Pharmacodynamics/Pharmacokinetics Flashcards
Define Pharmacokinetics
The quantitative study of absorption, distribution, metabolism, and excretion of drugs and their
metabolites.
4 processes studied by Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
“What the body does to a drug”
Pharmacokinetics
Pharmacokinetics allows the clinician to predict the drug ____________and thus the ____________ with time.
concentration at the site of action; intensity of the drug’s effect
Pharmacokinetics measures and calculates those parameters
VECBECR Volume of Distribution Effect site equilibration time(onset of action once med is given) Context sensitive half life (lipid soluble drug) Bioavailability Elimination half life Clearance Recovery time
Cell membrane and lipid soluble substances
Highly permeable
Since the cell is also permeable to water and other small lipid in-soluble substances it is postulated that the lipid membrane
has channels or pores that allow these substances to penetrate the cell.
• Simple diffusion Definition- characterized by the
rate of _________ both _____and _____of small size
transfer of a substance across a membrane from area of high concentration to an area of low concentration. Both lipid soluble and lipid in-soluble molecules of small size.
• Filtration-
When a porous membrane allows the flow of a solvent and the substances dissolved in it to except for large molecules (ex. glomerular filtration).
Most of the drugs given in anesthesia are
supplied in the form of a_________
salt solution.
• The active molecule of anesthesia is either a
weak acid or weak base.
• The active portion can be recognized as an
acid or a base by the
name given to the salt form.
If the active moiety is an acid, the acid
is listed
If the active moiety is a base, the base
will be listed
last (sodium thiopental)
first (Lidocaine HCl,
Morphine Sulfate)
• Acids (donate or accept protons)
donate protons
Bases (donate or accept protons)
accept protons
Henderson-Hasselbach equation
pH = pKa + log Proton acceptor/ Proton donor
Cell membranes are more permeable to which portion of a drug?
non-ionized portion of a drug.
The Henderson-Hasselbach equation helps to predict _____________Given the ________of that particular solution and the drugs ____
the portion of ionization of a given drug in solution given the pH of that particular solution and the drugs pKa
When pH=pKa, what can be infered?
50% of the drug is ionized and 50% in non- ionized.
Lower pKa= ______acid
stronger acid,
Higher pKa = ________base
stronger base.
A general rule with WEAK BASES states when the pKa minus pH < 0, then most of the drug will be in the
non-ionized form.
With WEAK ACIDS, the opposite is true. pKa minus pH < 0 then most of the drug will be in the
Ionized form
Weak acids will be more non-ionized in an ________therefore ________ is better
acidic solution (absorption, distribution).
Weak bases will be more non-ionized in a
Can therefore penetrate
basic solution.; blood brain barrier, renal tubular epithelium, GI epithelium, and hepatocytes
Define Ion Trapping?
Example?
Fetus is more acidic/basic than mother
A concentration difference of total drug can develop on two sides of a membrane that separates fluids with a different pH.
obstetrics when the administration of an epidural such as
local anesthetic can accumulate or become trapped in the fetus because the fetus is more acidic than the mother. This can lead to fetal toxicity.
How do you eliminate acidic drugs from the body?
Alkalinize the urine to help eliminate acidic drugs.
Define active transport? Requires ? Example is
With active transport a substances moves against a concentration or electrochemical gradient. Usually requires the use of energy by the cell.
Na-K pump
Define volume of distribution ? *(Vd)
• Calculated as the dose of drug administered IV divided by the resulting plasma concentration BEFORE ELIMINATION BEGINS
Vd is Influenced by physiochemical characteristics
of the drug (3)
Lipid solubility
Protein binding
Molecular size.
Drug with low lipid solubility and high protein binding will have a__________
low Vd.
What can be used to predict the plasma drug concentration after a bolus?
The volume of distribution
Question #1
“what is the predicted gentamicin concentration 30 minutes after 200mg of gentamicin is administered to a 70kg patient.” If the Vd of gentamicin is 0.28 L/Kg in adult
calculate
Question #2
“what dose of gentamicin is needed
to achieve a plasma concentration of 5 in a 3 Kg
neonate. “ The Vd in neonates is 0.5 L/Kg
Calculate
Most acidic drug bind to _______
Albumin
Most basic drug bind to_________
alpha 1 acidic protein.
Why does protein binding effects Vd?
because only unbound drug can cross cell membranes.
Relationship between Vd and protein binding?
Inversely proportional
Protein binding also effects clearance.
Clearance. Because only unbound drug can undergo metabolism and GLOMERULAR FILTRATION
Alterations in protein binding are only important for drugs that are
highly protein bound.
4 well known highly protein bound drugs
Warfarin
Phenytoin
Diazepam
Propranolol
The extent of protein binding is directly related to the______ _______
lipid solubility
In addition the fraction of total drug in plasma that is bound to protein is determined by (2)
Plasma concentration of drug
The number of protein binding sites
•___________ plasma concentration of drug will be highly protein bound compared to high plasma concentrations of the same drug.
Low plasma concentration
Can cause low concentrations of plasma proteins.
Renal Failure
Increased levels of Alpha 1 acid glycoprotein can occur in response to (3)
surgery, chronic pain, and acute MI.
_______can be low in neonates.
Alpha 1 acid glycoprotein
What is clearance ?
The volume of plasma cleared of drug by renal excretion and/or metabolism by the liver or other organs
Examples of non-organ metabolism include
2 processes: 4 meds examples
Hoffman elimination
Ester hydrolysis of succinylcholine,
atracurium, cisatracurium, and
mivacurium SAM-C
Define first order kinetics
Almost all drugs are cleared from the circulation at a rate that is proportional to the amount the amount present in plasma
Zero Order Kinetics
A constant amount of drug in cleared per unit of time.
In order to achieve steady state, the infusion rate must be equal to the
clearance.
Hepatic clearance is the the product of
hepatic blood flow and the hepatic extraction ratio.
If the hepatic extraction ratio is high >0.7, then
the hepatic clearance will depend on hepatic blood flow and changes in enzyme activity will have minimal change
Thus a high hepatic extraction ration results in a_________ example
perfusion-dependent elimination
Lidocaine
If the extraction ratio is <0.3 than the clearance will depend on
protein binding and enzyme activity
Most important organs for the elimination of unchanged drugs.
Kidneys
Renal excretion includes 3 processes;
Glomerular filtration.
Passive tubular secretion.
Passive tubular reabsorption
The amount of drug that enters the renal tubular lumen depends upon 2 things:
Fraction of protein binding and the
glomerular filtration rate.
Renal tubular secretion involves.
active transport processes.
• Highly lipid soluble compounds are almost
completely reabsorbed.
• Factors that effect reabsorption include;
pH (weak acids are excreted faster in alkaline
urine)
Rate of tubular urine flow
Formulas to use to estimate creatinine clearance
IBW male 50 +(2.3 x each inch >60) IBW in Kg
IBW female 45.5 + (2.3 x each inch >60) = IBW in Kg
Cockcroft-Gault equation
• (140 - age ) x IBW 72 x Serum creatinine x 0.85 for females.
Local anesthetics work on
sodium channels.
The role of metabolism is to
convert pharmacologically active, lipid-soluble drugs
into water soluble inactive compounds that
can be easily excreted.
Increased water solubility will _________Vd
for a drug and enhance its renal excretion.
decrease
• These compounds are called prodrugs.
The metabolism of an inactive compound to
a pharmacologically active compound can
also occur
The metabolism of a drug is highest when
the drug concentration is greatest.
Drug name first (base or acid)
base
The fraction of drug eliminated is independent of the drug concentration
First order kinetics
It will take 1 half-life for the plasma
concentration to decline
•
by 50%.
At 5 half-lives the drug plasma concentration declines by
96.9 %
Constant amount of drug is eliminated per unit of time
irregardless of the plasma concentration.
Zero order Occurs when the plasma concentration of
drug exceeds
the capacity of metabolizing enzymes
When inject basic to acidic
Precipitate
Drugs that undergo zero-order kinetics include
alcohol, aspirin, and phenytoin
Oxidation-
Reduction-
Loss of electrons
Gain of electrons
• Hydrolysis definition
Splitting molecule with the addition of water.
______,______,_____ are
Phase I reactions
Oxidation, reduction and hydrolysis
Conjugation-Phase II reaction.
The addition of an endogenous substrate such
as a carbohydrate or an amino-acid to form
a more water soluble, inactive substance
that is easily excreted from the body.
____________is the site of metabolism of most drugs.
• Other sites include the GI tract, kidneys, and the lungs
Hepatic microsomal enzymes
________is site for Hoffman degradation or ester hydrolysis
Plasma ; spontaneous degradation
Plasma is site for
Hoffman degradation or ester hydrolysis
Location of hepatic microsomal enzymes
Located primarily in the smooth endoplasmic reticulum of the liver
Cytochrome P-450 also called_________ system involves both __________steps.
mixed function oxidase
oxidative and reduction
Cytochrome P-450 is available in different
isoenzymes P-450______ is the most
abundant
3A4
Cytochrome P-450 3A4 is responsible for metabolizing more than 1/2 known drugs including
opiods, benzodiazepines, local anesthetics, immunosuppressants.
• Alfentanil clearance has been shown
to vary on different days of the menstrual cycle
Enzyme induction
• Drugs or chemicals have the ability to stimulate the activity of microsomal enzymes.
• Increased enzyme activity by certain compounds is known as_______
enzyme induction.
• Compounds known to stimulate enzyme
induction include, RPPCSC
Phenobarbital, phenytoin,
alcohol, cigarette smoking, rifampin,
carbamazepine.
Enzyme Inhibition
• When the metabolic rate of the microzomal enzymes is decreased leading to drug accumulation and possible toxicity.
Enzyme inhibitors include.
Acute alcohol ingestion Cimetidine Erythromycin Valproic acid Nefazodone Fluoxetine Amiodarone diltiazem, verapamil Protease inhibitors
**Nonspecific esterases in the liver, plasma, and
GI tract are examples on nonmicrosomal enzymes responsible for
SAMEE
hydrolysis of drugs that contain ester bonds
SUCCINYLCHOLINE, atracurium, mivacurium, ESMOLOL, ester local anesthetics.
The activity of these enzymes is determined
genetically, as emphasized by patients with
atypical cholinesterase, and slow acetylators
Nonmicrosomal enzymes such as______and______ do not undergo enzyme induction.
plasma cholinesterase and acetylating enzymes
Oxidative metabolism: Halogenated volatile anesthetics are susceptible to dehalogenation, which can lead to the release of
bromide, chlorine, and fluoride ions.
Enzyme induction and depletion of glutathione can increase
risk or organ damage.
Conjugation
• Conjugation with glucuronic acid involves_______ Glucoronic acid is available from glucose.
•
CYP-450 enzymes.
Glucose
This leads to the the formation of inactive water soluble compounds which are inactive and easily excreted from the body.
• Conjugation may be decrease during pregnancy due to increase levels of progesterone.
Factors that effect Vd and Clearance
Metabolism
Age
Hepatic disease
Kidney disease
Two compartment model
Central compartment
The drug is introduced directly into the central compartment then subsequently distributes to the peripheral compartment only to return to the central compartment where clearance occurs.
• Central compartment includes intravascular
fluid and highly perfused organs
(lungs, heart, brain, kidneys, liver).
• In adults highly perfused tissues make up of ____weight, but receive______ of cardiac
output.
10% ; 75%
• Drugs that have an affinity for the vessel
poor group have
higher volumes of distribution.
• Vessel poor group
•
(Muscles, fat, skin, etc)
FIRST ORDER KINETICS DRUGS
Vd works better
A large calculated peripheral compartment
suggest
extensive uptake of drug by those
tissues that make up the peripheral
compartment.
Redistribution
The drug distributes from it’s site of action to other tissues. (ex, thiopental)
New Concepts in interpretation of compartment modeling
• Rapid IV injection of drugs that attain
maximum effect in <2 minutes such as ___and____
• These drugs do not depend on the usual
organs for elimination. They are eliminated
by.
(atracurium, cisatracurium).
Hoffman degradation, and hydrolysis
The traditional concept that a drug’s pharmacological effect parallels its plasmas concentration is not
• For example 1 minute after the IV bolus of
cisatracurium the plasma concentration is
always valid
already declining while the pharmacological
effect is increasing.
The traditional concept of the drug’s pharmacological effect is parallel to plasma concentration is no longer valid. Therefore it is proposed that it is not the concentration in the _______Compartment but the concentration at ________that determines the pharmacological effect.
concentration in the central compartment but the concentration at the site of action that determines the pharmacological effect
Elimination half time is the time necessary
for
the plasma concentration to fall by 50% during the ELIMINATION phase.
• Elimination half-time is _______related to and__________ to clearance.
directly; Vd; inversely related to
• Elimination half time is unrelated to the
dose given
It take about_________for near total
(96.5%) elimination from the body
five t -1/2
Formula for half life
T1/2= 0.693/ke
ke can be calculated by checking
2 plasma drug concentrations after a single IV bolus
Elimination half time may be of little value
in describing drug
Pharmacokinetics in multicompartment models
Of more importance to the clinician is how
long will it take the Cp to decrease to allow
the patient to
awaken, rather than the slope of the plasma drug concentration time curve.
• Instead of t-1/2 the clinician should use the
context sensitive half time
Context Sensitive half life Describes the time necessary for the plasma concentration to
decrease by 50% after discontinuing a continuous infusion of a specific duration.
Context sensitive half life consider both___
combined effects of distribution and metabolism as well as duration of continuous infusion.
Depending on the_________and __________ the context sensitive t-1/2 as the duration of
the infusion increases
lipid solubility and the efficiency of its clearance,
increases
Effect-Site Equilibration
The delay between the IV administration of a drug and the onset of its clinical effects.
• Reflects time required to deliver the drug
to its site of action (ex. Brain).
Effect site equilibration
Drugs with a short effect site equilibration
such as ______, ______and______
will produce a ______onset of action.
remifentanyl, thiopental, propofol, TEP
rapid
Drugs with a longer effect site
equilibration ______and ______have a
onset of action.
, midazolam, fentanyl; slower
2 things affecting absorption
Blood flow
Surface area
Oral route advantage, principal site of absorption.
Disadvantages
Most economical and convenient
Principal site of absorption is the SMALL intestine
EMEsis, Destruction by digestive enzymes or gastric acid.
Drugs absorbed from GI tract enter the.
This is known as
portal venous blood and pass through the liver prior to entering systemic circulation
first pass hepatic effect.
• Drugs that undergo large first pass hepatic effect have large differences in pharmacological effect between IV and PO routes of administration. EX
(lidocaine, propranolol)
Zero order kinetics
Specific number of molecules removed, REGARDLESS of the dose given
Oral Transmucosal route
3 advantages
What does it bypass?
Permits rapid onset of action.
• Venous drainage into the superior vena cava bypasses the liver and avoids first pass effect.
• Explains why sublingual NTG is more effective than PO NTG.
Which route provides sustained therapeutic plasma
concentration.
• Examples of drugs available as transdermal
patch include;
Transdermal route
NTG, clonidine, fentanyl,
scopolamine, estrogen, nicotine
Characteristics of a drug that favors
transdermal administration include;
Combined water and lipid solubility Molecular weight < 1,000 pH 5-9 in a saturated aqueous solution absence of histamine release Daily dosing requirements < 10mg
Rectal : Drugs administered to_________
avoid the first pass effect.
lower rectum
Drugs administered into the________ _____are absorbed into the superior _______ _____and are transported to the liver, hence first pass effect.
proximal rectum ; hemorrhoidal veins
Most rapid and predictable route
IV
Only acceptable route in the unconscious and uncooperative patient. • More expensive • Most risky
IV
Distribution of drugs after systemic absorption Explain What happens after systemic absorption? What happen to plasma concentration?, what happen? Redistribution depends on what factors?
After systemic absorption , the highly perfused tissues (heart, brain, kidneys, liver) receive a disproportionately large amount of the total dose.
• As plasma concentration falls below that achieved in highly perfused tissues, the drug redistributes to less well perfused sites such as skeletal muscle and fat.
• Redistribution depends on blood flow, concentration gradient for non-ionized, lipid soluble, and unbound to protein portion
If drugs can access brain
Has to be lipid soluble
Redistribution concept explain
Tissue does what?
Repeated dose lead to
Drugs example?
A tissue that accumulates drug can act as a reservoir to maintain the drug concentration in the systemic circulation and prolong its duration of action.
• Repeated dosing or large doses may saturate inactive tissue sites and prevent the drug from distributing into inactive sites and thus prolong the duration of
action.
• This can occur with drugs such as fentanyl
or thiopental.
• Waning of drug effects now depend on metabolism rather than redistribution
Uptake into lungs
Basic lipophilic amines such as lidocaine, meperidine, fentanyl sufentanil, and alfentanil will quickly distribute to the lungs were they are inactive.
• Pulmonary uptake of drugs can influencethe peak arterial concentration and serve
as a depot for drug redistribution
Pulmonary uptake of drugs can influence the
peak arterial concentration and serve as a depot for drug redistribution
Blood brain barrier
• Prevents
distribution of ionized water soluble drugs to the CNS
Pharmacodynamics simple
“What the drug does to the body
”
Pharmacodynamics definition
study of the intrinsic sensitivity of responsiveness of receptors to a drug and the mechanism by which these effects occur.
Isomers are
different compounds that have the same molecular formula.
Sterioisomers -
are a particular kind of isomer that are different from each other only in the way the atoms are oriented in
space (but are like one another with
respect to which atoms are joined to which
other atoms)
Enantiomers
A pair of molecules existing in two forms
that are mirror images of one another but
cannot be superimposed.
Enantiomers that are dissolved in solution,
can be distinguished
–
by the direction that rotate polarized light.
– (d or +) rotate light to the
right
(l or -) rotate light to the
left
When two enantiomers are present in
equal
proportions (50:50), they are referred to as
a racemic mixture.
A racemic mixture (does/does not) rotate polarized light.
does not
Heparin PTT Drawn after 6 hours because
by that time, 5 half lives (steady state to occur)
Lock and Key Emphasizes the fact that
biological systems are inherently steriospecific.
Factors that effect the phamacodynamics of a drug
•CRC PAP
-Concentration or density of receptors.
- Responsiveness of the receptor.
- Clinical state of the patient;
- Preexisting disease
-Age of the patient
-pH balance effects the degree of
ionization
Hyperactive-
unusually low doses produces desired effect
• Hypersensitive-
Term used to describe patients that are allergic (sensitive) to a drug
• Hyporeactive-
patients that require unusually high doses to evoke a desired effect.
• Tolerance-describes
hyporeactivity that is
acquired from chronic exposure to a drug
• Tachyphylaxis is
tolerance that develops
after a few doses or short period of time.
An additive effect-
a second acting with the first drug will produce an effect equal to an algebraic summation (1+1=2)
Synergistic effect-
The two drugs interact to produce an effect that is greater than the algebraic summation (1+1=4)
• Agonist-
a drug that activates a receptor by binding to it
• Antagonist-
A drug that binds to receptor but does not activate the receptor and blocks any activation of that receptor.
Dose response curve
Show the relationship between the dose of a drug and the resulting pharmacological response
Morphine 6 glucorinide
More active than parent compound morphine itself
Dose response curves are characterized by differences in (PIES)
potency,
individual response
efficacy
slope,
The potency of a drug is depicted by its
location along the dose axis of the dose response curve
Factors that effect potency include
ADME + A
Absorption, distribution, metabolism, excretion, and affinity for the receptor sites
Potency has no real clinical difference as
long as the the
effective dose can be achieved.
The slope is influenced by
the number of receptors that must be occupied to have a certain effect.
______And ________are characterized by a steep
dose response curve.
• Small increases in dose will have a
Neuromuscular blockers and inhaled
anesthetics
dramatic increase in effects.
• An increase from 1 MAC to 1.3 MAC will
prevents movement in skeletal muscle from
50% of patients to 95% of patients
Efficacy
• Side effects may limit the dosage to below
the concentration associated with maximal
desirable effects.
• The efficacy is depicted by the plateau in dose response curve.
• Therapeutic index-
the difference between the the dose that produces the
desired effect and dose that produces undesirable effects.
• LD50/ED50
Competitive antagonist-
increasing concentrations of antagonist progressively inhibits the response to an unchanging concentration of
agonist.
Noncompetitive antagonist
Even high concentrations of agonist cannot overcome blockade of the antagonist
Events that determine variation in
drug response
• Pharmacokinetics
Bioavailability Renal function Hepatic function Cardiac function Patient Age
Events that determine variation in
drug response
Pharmacodynamics
Pharcodynamics
Enzyme activity
genetic difference
• Drug interactions
Elderly patients have those
Decreased cardiac output Enlarged fat content decreased protein binding, decreased renal function all lead to drug accumulation and increased risk of toxicity
Can effect the individual response curve
G6PD deficiency certain drugs can cause
hemolysis (Isoniazid)
Genetic disorders
Atypical pseudocholinesterase patients lack
the enzyme that breaks down NMB agents
Malignant hyperthermia produces a
devastating hypermetabolism
Intermittent porphyria evoked by
barbiturates purple urine
G6PD deficiency certain drugs can cause
hemolysis (Isoniazid)
Drug interactions
•
Impaired absorption
Competition for plasma binding sites
Enzyme induction and inhibition
Change in rate of renal excretion
(Example probenacid and PCN)Van der Waals forces-
weakest type of bond between atoms or groups of atoms.
Hydrogen bonds-
occur between hyproxyl or amino groups and electronegative carboxyl oxygen.
Covalent bonds-
Sharing of pair of electrons (strongest and hardest bond to break)
Ionic bond-
bond between groups of oppositely charged molecules
Plasma drug concentration
•
•
Clearance rate must match infusion rate to maintain plasma steady state.
• Changes in Vd will necessitate an
increase or decrease of initial loading dose
________ and __________is
a method to obtain therapeutic levels
quickly and steady state quickly
Loading dose and maintenance dose
Weak ACID pHpKa what form?
Non-ionized (lipid soluble)
Ionized (water soluble)
Weak BASE pHpKa what form?
Ionized (water soluble)
Non-Ionized (lipid soluble)
What form readily cross membrane
Non-ionized (lipid soluble)
2 factors context sensitive half life take into considerations
Clearance and volume of distribution
