Ch. 4 pharmacokinetics Flashcards
4 basic pharmacokinetic processes
Absorption: movement from sit of administration-> blood
Distribution: movement from blood-> interstitial space of tissues-> cells
Metabolism: enzymatically mediated change of drug structure
Excretion: movement of drugs and metabolites out of the body
elimination= metabolism and excretion
Crossing a membrane:
all these processes involve “drug movement” across a membrane
- cell membranes are made of fats (phospholipids)
3 ways to cross a cell membrane
- channels and pores: very few pass through these very small passageways (K+, Na+)
- transport systems: carriers that move drugs from one side of cell membrane to the other
- some require energy, some do not
- are selective
- depend on drug structure - Direct membrane penetration
- most drugs do this*
- resort to because:
-> most drugs are too large to pass through channels/pores
-> most drugs lack transport systems to escort them across membrane
- DRUGS MUST LIPOPHILIC
Absorption: getting into blood stream
Factors affecting absorption:
- rate of dissolution: before it can be absorbed, it has to be dissolved
- surface area: larger the surface area (small intestine) increases absorption
- blood flow: increased blood flow=increased absorption because of concentration gradients
- lipid solubility
- pH partitioning: if one side of membrane is more acidic, basic drugs will be more drawn to it and vice-versa because opposites attract
Routes of administration: IV
IV
- barriers: none
- Disadvantages:
-> irreversible: all blood in body circulates in about 1 min; best to inject drug over one minute to give as dilute delivery
-> take 15 sec for blood to get to brain from AC
–> ALWAYS check drug guide for recommended length of injection/infusion
- fluid overload- caution in diseases this would affect (kidney, HTN, HF, pulmonary HTN)
- Embolism: item in the blood stream blocks vessel- the IV van injure the venous wall causing clot formation, injection of hypotonic or hypertonic fluids can destroy RBCs and this debris can form embolus, also air in line or undissolved drugs
Route of administration: IM
water solubility- increased= absorption in 10-30 min
Advantages:
- poorly soluble: cannot be given IV (embolus)
- depot preparations: absorbed over long period (testosterone pellets, PCN G, depo-provera birth control)
route of admin: Other routes
- topical, transdermal, inhalation, rectal, vaginal, direct injection into specific site (joint), intrathecal, intradermal
When to prefer parenteral (IV,IM,etc) over oral?
- emergencies
- tight plasma drug levels are needed
- drug would be destroyed by gastric acid
- drug would cause severe local injury (anticancer meds)
- if drug cannot cross membranes to be absorbed
- when prolonged effect is desired
- pt cannot take oral drugs
Oral preparations
Chemical equivalence: two drug preparations with same amt identical chemical cmpd
Bioavailability: two preparations where drug is absorbed at same rate and to same extent
two formulations of same drug can cause pt variation in absorption/bioavailability
preparations:
- tablets, capsules
- enteric-coated (EC): coating made to be dissolved in intestine, not stomach
- sustained-release (SR): spheres with coating that dissolve at variable rates
Distribution:
The movement of drugs throughout the body
-> from blood->tissues->cells
Drugs leave the blood through the capillary beds
-> typically capillary beds: pass between the cells, so no problem
-> BBB (blood-brain barrier): tight junctions btween cells, so prevents drug passage between; must pass through so much be lipid soluble or have transport system
- offers protection, but an obstacle,
BBB is not fully developed at birth
-> placental drug transfer: NOT absolute barrier and drugs and drugs can cause serious harm; the lipid soluble, non-ionized drugs pass readily
-> Protein binding: plasma albumin is the most important
- always remains in bloodstream
due to large size
- if drug is bound to albumin, it will
not enter cell
- some drugs bind more tightly than
others to albumin
- drugs compete against one
another to bind to albumin
Metabolism:
Hepatic Drug Metabolizing Enzymes: cytochrome P450 system (CYP)
CONSEQUENCES of drug metabolism:
*accelerated renal drug excretion:
- glucuronidation (kidney can not excrete highly lipid soluble drugs, so they must be converted to water-soluble forms)
- drug inactivation
- increased therapeutic action
- activation of prodrugs: metabolized to active form of drug
- toxicity: metabolism can change a drug in many ways- make safe to unsafe, vice-versa
CONSIDERATIONS:
- Age: infants develop full liver capacity 1 yo
- Induction/inhibition: some drugs can increase/decrease production of enzymes causing increased/decreased metabolism
- First-pass: when absorbed through GI tract, go straight to liver through portal circulation, some drugs can be completely metabolized and inactivated this first go around
- Nutrition: enzymes require building blocks
- Competition: two drugs competing for same pathway= decreased rate of metabolism of one/both- can become toxic
Excretion:
- the removal of drugs from the body
Renal Excretion:
- glomerular filtration
- passive tubular reabsorption
- active tubular secretion
- issues: age (kidneys not fully developed until a few months after birth)
Non-Renal Excretion:
- breast milk: lipid soluable drugs can pass; nursing mothers should double check w doc before meds
- bile
- lungs
- small amounts in sweat and saliva
Time course of drug response:
Plasma Drug levels
- minimum effective concentration (MEC)
- toxic concentration
- Therapeutic range: the larger the range, the safer the drug b/c they can more of the drug with no reactions(between MEC and toxicity)
Drug Half-Life
- the amount of time required for the amount of drug in the body to decrease by 50%
- the half life determines the
dosing interval
- when the amount of drug
eliminated between doses
equals the dose administered,
average drug levels will remain
constant and plateau will have
been reached
- if dose remains constant,
plateau will be reached in 4 half
lives
Drug Response:
- peak concentration
- trough concentration
- loading dose: speeds up time to get plateau dose
- maintenance dose
- decline from plateau: 94% of drug will be gone in 4 half-lives
