Pharmacokinetics -> lecture 1 Flashcards
What is the most important clinical aim when developing drugs?
- To achieve a long enough effective drug conc at action site to cause an action.
What is the therapeutic range?
- Range = concentrations where the drug causes an effect, above min effective conc but below toxic conc.
Do we drug to stay in therapeutic range for a long or short time?
Long as possible as it means the drug conc is high enough to cause an effective action for longer.
How to calculate the therapeutic index?
Maximum non-toxic dose/Minimum effective dose.
What is LD50/ED50?
LD50 - lethal dose for 50% of people.
ED50 - effective dose for 50% of people. (smaller = higher potency)
What is the path of drugs through the body?
A - Adsorption
D- Distribution
M- Metabolism
E- Elimination
What is bioavailability?
How much of a drug dose is unchanged when reaching action site.
How can we create 100% bioavailability?
Make all drug reach site, mainly via IV drug (direct into bloodstream).
How does an orally ingested drug move from GI tract to Circulation?
Passive diffusion
How to measure rate of passive diffusion?
Fick’s law:
rate = (permeability * SA * Δ concentration)/membrane thickness
Permeability = only controllable factor.
Does the chemical state of drugs affect absorption?
Most are weak acids/bases. (lower rates of ionisation)
Uncharged/Unionised drugs = better absorption
What are the alternative methods to absorption?
- Active transport (taken up by transporters etc)
- Pinocytosis (vesicles capture, pinch + release drug)
Experimental = - Solvent drag (v lipid soluble drug = dissolve in solvent, carry drug through membrane)
Theoretical = - Ion-pair absorption (high retention, polar drugs only - bind to non-polar counter ions)
What is the main place drugs are absorbed in the body?
Small intestine => large SA, highly vascularised, alkaline.
What are some secondary places of drug absorption?
- Stomach => small SA, low blood flow, acidic.
- Colon => possible metabolism by bacteria + slow-release?
What are the 3 things that affect drug absorption?
- State
- Gut Motility
- Splanchnic blood flow.
How does a drugs physical state affect absorption?
- Solution = most rapid move into action site.
- Suspension = dissolution to solution
- Tables = disintegrate, de-aggregate (into fine particles), dissolution into a solution.
How does gut motility affect drug absorption?
- Meal size + composition affects motility.
- Ingestion of certain drugs.
- Position of body.
How does splanchnic blood flow affect absorption?
- Dependent on concentration gradient btwn blood flow + GI organs.
How are drugs distributed in blood?
Drugs enter plasma + bind to proteins.
What proteins do drugs bind to in blood?
- Weak acids = albumin.
- Weak bases = glycoproteins.
Is the binding saturation of a drug in blood linear or non-linear?
Non-linear relationship btwn dose + free drug conc.
i.e. There is a larger [free drug] in blood just from small increase in [drug].
How are drugs distributed in tissues?
Depends on: solubility, binding affinity, size etc.
- Anaesthetics go into fat.
- Antidepressants go into extravascular tissue.
How are drugs distributed in the brain?
Brain = protected by blood brain barrier.
- Lipid-soluble = passive diffusion.
- Water-soluble = via carriers.
What is the blood brain barrier and how does it protect against drugs?
A layer of endothelial cells which contain a p-glycoprotein pump which is an efflux pump i.e. has an active drug outflow pump.
What is the main organ in which orally-ingested drugs get metabolised before entering blood?
The liver
How are drugs metabolised in the liver?
- First pass metabolism -> i.e. reduces drug conc before reaching blood stream.
What is meant by high first pass metabolism?
If drug almost completely metabolised = high first pass i.e. there is little left to enter blood stream.
What are the 3 metabolic modes of action in the liver?
- Converts drug to inactive metabolite.
- Converts drug to active metabolite.
- Drug isn’t changed + so is excreted.
What are the 2 phases of metabolism in liver?
1:
- Change molecular structure via cytochrome P450 enzymes.
- Reduction, hydrolysis etc.
2:
- Conjugate via transferase enzymes
- Add ionised group, making more water soluble (easier excretion, lower activity).
Do drugs have to undergo both phases of liver metabolism?
No, can undergo both in either order or just do one.
How can we bypass high rates of first-pass metabolism ?
Change drug administration method:
- Inhalation -> direct to blood.
- Transdermal -> through skin to blood.
- Buccal/sub-lingual -> passive absorption into blood.
- Rectal -> upper (veins = still first pass), middle = avoids.
- Injections:
-> sub-cutaneous = small vols but passive diff into blood.
-> Intramuscular = larger vols, long lasting in blood stream etc.
What’s the main organ drugs are excreted by?
- Mainly the kidneys
What type of drugs are excreted?
- Only unbound (not bound to plasma proteins etc).
What can happen to highly lipid soluble drugs in the kidneys and what is the effect?
Possibly be re-absorbed into renal tubes.
This prolongs the drugs action.
Can excretion be increased?
Yes, change the urine pH by adding bicarbonate/aspirin etc.
What happens to un-metabolised drugs?
Are excreted unchanged which is dangerous.
Can cause possibly kidney damage particularly due to toxic drug accumulation levels.
Are drugs excreted anywhere else in the body except for the kidneys?
- In bile into intestine -> conjugates drug. Potential for reabsorption via enterohepatic circulation back into bloodstream after absorption in small intestine.
- Saliva/sweat.
- Breastmilk
