F9. Intro to pharmacokinetics Flashcards
drug delivery challenge?
Supply active drug to cellular targets at an effective
dose, with minimal side effects
how can a drug reach target site?
direct to site:
-Relatively easy for skin, eye, gut, lung
-Much more difficult for other sites, but can be done
Indirect:
* Via systemic circulation (i.e. blood)
* Introduces problems of loss or dilution of dose
How can drugs be removed from the body?
Metabolism and/or Excretion
Inhalation medicines?
Gases
Volatiles
oral medicines?
Tablets
Capsules
Solutions
Buccal
Injection medicines?
Intravenous (i. v.)
Intramuscular (i. m.)
Subcutaneous (s. c.)
Intrathecal
transdermal medicines?
Patch
Cream
where does absorption of drug into bloodstream happen in oral medicines?
Somewhere along the gastrointestinal tract
where does absorption of drug into bloodstream happen in transdermal medicines?
Across the skin
where does absorption of drug into bloodstream happen in hypodermic injection medicines?
From injection site (muscle, adipose tissue)
where does absorption of drug into bloodstream happen in lung medicines?
Alveolar surface
Describe passive diffusion of drugs across lipid bilayer
Passive diffusion across lipid bilayer down concentration gradient, determined
by lipophilicity of drug
Describe active transport of drugs across lipid bilayer
Active transport can carry some drugs with low lipid solubility into the cell, regardless of gradient. This depends from charge (depends on pH) and size.
what is a closed system?
Blood makes continuous,
multiple passes around the
vascular system
what determines drug distribution?
-binding to plasma proteins
-structure of vascular endothelium
-accumulation in tissue depots
Describe how binding of plasma proteins affects drug distribution?
- Reversible binding can ferry drug around the circulatory system
- Very high affinity binding can limit escape from plasma
Describe how the structure of the vascular endothelium affects drug distribution
- Pores between endothelial cells in most vessel beds
- Some special cases: blood brain barrier, placenta
How does accumulation in tissue depots affect drug distribution?
- Protein binding sites (including target!)
- Adipose tissue
accumulation of drugs depends on?
blood flow
highly- perfused lean tissue groups?
blood cells, heart, lung, liver, kidney, glands, brain
poorly-perfused lean tissue groups?
muscle, skin
Fat group tissues?
adipose tissue, bone marrow
Negligible perfusion tissue groups?
teeth, hair, bone, tendon, cartilage
Describe how the liver is involved in metabolism
-The liver is packed full of broad-spectrum metabolic enzymes
-Evolved to protect against environmental toxicants
Two phases of metabolism?
- Redox reactions to add charge and/or reactive centres
- Conjugation reactions to add bulky groups
ONE NOTE
how does metabolism affect drugs?
increases:
-hydrophilicity
-reactivity
-size
how are drugs usually excreted from the body?
Mainly in the urine via the kidney
* Some large drugs excreted in bile
what are the three key stages of excretion in the kidneys?
-Passive filtration
-Active secretion
-Reabsorption
ONE NOTE
Describe passive filtration in glomerulus stage of excretion in kidneys
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 active secretion in proximal tubule stage of excretion in kidneys
Transporter proteins extract drug from blood and
drive into filtrate (using counter-ion transport and
ATP hydrolysis). Drug can be concentrated.
Describe reabsorption in distal tubule stage of excretion in kidneys
Lipid soluble drugs can diffuse back out of the filtrate and into the blood
Describe how the concentration of drug changes in the plasma
Concentration in plasma rises during absorption phase, peaks, then declines due to elimination
ONE NOTE
Why do we measure drug plasma concentration?
- We cannot realistically measure drug concentration at target site
- Plasma concentration is more accessible
- Assume a direct correlation between plasma concentration,
concentration at the target, and drug effect
Quantification of processes?
ONE NOTE
what is the therapeutic window?
Plasma concentration range
spanning minimum required
for therapeutic effect, and
onset of side effects
ONE NOTE
Challenges with systemic delivery?
Drugs with a narrow therapeutic range:
-Difficult to use
-Patient may need frequent therapeutic drug monitoring:
-therapeutic effect, side effect, or blood level
Relationship to plasma concentration may not hold if:
-Effect is mediated through a metabolite
-Effect is irreversible
-Kinetics in the target compartment is different from that in blood
