ADME 1 Flashcards
What are the boundaries of the therapeutic window?
Maxima:
- Minimum Toxic Concentration/ Maximum Tolerable Concentration
Minima:
- Minimum Effective Concentration
What is the Therapeutic index?
Therapeutic Index = Minimum Toxic Conc. (for 50%)/Minimum Effective Conc. (for 50%)
See Graph for differences in getting into the therapeutic window for IV and Oral administration methods.
See Graph for differences in getting into the therapeutic window for IV and Oral administration methods.
What is the principle concern of pharmacokinetics?
The Fate of the Drug in the body
- How does it get in
- Where does it go
- what changes are made to it
- how does it get out
What determines the pharmacokinetics of a drug?
- what do the factors govern?
- Absorption
- Distribution
- Metabolism
- Excretion
(ADME)
These govern:
- Onset
- Intensity
- Duration of drug action
What is the relationship between absorption, metabolism and excretion during the rising and falling phase of a drug?
Rising Phase:
Abs. > Metabolism and Excretion
Falling Phase:
Metabolism and Excretion > Abs.
Determine the following for a lipid membrane:
- water permeable?
- Size of Drug that can pass through?
- Permability to peptides?
- What passes through best?
- Yes, its water permeable, small polar uncharged particles can cross
- Low MW (100-200 Da) drugs can pass through pores
- Relatively impermeable to proteins and peptides
- Lipophilic and Non-polar and non-ionized compounds may pass through the membrane
What methods do most drugs used to cross membranes?
Passive Diffusion
What is Fick’s Law?
- what do each of the variables mean?
Diffusion Rate = -DAK(Cin-Cout)/∆x
D - Diffusion coefficient (inverse proportion to size)
A - Surface area
K - Solubility of the Drug (affects by ionization and thus pH)
∆x - membrane thickness
What methods do large and/or polar molecules use to get across lipid membranes?
They must be carried by Carrier-Mediated Biotransport
T or F: the electrochemical gradient dictates the direction of movement of molecules transported by Carrier-Mediated Biotransport.
True, drugs carried by this method CANNOT go against their biochemical Gradient
Determine which if the following applies to facilitated diffusion, active transport, or both?
- Movement against Concentration Gradient
- Utilization of Energy
- Saturation Kinetics
Facilitated Diffusion:
- CANNOT move against gradient
- DOES NOT use energy
- YES, it DOES display saturation kinetics
Active Transport:
- Yes, it can move against gradient
- Yes, it requires energy
- Yes, is displays saturation kinetics
How do riboflavin and B12 cross membranes?
Via Facilitated Diffusion
How does 5-flurouracil cross membranes?
Active transport
Don’t for get about co-transport and counter-transport.
Don’t for get about co-transport and counter-transport.
What does P-glycoprotein act on?
Its an MDR pump that pumps out chemotherapeutic agents
How are vitamins A, D, E, and K taken up?
Pinocytosis
**This can be clathrin dependent or independent
What are the two requirements for a drug to get into and out of a lipid membrane?
Must be soluble in the membrane
Must be soluble in the AQUEOUS phase to get out of the membrane
What is the pH-partition theory?
Says that pH and pka determine if a drug will be charged in a given environment, if that molecule neutral at a time, it will be much more likely to cross the lipid membrane.
What is the driving force for a drug across the membrane?
**the concentration gradient that exist for the NONionized form.
What is the Henderson Hasselbach equation for acids and for bases?
Acids:
- pH = pKa + log[A-]/[HA]
Bases:
- pH = pKa + log [B]/[BH+]
What is the implication of most drugs being weak electrolytes?
Ion trapping can occur - acidic drugs will be neutral in an acidic environment, and they can move across the membrane into a more basic environment. When they move into the basic environment they get trapped because they become charged and can no longer cross the membrane
If there is an acidic and basic side to a membrane, which side will basic drugs get trapped on?
The acidic side
Define absorption.
The RATE at which a drug leaves its entry point and the EXTENT to which that occurs
What is bioavailability and what is the range of bioavailability?
Bioavailability - a range from 0 to 1 to describing the fraction of drug that reaches its site of action or a biological compartment to where is can reach its site of action.
- IV drugs are naturally 1
What are the two general ways in which a medicine can be adiministered?
Enteral (by GI tract) and Parenteral (not by GI tract)
What are the Enteral Routes of Administration?
- Oral
- Sublingual
- Rectal
What are the Parenteral Routes of Administration?
- Intravenous (IV)
- Subcutaneous
- Intramuscular
- Intraarterial
- Inhalation
- Topical
For drugs that have low solubility or that are given a high dose enterally, do you expect dissolution or absorption to be the rate limiting step?
Dissolution controls the rate in these cases
What are the advantages and disadvantages to oral administration of drugs?
Advantages:
- Safe and Painless
- Cheap
- no need to sterilize
Disadvantages:
- Slow onset usually > 1hr
- Patient noncompliance
- First pass metabolism - low bioavailability
What two methods of GI administration allow for bypass of 1st pass metabolism?
- Buccal
- Large Intestine
Why are drugs absorbed so quickly by the buccal route of administration?
- what is the surface area and pH of the buccal route?
Thin Membranes
Good Blood Supply
pH = 7
Surface area = Small
What areas of the GI tract have a large surface area?
- what is their pH?
Duodenum - pH = 5-6.5
Small Intestine - pH = 8
How much time do drugs spend in:
- Stomach
- Duodenum
- Small Intestine
Stomach - 30-40min
Duodenum - very short
Small intestine - Long ~3hr
Why does increasing gastric emptying time typically increase drug absorption?
- how would you increase gastric emptying time?
- Large surface area of the Small Intestine typically allows for better absorption so the quicker you get it out of the stomach and into the S.I. the better.
- Gastric Emptying time can be increased by Taking drinking water with your pill
Which would you expect to get absorbed better in the stomach: acidic or basic drug?
Acidic drugs because they will be neutral in the stomach and can more easily cross membranes
What factors affect gastric emptying?
Volume of ingested material: Bulky Materials tend to empty more slowly than liquids
Type of Meal: Fatty Foods Decrease Gastric Emptying
Lying on the left side: Decreases Gastric Emptying (because pyloric sphincter is on the right)
Drugs: Anticholinergics, Narcotics, Analgesics reduce gastric emptying
What are the advantages and disadvantages to administering a drug sublingually?
Advantages:
- Avoid First Pass
- Rapid absorption (good bs to the mouth)
- Neutral pH in mouth means drug is stabile
Disadvantages:
- Holding dose in the mouth is inconvenient
- Useful when drug dosage is small
Rectal Route advantages and disadvantages
Advantages:
- Useful in Children
- Unconscious/Vomitting Patients can take it
- Not 1st pass
Disadvantages:
- Absorption is erratic
- People don’t like Sticking things up their ass
There are lots of advantages and disadvantages to IV drug admin. What are some important ones?
Advantage
- You can control how fast the drug gets in
- high bioavailability
Disadvantage
- Expensive because it must be sterile
- you need trained personnel
What are some advantages and disadvantages to Subcutaneous drug admin?
Adv.
- no 1st pass
- absorption can be varied with rapid aqueous solutions and slow delivery from insoluble preps.
- Patient can give it themselves
Dis.
- painful
- local tissue damage
- must be given in small volumes (2mL max)
What are the advantages to IM admin?
Adv.
- Avoid 1st pass
- Rapid
Dis.
- Trained personnel needed
- Site of injection influences absorption
- gender differences
- Pain
- Volume limited to (4-5 mL)
Why would you give a drug intraarterially?
adv.
- Can be used to target specific organs
dis.
- Experts only can do this
What is an intrathecal injection?
- Injection into the subarchnoid space to rapidly transverse the BBB
What are examples of some systemic and local drugs administered via inhalation?
*what to watch out for when giving these
Local - Bronchodilators
Systemic - General Anesthesia
- Allergic Reactions can happen
What chemical properties must a drug have that is given topically?
Must be lipid soluble
What factors determine the Rate of Distribution of a drug?
- Cardiac output and regional Blood Flow
- Tissue Volume
- Capillary Permeability
What factors determine the Extent of Distribution for a drug?
- Membrane Transport Abilities
- Plasma Protein Binding
- Intracellular Binding
Where is total blood flow greatest in the body?
Which have the highest perfusion?
What is the consequence of this?
- Brain
- Kidneys
- Liver
- Muscle
Same for perfusion except muscle is not included and the Heart is
Consequence:
- These are the organs where you would expect drug concentration to rise the most rapidly
Take a drug that is 30 kD in weight, how do you think it will be absorbed?
Most likely absorbed via Pinocytosis
What two variations in capillary structure result in variation from normal Drug tissue permeability?
- Renal Capillaries have large fenestrations leading to more drugs going out of the capillary bed via Filtration
- Brain Capillaries have tight junctions creating the BBB
How can plasma proteins affect the concentration of free drug in the blood?
- What plasma proteins are involved with what drugs generally?
Causes drugs to stay in the central blood compartment and limits distribution of free drug to its site of action
Albumin - soaks up acidic drugs
Globulins - soak up basic drugs
What determines how much of a drug will be bound by a plasma protein?
- what does this entail?
AFFINITY of the Plasma Protein binding sites for the drug at low concentration
At high concentration the NUMBER of binding sites becomes the main variable
**Will show typical characteristics of binding kinetics, its a SATURABLE and NON-LINEAR process
T or F: even slight changes in the percent of Drug bound to plasma protein can cause HUGE changes in the free drug concentration.
True, this is of greatest concern with drugs that have a narrow therapeutic window
What is often the cause of Drugs accumulating in tissues?
- what are the kinetics of this process?
Active Transport into the tissue or Tight Binding to the Tissue
Kinetics = Reversible and Saturable
What can be an advantage of ion trapping of a drug?
Bound ion Trapped Drugs are relatively inaccessible to systemic circulation and will be released at low levels over a long period of time to prolong the drugs effect
What are some Common Reservoirs for Drugs?
- what drugs do they often trap?
- Stomach - Traps BASIC drugs due to ionization (ex. Codeine)
- Albumin - Limits the availability of free drug (Warfari 99% bound)
- Tissue - Liver Concentrates drugs like quinacrine
- Thyroid concentrates Iodine
- Bone - can accumulate Tetracycline, Divalent Chelating agents, and Heavy Metals - Fat can accumulate lipid soluble compounds
What is drug redistribution?
- When the drug moves from the site of action to other tissues or to bound proteins
- Direction of blood flow often affects this
What are the 4 drug distibution patterns?
- general types of drugs that lead to these patterns?
- What pattern do most drugs adhere to?
- Drug remains largely in the vascular system
- Plasma substitutes and Drugs Strongly bound to plasma Protein - Uniform distribution through body water
- Water soluble drugs (e.g. EtOH) - Concentration into one or more tissues
- Iodine in thyroid
- Tetracycline in developing Teeth - Non-uniform Distribution in the body MOST DRUGS
- due combined effects of 1,2,3
What is the Volume of Distribution and What is its formula?
- Tells you what volume of H2O that drug is in
- Tells you (generally) which compartment the drug is in
Vd = Drug administered / [Drug in Plasma]
What are the volumes of distribution for:
- Extracellular Fluid
- Plasma
- Intrerstitial Fluids
- Intracellular Fluids
- Total Body Water
- Extracellular Fluid - 13-16 liters
- Plasma - 4
- Intrerstitial Fluids - 10-13
- Intracellular Fluids - 25-28
- Total Body Water - 40
If a drug has a Vd of 8 what could you assume?
The drug is likely concentrated in the plasma or interstitial Fluid
If a drug has a Vd of 35 what could you assume?
That it is uniformly distributed throughout the total body water
If a drug has a Vd or 130 what could you assume?
The drug is concentrating in multiple tissues, really you would assume this with anything much greater than 40
The effects of the body on the drug is what?
Pharmacokinectics
pharmacodynamics is what the body does to the drug
Compare the Rate of Distribution to the Extent of Distribution based on the factors that they are dependent on.
Rate of Distribution:
- Cardiac Output
- Tissue Volume
- Capillary Permeability
Extent of Distribution:
- Membrane Transport Ability
- Plasma Protein binding
- Intracellular Binding
