pharmacokinetics and pharmacodynamics of injected drugs pp page 5-8
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CNS distribution of drugs and BBB
- BBB restricts ionized hydrophilic drugs (water soluble)
- -can be overcome by large doses of meds
- -cerebral perfusion is the only limitation to permeation of CNS by non-ionized lipid soluble drugs
What can interrupt BBB
hypoxia, head injury (acute)
volume of distribution
- sum of apparent volume of the compartments that constitute the compartment model.
- -depicts the distribution characteristics of drug in the body
- -calculated= dose of IV drug divided by resulting plasma concentration before elimination begins.
what is volume distribution influenced by
- physiochemical characteristics of drug
- -lipid solubility
- -binding to plasma proteins
- -molecular size
most drugs are what
- are weak acids or bases that are present in ionized and non ionized form
- -solubility characteristics of ionized and non ionized determine the ease of which drugs may diffuse through lipid components of cell membranes
If a drug is water soluble can it cross BBB
Test question from last year
characteristics of ionized molecules
- poorly lipid soluble
- cannot penetrate cell membranes with ease
- ionization causes cell to be repelled from membrane of cell with similar charge preventing their diffusion across the membrane
- pharmacologic effect inactive
- water soluble
- can not cross lipid barriers
- excreted by renal mechanism
- not metabolized by liver
characterestics of non ionized molecules
- pharmacologically active
- lipid soluble
- can cross lipid barriers (GI, BBB, placenta)
- hepatic metabolism
- not excreted by kidneys, reabsorbed
Test question from last year
- the ionization constant of a chemical compound.
- Test question: definition= it is the pH at which the drug will exist in a solution as 50 percent ionized and 50% non-ionized.
- -small changes in pH can result in large changes in ionization especially if pH and pKa values are similar.
the extent of ionization has a major effect on what?
drug absorption, distribution, metabolism, and elimination
acidic drugs (like barbiturates) tend to be highly ionized at what pH
- -the more alkaline the pH the higher ionized the drug will be
basic drugs (like opioids, and lidocaine) are highly ionized at what pH
- -the more acidic the pH the more ionized it will be
If pH-pKa = 0
then the ration equals
if pH- pKa = 0.5
then the ration =
if pH-pKa= 1 or greater than the ratio equals
acid in acid pH=
base in an acid pH=
base in a base pH=
ion trapping example
giving a weak base orally can result in accumulation of ionized drug (trapping) in the acidic environment of the stomach
- see notes way to much info!!!!!
- and page 30 of naglehaut book we printed
most acidic drugs bind to what protein
most basic drugs bind to what protein
alpha-acid glycoprotein and lipoproteins
can protein bound drugs cross cell membrane
- only free or unbound portion can cross
- -protein binding limits passage of drug into tissue resulting in increased plasma concentration
how is clearance influenced by unbound drugs in plasma
unbound drug in plasma have accss to hepatic drug metabolizing enzymes and undergoes glomerular filtration
drug protein complexes are maintained by a ____ bond and can dissociate when
weak bond and can dissociate when plasma concentration declines as a result of hepatic and renal clearance of an unbound drug or if another drug that binds to the same protein is introduced
what is the most abundant plasma protein
protein binding is proportional to what
how does protein binding affect distribution
high protein binding prevents drugs from leaving the blood to enter tissue which results in high plasma concentrations
true or false
there are an infinite number of binding sites on plasma proteins for drugs
- there are an finite number, sites can become saturated resulting in more free drug leading to increased plasma concentration
What is the main determinant of protein binding
the extent of binding parallels lipid solubility
- the fraction of total drug in plasma that is protein bound is determined by the drugs plasma concentration and the number of available binding sites.
- -low plasma concentration of a drug are like to be more highly protein bound than a higher plasma concentration of the same drug.
percent of protein binding of a drug is useless unless you know what
the plasma concentration of the drug and binding sites are known
volume of plasma cleared drug by renal excretion or metabolism in the liver or other organs
first order kinetics
- drugs administered in therapeutic ranges are cleared from circulation at a rate proportional to the amount of drug in the plasma.
- -more drug cleared at beginning when plasma concentration the highest
zero order kinetics
Test question from last year
- Test question: constant amount of drug cleared per unit of time with out regard to drug concentration
- -occurs when plasma concentration exceeds the capacity of metabolizing enzymes
- ex= 5mg/hr
- unchanging plasma concentration of a drug
- -is achieved with repeated doses or sustained delivery within 4-5 half lives, elimination also takes about 4-5 half lives
- -determined by dosage and clearance
- -infusion rate=clearance rate
product of hepatic blood flow and excretion ratio
high hepatic ratio for clearance
- > 0.7
- clearance depends on hepatic blood flow
- perfusion dependent elimination
low hepatic ration for clearance
- only small fraction of drug is delivered to liver to be removed
- as a result excess drug is available for hepatic elimination mechanism and changes in hepatic blood flow will not influence clearance.
capacity dependent elimination
decrease in protein binding or increase in enzyme activity increases clearance of a drug with a low hepatic clearance ratio (<0.3)
most metabolites of drugs produced in liver are excreted in the bile of the GI tract, then reabsorbed from the GI tract for elimination in the urine
- most important organ for elimination of unchanged drugs and their metabolites
- -water soluble compounds are excreted better by the kidneys than lipid soluble compounds.
- - lipid soluble drugs are completely reabsorbed
- -renal excretion involves glomerular filtration, active tubular secretion, and passive tubular reabsorption
role of metabolism
- convert pharmacologically active lipid soluble drugs into water soluble inactive metabolites.
- increased water solubility decreases VD and enhances renal excretion and sometimes GI elimination
4 pathways of metabolism
phase I metabolism
- includes pathways 1,2,and 3 ( oxidation, reduction, and hydrolysis)
- -increase polarity of (lipid soluble) molecule transforming it into a water soluble one and prepare it for phase 2
phase II metabolism
- includes pathway 4 (conjugation)
- -links drug or metabolites with polar molecule and makes it more water soluble leading to enhanced renal or biliary excretion
for the most part where does metabolism of most drugs occur
- -however considerable levels of drug metabolizing enzymes are also found in other tissues including lung, kidney, GI tract, placenta, and GI tract bacteria
enzyme induction and metabolism
- many drugs, environmental chemicals, air pollutants, and components of cigarette smoke stimulate the synthesis of drug metabolizing enzymes.
- -increases hepatic metabolism of drug
- see page 26 of nagelhout work book
enzyme inhibition of metabolsim
- several substances can result in less metabolism of a variety of drug leading to an increase in their effects.
- Nagelhout work book page 26
- the extent to which the drug reaches its effect site after its introduction to the circulatory system.
- -the rate at which systemic absorption occurs establishes drug duration of action and intensity.
what plays a role in bioavailabilty
- -bioavailability differs depending on how drug is administered and other factors play a role such as lipid solubility, solubilty in aqueous or organic solvents, molecular weight, pH, pKa, and blood flow.
- Test question :Also depends on age, diet, physical properties of drug
Phase I enzymes
- cytochrome P-450 enzymes-
- non-cytochrome P-450 enzymes (esters)
- flavin-containing monooxygenase enxymes
Phase II enzymes
- *transferase enzymes
**family of hepatic enzymes that catalyze covalent addition of glucoronic acid making them more water soluble (propofol undergoes this)
oxidative metabolism (first step)
- hepatic enzymes P450 are crucial for oxidation and resulting metabolism of many drugs
- -enzymes require and electron donor in the form of reduced nicotinamide adenine dinucleotide (NAD) and molecular O2 for activity
- -O2 is split, 1 atom oxidized molecule of drug and one is incorporated into H2O
- -a loss of electron results in oxidation
reductive metabolism (second step)
- involve p450
- -low O2 partial pressures
- -CYP450 enzymes transfer electrons directly to a substrate such as halothane rather than O2
- -this electron gain only occurs when insufficient amounts of O2 are present to compete for electrons
- -gain of electron is reduction
hydrolysis (3 step)
- does not involve cyp450
- -hydrolysis of glucoronide conjugates secreted into bile occurs in GI tract and is necessary for release of a drug to become available for enterohepatic recirculation
- involves glucuronic acid and cyp450
- -glucurinic acid available from glucose
- -when conjugated to lipid solube drug or metabolite, hydrophilic glucuronic acid renders its inactive and more water soluble
- -unlikely to be reabsorbed
- -excreted in bile or urine
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