capsules, and tablets, which has the slowest and which has the fastest disintegration?
Slowest = liquid > capsule (no disintegration) > tablet (2x disintegration)
How do drugs cross intestinal microvilli?
Diffusion b/c no forces to pull the drug
Which formulation can bypass first pass metabolism and how?
- Rectal suppositories
- Vessels supplying the rectum go into IVC and then into vasculature
A drug must be ______ before it can be absorbed
In solution
What is the pH of the stomach?
1-3
What is the pH of the duodenum?
5-7
What is the pH of the colon?
7-8
What dose absorption of a drug across the gut depend on?
- pKa
- Lipid solubility
- pH of solution
- Ionization (increased ionization decreases absorption)
- Polarity
- Lipophilicity
Does much absorption occur in the stomach?
No
Why are most drugs absorbed across the small intestine?
- Large blood flow
- Microvilli
- Bile helps solubilize drugs
- Presence of microflora (in some cases)
A drug w/ pKa = 3 is more soluble in ____ than _____
Duodenum than stomach
How many zones are in the liver and what are they separated based on?
- 3 zones
- Separated based on size of liver cells
What is a simple unit of the liver composed of?
Hepatic portal vein and hepatic artery
What is the hepatic triad?
Hepatic artery, hepatic vein, and bile ductule
Where so the hepatic portal vein and hepatic artery feed into?
Sinusoids that dump into central vein, leading to IVC and the heart
What happens when a person has nodules on their liver?
Nodules are fat deposits, so the fat puts pressure on structures like microsomes and nuclei, disrupting the internal infrastructure of the liver
Can a cirrhotic liver be reversed?
No
Can a fatty liver be reversed?
Yes, w/ diet and exercise
How is the liver able to regenerate itself?
- 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 size, enzymes, and function will differ
Can you transplant an adult liver into a child?
Yes, the liver will know the cavity is too small and will shrink to fit
Endothelial cells in most organs are ______
Continuous (do not allow things to pass by conductive flow)
What are fenestrations? Where are they found?
- Small openings that allow plasma proteins through (not RBC’s)
- Found in liver cells
What happens once plasma proteins enter the fenestrations?
They must diffuse to enter hepatocytes
Do hepatocytes have microvilli?
Yes
Is the concentration on either side of hepatocytes and sinusoid the same?
Yes
Blood supply from ___ and ____ mix before going down sinusoid into hepatic vein
Portal vein and hepatic artery
Blood from portal vein and hepatic artery are rich in ____
Oxygen, nutrients, drugs, and toxins
Which cells of the liver have the highest [ ] of metabolic enzymes and oxygen?
Zone 1 (closest to hepatic artery and portal vein)
What happens to the cells as they get closet to central vein?
Drug [ ] (and [ ] of everything else) decreases
What happens if a hepatocyte sense that there is nothing around it? Why do they do this?
- Will travel to couple w/ another hepatocyte, then the couplet will migrate towards other hepatocytes to create a chain to form a sinusoid
- Do this so that uptake proteins are everywhere else and export proteins are closer to the inside
1 hepatocyte = ___ microns
15-20
What is another name for a sinusoid?
Bile canaliculi
Why is direct drug diffusion rare in the plasma membrane?
B/c surface of the cell has many components (proteins, glycolipids, oligosaccharides) and few areas of just lipid bilayer, so it is hard to find a direct lipophilic area for drug diffusion
What do drug transporters control when they are in the membrane of cells?
- Intracellular drug [ ]
- Access to drug metabolizing enzymes
- Systemic drug [ ], absorption, and excretion
- Drug [ ] at site of action
What travels through efflux transporters?
Drug and/or metabolite
Do transporters only recognize one substrate?
No, can recognize many, sometimes from structurally unrelated classes
What are the types of SLC transporters?
- Organic anion transporters (OATs) and transport proteins (OATPs)
- Organic cation transporters (OCTs)
- Peptide transporters (PEPTs)
- Multidrug and toxin extrusion protein (MATEs)
What are the types of ABC transporters?
- ABC = ATP binding cassette
- P-glycoprotein (P-gp (ABDB1))
- Breast cancer resistant protein (BCRP (ABCG2))
- Multi-drug resistant proteins (MRPs)
- Bile salt extrusion protein (BSEP)
What is known when a drug is a substrate of a transporter?
- Determinant of drug disposition (ADME)
- Prediction of potential drug-drug interactions (DDI)
What is known when a drug is an inhibitor of a transporter?
- Affects intracellular/systemic concentrations of affected drugs
- DDI potential w/ other substrate drugs
How do transporters cause DDIs?
If 2 drugs have the same carrier, the one w/ highest affinity will be taken up while the other will be eliminated
What are SLC transporters generally responsible for?
Uptake of molecules into cells
Where are most SLC transporters located?
- Cell membrane
- Some located in mitochondria or other intracellular organelles
How are SLC transporters named? Which family is an exception to this?
- nXm
- n = family number (1-52)
- X = letter for subfamily
- m = number representing individual family member
- Exception = family 21 (OATPs)
What happens if bile acids are not removed from a cell?
Will solubilize everything and cause apoptosis
What are ABC transporters generally responsible for?
Efflux (removal) of molecules from cells
Where are ABC transporters found? What do they use for energy?
- Transmembrane
- Use ATP hydrolysis as an energy source to translocate substrates across membranes
How are ABC transporters named?
- xN
- x = family (A-G)
- N = number representing individual family member
Are ABC transporters small or large?
Can be very large
Do SLC and ABC transporters work together or against each other?
Together, in vectorial transport
What are the main characteristics of active transport?
- Can move substrate against [ ] gradient
- Requires energy expenditure
- At low [drug], rate is proportional to [drug]
- At high [drug], carrier mechanism is saturated
- Shows specificity in certain organs and certain transporters
- Subject to competitive inhibition
- Shows site specificity
- Inhibited non-competitively by substances that interfere w/ respiration/energy production of cells
What happens if the amino acids of an ABC transporter are changed?
There will be a dramatic change in the concentration-time curve (increased Cmax and greater AUC)
How could you determine if a drug undergoes active transport or passive diffusion?
Active transport will diminish when temp. is decreased, but passive diffusion won’t b/c it is temp. dependent in Kelvin
What influence does volume have on gastric emptying?
- Larger starting volume = greater initial rate of emptying
- After initial period, rate slows
What influence do fatty acids have on gastric emptying?
Reduce emptying, in proportion to chain length
What influence do triglycerides have on gastric emptying?
Reduce rate of emptying, unsaturated more effective, linseed and olive oils most effective
What influence do carbs have on gastric emptying?
Reduce
What influence do amino acids have on gastric emptying?
Reduce, proportional to concentration
What influence does osmotic pressure have on gastric emptying?
- Increase at lower concentrations
- Decrease at higher
What influence does the physical state of food have on gastric emptying?
Solutions or suspensions empty more rapidly than solids
What influence do acids have on gastric emptying?
Reduce
What influence do alkali chemicals have on gastric emptying?
Increase
What influence do anticholinergics have on gastric emptying?
Decrease in emptying
What influence do narcotic analgesics have on gastric emptying?
Decrease in emptying
What influence does metoclopromide have on gastric emptying?
Increase in emptying
What influence does ethanol have on gastric emptying?
Reduction
What influence does body position have on gastric emptying?
Lying on left side reduces emptying
What influence does viscosity have on gastric emptying?
Increase viscosity reduces emptying
What influence does emotional state have on gastric emptying?
- Aggressiveness increases contractions and emptying
- Depression reduces
What influence do bile salts have on gastric emptying?
Reduces
What influence do disease states have on gastric emptying?
Rate is reduced in some hypothyroidism, pyloric lesions
What influence does exercise have on gastric emptying?
Vigorous exercise reduces
What influence does gastric surgery have on gastric emptying?
Emptying difficulties can be a serious problem
___ is a major factor in drug absorption in the gut
Food
Should drugs be taken w/ water? Why?
- Yes b/c helps disintegration and drug needs to be in solution to be absorbed
- Don’t take w/ caffeinated drinks b/c can alter pH
- Don’t take w/o water b/c can get stuck in esophagus and result in a delay of onset
What are some factors that affect drug absorption?
- Age (# of transporters)
- Blood flow
- pH
- Food
- Drugs
What is intensity?
- Distance btwn minimum effective concentration and Cmax
- May correlate w/ therapeutic window
What is duration?
Time of onset to termination
Can a drug have 2 Cmax values?
Yes, b/c food affects absorption
What are some drug related factors that affect dissolution rate?
- Solubility
- Solvation
- Crystalline
- Particle size
- Complexation
