Pharmacokinetics & Dynamics

pharmacokinetics

effect of body on a drug (ADME)

absorption, distribution, meatbolism, excretion

what does pharmacokinetics include?

pharmacodynamics

effect of drug on the body 

MOA, organ system effects, therapeutic effects, toxic effects 

what do pharmacodynamics include?

administration

means by which you get drug into patient

absorption

drug gets into bloodstream

distrbution

blood transports drug to tissues 

drug action

drugs binds to effects cells

termination of effect

metabolism and/or excretion

administration, absorption, distribution, drug action, termination of effect 

what are the 5 steps of administration to excretion?

determine onset, intensity, duration

understanding pharmacokinetics allows us to…

enhancing efficacy and reducing toxicity

pharmacokinetics provide effective therapeutic management by _____ ______ and ______ ______

absorption, distribution, metabolism, excretion

what are the 4 properties pharmacokinetics are dependent on?

biologic membranes

medication given extravascularly must be absorbed across _____ ______ to reach systemic circulation

delays effect of drug, dependent on body specific factors as well as drug specific factors

what can giving medication extravascularly do to the effect of the drug? What is it dependent on?

uncharged 

what type of drugs pass through membranes more readily?

stomach

mildly acidic medications are better absorbed in ______

duodenum

mildly basic medications are better absorbed in ______

intestine

does the intestine have more blood flow or the stomach? 

higher

does higher or lower vascularity increase absorption?

disease states (alter blood distribution)

absorption routes can be disrupted how?

shock, blood supply to GI tract & cutaneous tissue decreases, IV preferred 

what dx state can disrupt absorption? how? 

total surface area, contact time at absorption site

what factors affect site contact (absorption)

GI motility, celiac disease, orlistat (Alli)

contact time at absorption site is dependent on what? what disease/drug can affect it?

site contact

medication exposure to the absorption site

large surface area increases absorption 

describe site contact of the oral route 

diffuse application increases absorption

describe site contact of topical route

reduced enteral absorption

how is site contact affected in patients with bowel resection?

food vitamins and minerals (calcium, vitamin C, medications) 

what are substances that disrupt absorption?

reduced iron absorption, reduce tetracycline abx absorption

how does calcium disrupt absorption?

increase iron absorption

how does vitamin C affect absorption

p-glycoprotein - multidrug resistance protein I

substances that facilitate excretion

present on tissues throughout the body, pumps foreign substances out of cells, protects cells from toxic substances and metabolites, expression in GI tract and other cells decreases absorption

what are the functions of MDRI?

tissues throughout the body 

where are MDRI found in the body?

pumps foreign substances out of cells

what is the MAIN function of MDRI?

increased vascularity, increased contact time at absorption site, increased total surface area of absorptive tissue, decreased MDRI

what causes an increase in absorption?

decreased vascularity, decreased contact time at absorption site, decreased total surface area of absorptive tissue, increased MDRI

what decreases absorption?

route of administration, distinct properties of the drug

what drug properties effect absorption?

formulation, concentration, solubility, molecule or particle size

what distinct properties of the drug affect absorption?

bioavailability

the fraction of the drug absorbed into systemic circulation after administration 

route, metabolism, solubility

bioavailability is influenced by…

low bioavailability

highly metabolized means low or high bioavailability

low bioavailability 

poor solubility means low or high bioavailability

enteral

what route? administration through GI tract 

• most common

• safe, convenient, low cost, less invasive

• bioavailability differs between types

oral, sublingual, buccal

what are the types of enteral adminstration?

first pass metabolism

oral route undergoes what after absorption in the GI tract?

sublingual and buccal

what type of enteral type avoids gastric environment, bypasses first pass metabolism (does not enter acidic stomach), allows for rapid absorption?

parenteral

what route? administration directly into systemic circulation

• higher cost

• more invasive

• 100% bioavailability

meds that have poor GI absorption/unstable GI environment, patients unable to take oral formulations available, rapid onset required

uses of parenteral route?

IV, IM, SC, ID, inhalation/intranasal, transdermal, rectal

what are the types of parenteral administration?

immediate delivery into systemic circulation, gradual delivery into systemic circulation

what are the pros of IV route?

requires IV access, irreversible, infection risk

cons of IV route?

rapid, can produce depot effect, patients can be trained to self administer 

pros of IM

local pain, risk of intermuscular hemorrhage

cons of IM

gradual diffusion into systemic circulation, great for slow release medications

pros of SC

skin necrosis, lipodystrophy killing of fat cells 

cons SC

minimally invasive

pros ID

skin testing (TB, allergy testing)

ID is commonly used for?

rapid delivery, large surface area, drugs are delivered to site of action (reduced systemic side effects)

inhalation/intranasal pros

painless, convenient, continuous, long acting, absorbed to systemic circulation through skin, bypasses first pass effect

transdermal pros

rate of absorption can vary based on site/patient, local skin allergic reaction

cons of transdermal

nicotine, fentanyl, clonidine patches, creams, lotions ointments

transdermal examples

1 FTU = 0.5 g

dosing of transdermal creams ?

N/V, unconscious, partially bypasses first pass effect

pros of rectal route

irritation of rectal mucosa, invasive

cons of rectal route

protect drug from stomach acid 

what does the enteric coating of a drug do?

drug unstable in gastric pH, drug irritating to stomach

uses of enteric coated drugs?

extended release

what formulation — chemically composed to control drug release, slow absorption, prolonged duration, may increase compliance

transfer of a drug from one location in body to another 

distribution 

bound drugs

what drugs are phamacologically inactive?

highly selective semipermeable membrane with tight junctions between endothelial cells forming a continuous wall

blood brain barrier

diffusion or active transport 

crossing BBB requires… 

ionized/polar

what drugs cant pass through BBB?

infection

BBB is more permeable in times of ______

inrathecal

what can bypass BBB directly?

SSRIs

what can bypass BBB indirectly?

metabolic breakdown of drugs by the body

• active molecule → inactive

• toxic → non-toxic

• inactive → active

• non-toxic → toxic substance

metabolism

liver

what serves as a defense mechanism limiting absorption of toxic substances but can effect medications as well?

first pass effect

phase I metabolism is commonly referred to as what?

portal vein, hepatic artery

the liver is supplied by what?

liver via portal vein

drugs absorbed in gut are circulated to ____ via ____ ______

liver via hepatic artery

drugs in systemic circulation are circulated to ____ via _____ _____

phase I (first pass)

what metabolism phase?

• carried out in liver

• chemically changes drugs into more polar substances

• chemical change occurs via CYP450 enzymes

• under go oxidation, reduction and hydrolysis

CYP450

what enzymes are found in high concentration in smooth ER of liver, and have a role in phase I metabolism?

age, genetics, disease states, environmental factors, presence of inhibitors or inducers

what factors effect CYP450 isoenzymes?

considerably higher oral route dose when compared to parenteral dose

drugs that have a higher first pass effect require…

inhibitors/inducers

medications that disrupt CYP450 activity 

inhibitors

block enzymatic activity of one or more P450 enzymes

• decrease metabolism

• increase drug concentrations

• produce IMMEDIATE effect

• inhibit elimination

inducers

increase P450 enzyme activity by increased enzyme synthesis

• increase metabolism

• decrease drug concentrations (loss of therapeutic effect)

• produce a delayed effect

• induce elimination

enhance effect of patient’s coumadin dose, increasing INR and making them prone to bleeding 

addition of an inhibitor to coumadin will do what?

reduce effect of a patient’s coumadin dose decreasing the patient’s INR and making them prone to thrombosis

adding an inducer to coumadin will do what?

inhibits CYP450 which also metabolizes statins

how does grapefruit juice effect metabolism?

prodrug 

drug that is converted into the active metabolite with hepatic metabolism

half life

the time required for the concentration of the drug in the plasma to decrease by one half of its initial value

steady state

drug intake and drug elimination are in equilibrium

5 half lives 

steady state is usually achieved after… 

therapeutic index

range at which a medication is therapeutic without producing toxic effects

fluctuations in drug concentrations

frequency of doses impacts?

loading dose

initial dose of a drug is given rapidly to attain therapeutic levels of a drug and is followed by a standard dose to maintain steady state 

trough

the point lowest concentration in a patient’s blood stream