N116 Unit 2 Pharmacokinetics

movement of a drug through the body

what the body does to a drug as it enters the blood as it moves to target tissues, as it is metabolized and as it is removed from the body. Drugs must pass a series of barriers to reach target tissue
-depends on physiologic processes

high enough concentration

-route of administration
-patient characteristics

ADME
-absorption
-distribution
-metabolism
-excretion

how drug reaches the circulation

how drug reaches target tissue

how drug is altered by body

how drug is removed from body

multiple membranes (gastric mucosa -> liver cells (hepatocytes), BBB, kidney tubules)

how lipophilic (or hydrophobic) the molecule is

lipophobic, hydrophilic

lipophilic, hydrophobic

-concentration gradient: related to dosage of drug
-size of drug molecule: smaller molecules absorbed faster
-lipid solubility: structure, ionization (influenced by pH)

lipophilic drugs cross membranes more easily than hydrophilic drugs

small, nonionized, lipid-soluble drugs will usually pass through plasma membranes

-diffusion across a membrane that requires a transport protein
-ion channels
-co-transporters, antiporters
-show specificity & saturation kinetics
-don't require energy

-movement of a substance from area of low conc. to high coc.
-requires source of energy, usually ATP

-movement of drug from site of administration to circulation
-Primary factor for determining onset of drug action
-Quantified as bioavailability
-Impacted by several factors affecting rate of absorption

-administration route (will change absorption dramatically)
-molecule size
-molecule characteristics

-The body must absorb drugs administered PO, IM, SQ, Intradermally, or by nebulizer (metered dose inhaler) before the system can respond.
-*The IV route does not involve absorption as a step after IV administration because it bypasses absorption barriers and results in an immediate systemic response.

-Presence of food may decrease absorption
-Presence of certain foods and drugs may alter rate of absorption
-Motility - influences time during which absorption can occur

-Increase blood flow = increase rate of absorption
-Increase surface area = increase rate
-Route of administration
-Impact of temperature on blood flow

Depending on pH of surrounding fluid, most drugs in either charged or uncharged state
-Acids are absorbed in acids because they are nonionized.
-Bases are absorbed in bases because they are nonionized.
-Acid in a basic environment is ionized and therefore less able to cross plasma membranes

-subcategory of absorption
-is the fraction (%) of an administered drug that reaches the systemic circulation

-Rapid, emergency use, bioavailable, predictable
-Req's expert knowledge, painful
-ABSORPTION: seconds

-bioavailability depends on preparation (can be altered by size, pH, charge)
-Pain, irritation of site

-50-75% bypasses first-pass metabolism
-Unpredictable & varied absorption, patient dependent

-AKA controlled release, extended-release, sustained-release, prolonged-action
-Slow absorption >8 hrs

tablets, transdermal patch, IM injection (depot preparation)

-Slow & sustained release of the desired drug to deliver its effect over longer time
-Absorption enhanced with oily surface
-ABSORPTION: days

-Microsomal enzymes in liver carry out most metabolic activities
-Cytochrome P450 (CYP)
-An enzyme that metabolizes many drugs
-Many isoenzyme systems within CYP
-Determine speed at which drug is metabolized

CYP1, CYP2, CYP3

presence of one drug may alter metabolism of another drug by competing for same isoenzyme

Inhibiting isoenzyme could reduce metabolism of another drug → toxic levels

Inducing isoenzyme could increase metabolism of another drug → reduce amount of functional drug

primary metabolic organ (1st pass then every time the drug passes through hepatic circulation)

an enzyme-catalyzed irreversible alteration in a drug's structure

-only some drugs
-A large polar molecule is added to the drug structure to increase excretion potential via kidney or GI tract (conjugation)

the molecular structure is changed or added onto

Oral administration
-Absorption from intestines
-Portal circulation to Liver
-Metabolized by liver (hepatic enzymes/CYP450)
-Fraction of the given drug now enter circulation
-Some lost to: metabolism & biliary excretion

throughout life cycle

microsomal enzyme systems

older adults

-Decreased metabolism with liver impairment
-Genetic variations of CYP enzymes

Transportation of drugs throughout body to target tissue

blood flow to target tissue, drug solubility, drug-protein binding

Increased blood flow = more drug reaching target tissue

-Hydrophilic drugs transported in solution
-Lipophilic drugs - a portion is bound to plasma proteins (ie albumin); a portion of drug is in solution

-Lipophilic drugs in equilibrium between being in solution and being bound to plasma protein
-Only portion of drug in solution is available to diffuse to target tissue
-Properties of drug allow some lipophilics to bind better to plasma proteins than others - competition for binding sites on plasma proteins can create drug interactions

capillaries within the CNS are lined by specialized endothelial cells that allow only selective transport of substances into and out of the brain.

-The placenta acts as a filter but mostly for maternal proteins
-Most drugs can pass across from maternal to fetal circulation to varying degrees

reversibly

-only unbound fraction of drug:
-moves between membranes
-is pharmacologically active and interacts with receptors

varying, expressed as a ratio of unbound to bound concentration

increase duration of action and decrease risk of adverse affects

Vd = (amount of drug in the body) / (plasma concentration)
-how widely distributed a drug is compared to the plasma

the more widely distributed in tissues

the more concentrated in plasma

kidneys, but primary pathway of excretion dependent on size of molecules

fecal, lungs, sweat, renal

-Glomerular Filtration
-Active Tubular Secretion
-Tubular Reabsorption

-Renal Insufficiency: integrity of the glomerulus
-Urinary pH: artificially or due to pathophysiology
-Cardiac Output: renal blood flow

-Plasma drug levels rise as drug is absorbed and then decrease as drug is excreted
-If plasma levels exceed the therapeutic range (toxic range), drug is more likely to produce more adverse effects
-Therapeutic range can be very narrow

-Provides estimate of duration of action
-Time that it takes for the plasma concentration of a drug to be reduced by 50%. a.k.a. (t50)

assume steady state is reached after 6-7 t1/2s

have to be given more frequently to maintain drug in therapeutic range

can be given less frequently

more than 90% of drug is excreted and is considered eliminated

careful dosing, consider magnitude and frequency of dose as well as half life

next dose given before plasma concentration dips out of therapeutic range

loading dose is given

-Larger dose that leads to more rapid absorption and shorter onset of action

given to maintain drug within therapeutic range