F9 Introduction to pharmacokinetics (ADME) Flashcards
what is pharmacokinetics?
- the movement of the drug (ADMET)
what is pharmacodynamics?
- the effect of the drug on the body
how can drugs access their target sites?
direct to site
- easy for skin, eye, gut, lung
- much more difficult for other sites but can be done
indirect
- via systemic circulation (blood)
- introduces problems of loss or dilution
- how will drug reach target site only?
- certain body places can only be accessed through systemic circulation
what does the umbrella term ‘elimination’ involve?
- metabolism
- excretion
what are the main routes for drug administration?
- inhalation
- oral
- injection
- transdermal
- rectal
what is the inhalation administration method of drugs preferred for?
- gases
- volatiles
what is the oral administration method of drugs preferred for?
- tablets
- capsules
- solutions
- buccal
what is the injection administration method of drugs preferred for?
- intravenous
- intramuscular
- subcutaneous
- intrathecal
what is intrathecal administration of drugs?
- in the spinal cord into the spinal fluid
what is the transdermal administration method of drugs preferred for?
- patch
- cream
what is absorption in ADME and what routes of administration require this?
- drug must enter the bloodstream from the site of administration
- all routes other than intravenous injection require an absorption step
what is the site of absorption for oral administration?
somewhere along the GIT
what is the site of absorption for transdermal administration?
across the skin
what is the site of absorption for hypodermic injection administration?
from injection site (muscle, adipose tissue)
what is the site of absorption for lung administration?
- alveolar surface
what feature makes molecules more likely to passively diffuse across a lipid bilayer?
more lipophilic = more likely to passively diffuse
describe the distribution step of ADME
- drug travels in systemic circulation after absorption
- perfuses all organs and tissues of the body
- closed system: drug makes continuous and multiple passes around the body and allows drugs to reach organs due to passing through continuously
what determines drug distribution?
- drug binding to plasma proteins
- structure of vascular endothelium
- accumulation in tissue depots
how does the drug binding to plasma proteins affect drug distribution?
- reversible binding can ferry drug around the circulation
- very high affinity binding can limit escape from the plasma and limits ability of drug to into the tissues
how does the structure of vascular endothelium affect drug distribution?
- there are pores between endothelium cells in most vessel beds
- some special cases = blood brain barrier and placenta
describe the blood brain barrier in terms of distribution
- capillary cells into brain have tightly packed endothelial cells and have an additional layer of these cells
- this makes the access to the brain tightly regulated
describe the placenta in terms of distribution
- has the capacity to protect the foetus from harmful components of the blood
how does the accumulation in tissue depots affect drug distribution?
- protein binding sites (including target!)
- adipose tissue
state the body parts in the highly-perfused lean tissue group
- blood cells
- heart
- lung
- liver
- kidney
- glands
- brain
- blood-rich organs so lots of blood gets to these
state the body parts in the poorly-perfused lean tissue group
- muscle
- skin
state the body parts in the fat group
- adipose tissue
- bone marrow
state the body parts in the negligible perfusion group
- teeth
- hair
- bone
- tendon
- cartilage
- extremely minute blood flow
what is the liver packed full of?
- broad-spectrum metabolic enzymes
- many isoforms
- many substrates
- many reactions
- many products
what are the 2 phases that occur to drugs in the liver and what is their purpose?
- redox reactions to add charge and/or reactive centres
- conjugation reactions to add bulky groups
- purpose is to make drug into a form that can easily be excreted from the body by the kidney
how does excretion mainly occur?
- mainly in the urine via the kidney
- some large drugs are excreted in bile
- can also occur in other ways eg. via the lung, but this isn’t as common
what are the 3 key stages of excretion?
- passive filtration
- active secretion
- reabsorption
describe the first stage of renal clearance: passive filtration in the glomerulus
- plasma is forced from blood into Bowman’s capsule of the tubule
- any drug in free solution will be passively carried over into the filtrate
describe the second stage of renal clearance: active secretion in proximal tubule
- transporter proteins extract drug from blood and drive into filtrate (using counter-ion transport and ATP hydrolysis)
- drug can be concentrated
describe the third stage of renal clearance: reabsorption in distal tubule
- lipid soluble drugs can diffuse back out of the filtrate and into the blood
what simplification / assumption can be made to theoretically measure drug concentration at the target site?
there is a direct correlation between plasma concentration, concentration at target and drug effect
what is the therapeutic window of a drug?
plasma concentration range spanning minimum required for therapeutic effect and onset of side effects
what are the issues of drugs with a narrow therapeutic window?
- difficult to use
- patient may need frequent therapeutic drug monitoring
why may the relationship of systemic delivery to plasma concentration may not hold?
- effect is mediated through a metabolite
- effect is irreversible
- kinetics in the target compartment is different from that in the blood
