Pharmacokinetics

pharmacokinetics

The process by which drugs are absorbed, distributed within the body, metabolized, and excreted.

what the body does to the drug

ADME

- absorption

- distribution

- metabolism

- excretion

oral route

Advantages:

- most convenient

- produces slow, uniform absorption

- mostly safe

- economical

Disadvantages:

- destruction of drug by enzymes or low pH

- poor absorption of large and charged particles

- drugs bind with GI content

- can NOT be used for drugs that irritate the intestines

rectal route

Advantages:

- limited first pass metabolism

- useful when oral route precluded

Disadvantages:

- absorption often irregular and incomplete

- can cause irritation to rectal mucosa

sublingual/buccal route

Advantages:

- rapid absorption

- avoids first pass metabolism

Disadvantages:

- absorption of only small amounts

parenteral route

anything outside of the oral tract (injectables)

intravenous route

Advantages:

- 100% bioavailability

- most direct route

- bypasses barrier to absorption (immediate effect)

- suitable for large volumes

- dosage easily adjusted

Disadvantages:

- increased risk of adverse effects from high concentration immediately after injection

- not suitable for oily substances or suspensions

intramuscular route

Advantages:

- quick and easy administration

- possible rapid absorption

- can be used as depot

- suitable for oily substances and suspensions

- can be used as a reservoir for slow releases

Disadvantages:

- painful

- bleeding

- may lead to nerve injury

subcutaneous route

Advantages:

- quick and easy administration

- fairly rapid absorption

- suitable for suspensions and pellets

Disadvantages:

- painful

- can't give large amounts

inhalation route

Advantages:

- uses for volatile compounds and drugs that can be administered by aerosol (albuterol)

- rapid absorption due to large surface area of alveolar membranes and high blood flow through lungs

- aerosol delivers drug directly to site of action and may minimize systemic side effects

Disadvantages:

- variable systemic distribution

Topical route

Advantages:

- application to specific surfaces (skin, eye, nose, vagina) allows for local effects

Disadvantages:

- May irritate surface

transdermal route

Advantages:

- allows controlled permeation through skin (nicotine, estrogen, testosterone, fentanyl, scopolamine, clonidine)

Disadvantages:

- may irritate surface

absorption

the process by which a drug enters into the body. it is the movement of a drug from its site of administration into the central compartment (systemic circulation)

drugs are mostly absorped in the small intestine

factors that affect absorption

- solubility

- concentration

- blood flow

- absorbing surface

- contact time

- pH

drugs have to be ____ to be absorbed

non-polar / not charged / lipophilic

higher drug concentration =

more of the drug being absorbed

pKa

pH at which the drug is 50% ionize and 50% unionized therefore only the 50% unionized part is absorbed

higher the absorbing surface area =

more of the drug being absorbed

more contact time =

more absorption of the drug

a weak acid drug (aspirin) placed in a strong acid (stomach acid) keeps it

non-ionized and allows it to be absorbed

bioavailability

the amount of an administered drug that reaches the systemic circulation

factors that influence bioavailability

- first pass metabolism

- drug formulation

- bioequivalence

- route of administration

- distribution

distribution

delivery of a drug from systemic circulation to tissues

there is variation of how drugs distribute into certain body compartments

volume of distribution (Vd)

space in body into which drugs appear to disseminate.

a measure of the APPARENT space in the body available to contain the drug based on how much is given versus what is found in the systemic circulation

Vd formula

Vd = dose (Amt of drug given by IV injection) / Co (initial concentration achieved)

drug distribution in certain body compartment: plasma water volume 0.045 L/KG

in a 70KG human its 3L

drug distribution in certain body compartment: extracellular body water volume 0.20 L/KG

in a 70KG human its 14L

drug distribution in certain body compartment: total body water volume 0.60 L/KG

in a 70KG human its 42L

drug distribution in certain body compartment: tissue volume >0.70 L/KG

in a 70KG human its >49L

large Vd =

drug concentrated in tissue

small Vd =

drug remains in ECF or plasma

Vd is inversely related to

plasma drug concentration

factors affection distribution

- plasma protein

- tissue binding

- gender

- age

amount of body fat

- relative blood flow

- size - tissue, molecules

- lipid solubility

drugs bound to protein are inactive therefore it

increases the drugs availability and can last longer and used later (increasing duration)

drugs not bound are active and used

higher blood flow can ____ drug concentration

increase

plasma protein binding

- drugs with high plasma protein binding remain in the plasma

- low Vd and a prolonged half life

ie. warfarin, diazepam

binding acts as a drug reservoir, slowing onset and prolonging duration of action

many drugs bind reversibly with one or more plasma proteins (usually albumin) in the vascular compartment

tissue protein binding favors ____ Vd

larger

Examples: chlordiazepoxide, fluoxetine, tolbutamide

disease states such as liver disease that affects albumin concentration or drugs that alter protein binding influences the

concentration of drugs

examples: furosemide or valproate can displace warfarin from albumin

competitive binding can lead to

toxicity

site of drug concentration: fat

characteristics:

- stores lipid soluble drugs

site of drug concentration: tissue

characteristics:

- may represent sizable reservoir, depending on mass, as with muscles

- several drugs accumulate in liver

site of drug concentration: bone

characteristics:

- tetracyclines are deposited in calcium rich regions (bones and teeth)

site of drug concentration: transcellular reservoirs

characteristics:

- GI tract serves as transcellular reservoir for drugs that are slowly absorbed or that are undergone enterohepatic circulation

site of drug exclusion (places where it is difficult for drugs to enter)

- cerebrospinal

- ocular

- endolymph

- pleural

- placenta

components of blood brain barrier (BBB)

- tight junctions compared to fenestrated junctions in capillaries of most tissues

- glial wrappings around capillaries

- low cerebral spinal fluid drug binding proteins

- drug-metabolizing enzymes in endothelial cells (monoamine oxidases, cytochrome P450s)

- efflux transporters

biotransformation = metabolism

- liver is the primary site

- livers primary role is drug inactivation

- diseases that affect liver influence drug metabolism

- metabolic products of drugs usually less active pharmacologically

- metabolic products may be active drugs where the prodrug form is inactive and the metabolite is the active drug (valacyclovir). (??)

Phase I biotransformation

Oxidation, reduction, hydrolysis

- Cyp450 enzymes mainly involved in oxidation

Phase II biotransformation

conjugation-attach polar groups such as sulfate or glucuronic acid to the drug

transverse enzymes:

- glucuronsyltransferase

- acetyltransferace

- methyltrasferase

phase III disposition processes

occurs post phase II, drug can undergo further metabolism and excretion

P-450 Enzymes

check diagram on slide 22

(EXAM) drug interactions may occur as a result of changes to the

cytochrome P-450 enzyme system

(EXAM) Inducers of cytochrome P-450 increases metabolism of drugs and

lowers therapeutic drug levels

decreases efficacy and breaks it down faster

(EXAM) Inhibitors of cytochrome P-450 decreases metabolism of drugs and

raises therapeutic drug level (danger of toxicity)

more of the drug will be used and can become toxic since its breakdown is slowed down

(EXAM) most drugs that are either inducers or inhibitors of cytochrome P-45O are categorized as

hepatotoxic

excretion

amount of drug and drug metabolites excreted by any process per unite time

excretion processes in the kidney

- glomerular filtration rate (GFR)

- tubular secretion

excretion processes in the liver

bile and feces

GFR excretion

- depends on the size, charge, and protein binding of a particular drug

- is lower for highly protein-bound drugs (excreted through tubular secretion )

- drugs that are NOT protein bound and NOT reabsorbed are eliminated at a rate equal to the creatinine clearance rate (125mL/min)

tubular secretion

- occurs in the middle segment of the proximal convoluted tubules

- has a rate that approaches renal plasma flow (660mL/min)

provides transporters for:

- anions (penicillins, cephalosporins, salicylates)

- cations (pyridostigmine)

can be used to increase drug conc. by use of another drug that competes for the transporter (probenecid inhibits penicillin secretion)

characteristics of tubular secretion

- competition for the transporter

- saturation of the transporter

- high palm protein binding favors increased tubular secretion because the affinity of the solute is greater for the transporter than the plasma protein

large polar compounds or their conjugates (molecular weight > 300 daltons) may be actively secreted into

bile

separate transporters are used for

- anions

- neutral molecuels

- cations

large drugs often undergo enterohepatic recycling in which drugs secreted in the bile are again reabsorbed in the small intestines but

the cycle can be interrupted by agents that bind drugs in the intestine

clearance kinetics

clearance refers to the volume of plasma from which a substance is removed per unit time

total body clearance formula

Cl= Vd X Kel

Vd= volume of distribution

Kel = elimination rate

renal clearance

Cl r = U X Cur / Cp

U = urine flow (mL/min)

Cur = urine conc. of a drug

Cp = plasma conc. of a drug

elimination kinetics

- first order kinetics

- zero order kinetics

first order kinetics

refers to the elimination of a constant percentage of a drug per unit time

- rate of elimination is proportional to drug concentration

- drug concentration changes by some constant fraction per unite time

- half life is constant for each drug

elimination half life

refers to the time required for drug conc. to drop by one half; independent of dose

zero order kinetics

a constant amount of drug is eliminated per unit time

- rate is independent of drug conc.

- elimination pseudo - half life is proportional to drug conc.

- small increase dose can produce a larger increase in conc.

- process only occurs when enzymes or transporters are saturated (at high doses)