PHARMACOLOGY-pharmacokinetics Flashcards
Define loading dose
Loading dose equation
The amount of drug required to achieve a therapeutic plasma concentration quickly
Loading dose = (Vd x desired Cp)/bioavailability
Describe volume of distribution
The relationship between the administered drug dose and the resulting plasma concentration
Theoretical measure of how drugs are distributed in the body
Define concentration as it pertains to pharmacokinetics
The measure of the amount of drug in a given volume
A drug is most concentrated before it is given
At what Vd is a drug considered lipophilic
When Vd exceeds total body water
>0.6 L/kg or >42 L
How does a loading dose correlate with Vd
The higher the Vd, the higher the loading dose that must be given to achieve effect
Describe the breakdown of body water distribution in a 70-kg patient
Total body water =
- ECF =
- -Plasma volume =
- Interstitial fluid =
- ICF = 28 L
Total body water = 42 L
- ECF = 14 L (33%)
- -Plasma volume = 4 L (10% TBW/29% of ECF)
- Interstitial fluid = 10 L (24% TBW/71% ECF)
- ICF = 28 L (67%)
Define clearance in relation to pharmacokinetics
The volume of plasma cleared of a drug per unit time
What 3 variables is clearance directly proportional to
Drug dose
Extraction ratio
Blood flow to target organ
What 2 variables is clearance inversely proportional to
Half-life
Drug concentration in central compartment
How can a stead-state concentration of a drug in plasma be achieved
The infusion rate or dose interval (time) must equal the rate of drug clearance
How many half-times before stead-state is achieved
5
How can steady-state be achieved fast in drugs that have long half-lifes
Administer loading dose
What are 3 major routes drugs are eliminated
Liver
Kidney
Organ independent (Hoffman elimination or ester hydrolysis in plasma)
Describe the plasma concentration curve as it relates to the multi-compartment model
i.e. alpha and beta phase of curve
Alpha phase represent distribution of drug from central compartment (plasma) to the peripheral compartment (tissues)
- This represents Vd
- steeper slope = more lipophilic drug
Beta phase represents elimination from the central compartment (plasma)
What does the beta portion of the plasma concentration curve represent
Elimination
As plasma concentration declines due to elimination, drug is redistributed from tissues following the concentration gradient
flatter slope represents elimination from the central compartment
Define rate constant pertaining to pharmacokinetics
Describes the speed at which a reaction occurs, how fast a molecule moves between compartments
Define elimination half-life
The time it takes for 50% of the drug to be eliminated from the body after IV injection
When is a drug considered fully cleared from the plasma
When 96.9% has been cleared or 5 half-times
What is the difference between elimination half-life and context-sensitive half-time.
Context-sensitive half-time takes the duration of drug administration into account
Define context-sensitive half-time
The time required for the plasma concentration to decline by 50% after an infusion is stopped
What is elimination half-TIME
The time it takes for 50% of the drug to be removed from the plasma during elimination phase
How does ionization affect medications in the body
It’s when a molecule gains a positive or negative charge affecting the ability to diffuse through lipid membranes
How do drugs that are weak acids or bases react in plasma/water
Weak acids will donate a proton to water
weak bases will accept a proton from water
Definition of a drug’s pKa
When the pKa equals the pH where 50% of the drug is ionized and the other 50% is non-ionized
Describe the difference between acids and bases
acids DONATE a proton
HA+ H+ + A
Bases ACCEPT a proton
B- + H+ BH
What does pH measure
the concentration of hydrogen ions in an aqueous solution determining the acidity or alkalinity of a solution
What is the difference between strong acids and bases
when strong acids or bases in water, they will completely dissociate
When a weak acid or base is in water, they will partially dissociation leaving a fraction of ionized and non-ionized acid/base
What 2 factors is ionization dependent on
pH of a solution
pKa of a drug
What does the level of pKa indicate
How much a molecule wants to behave like an acid
low pKa = amazing acid
high pKa = terrible acid
What is the Henderson-Hasselbach equation
pH = pKa + log([base]/[conjugate acid])
According to the henderson-hasselbach equation, how does a basic drug act in an acidic environment
It predicts that ionized fraction (conjugate acid) will dominate the base
More ionized than non-ionized
How does a drug that is a weak base act in a weak base solution
Is it lipid-soluble or not?
more NON-IONIZED than ionized
Lipid-soluble
How does a drug that is a weak base act in an acidic solution
Is it lipid-soluble or not?
More IONIZED than non-ionized
Water-soluble NOT lipid-soluble
How does a drug that is a weak acid act in an acidic solution
Is it lipid-soluble or not?
More NON-IONIZED than ionized
YES lipid-soluble
How does a drug that is a weak acid act in a basic solution
Is it lipid-soluble or not?
More IONIZED than non-ionized
NOT lipid-soluble – water soluble
How does ionization affect a drugs activity
It determines if a drug can pass through cell membranes (lipophilic)
How are drugs compounded to become weak acids or bases
ACIDS:
combined with Na+, Ca++, Mg++
BASES:
combined with Cl- or SO4(2-)
How does ionization affect solubility.
ionization affects ability to be lipophilic vs hydrophilic
Ionized in water
- hydrophilic
- lipophobic
Non-ionized lipid
- lipophilic
- hydrophobic
How does ionization alter the pharmacologic effect
Ionized = not active Non-ionized = active
How does ionization affect hepatic biotransformation
Ionized = less likely to transform
Non-ionized = more likely to transform
How does ionization affect renal elimination
Ionized = More likely to eliminate
Non-ionized = less likely to be eliminated
How does ionization affect diffusion across the following barriers?
BBB
GI tract
Placenta
Ionized
- No
- No
- No
Non-ionized
- Yes
- Yes
- Yes
In what situations dose the ionized fraction predominate
-Molecule is a weak base and the solution pH < pKa of drug
(base added to an acid)
-Molecule is a weak acid and the solution pH > pKa of drug
(acid added to a base)
In what situations does the non-ionized fraction predominate
-Molecule is a weak base and solution pH > pKa of drug
(base added to basic soln)
-Molecule is weak acid and solution pH < pKa of drug
(acid added to acidic soln)
How does being pregnant affect ion trapping
Fetal pH < maternal pH
A basic drug in a basic solution has more non-ionized molecules and can pass through the placenta
Once the basic drug is in the acidic fetus it becomes more ionized and cannot pass back through the placenta
Which local anesthetic is most likely to cross the placenta and undergo fetal ion trapping
Lidocaine
Chloroprocaine is least likely to be ion-trapped
What plasma proteins can drugs bind to?
albumin
alpha 1-acid glycoprotein
beta-globulin
Which plasma protein primarily binds with acidic drugs
Albumin
Which plasma protein primarily binds with basic drugs
Alpha 1-acid glycoprotein
Beta-globulin
What do drugs bound to plasma proteins do?
nothing
They are not available to bind to any receptors or to be eliminated
What are 5 conditions that can decrease protein concentration
Liver disease Renal disease Old age Malnutrition Pregnancy
When plasma protein levels are decreased, what is the effect on the drug
The unbound drug fraction is increased
What is the liver’s role in plasma proteins. How is this affected with liver disease
The liver synthesizes plasma proteins
Liver disease will decrease plasma protein production
Which plasma protein is most plentiful
Albumin
What charge does albumin carry
negative
which is why it primarily binds to acidic drugs
What is the half-life of albumin
3 weeks
What 5 factors increase alpha 1-acid glycoprotein concentration
Surgical stress Myocardial infarction Chronic pain Rheumatoid arthritis Advanced age
If a drug is 98% protein bound then becomes 96% protein bound, what percent increase has become unbound
What is the formula
100%
Percent change = ([NEW % - OLD%]/old%) x 100%
([4-2]/2) x 100% = 100%
If a drug is 50% protein bound then becomes 48% protein bound, what percent increase has become unbound?
What is the formula?
4% increase unbound
Percent change = ([NEW % - OLD%]/old%) x 100%
([52-50]/50) x 100 = 4%
What 3 physiologic factors decrease plasma protein
- Reduced synthetic function (liver dz, malnutrition)
- Increased protein excretion (renal dz)
- Altered distribution (3rd trimester)
How is volume of distribution related to the degree of plasma protein binding
INVERSELY related
higher Vd = decreased degree of protein binding
Lower Vd = increased degree of protein binding
What does an increased unbound fraction of drug clinically look like
increased potency
How is metabolism and elimination affected by highly protein-bound drugs
Both are slower
What drug characteristic increases the risk for adverse effects with increased unbound fraction
When the drug has a narrow therapeutic index
Define zero order kinetics
Constant amount of drug is metabolized per unit time
Define first order kinetics
constant FRACTION of drug is metabolized per unit time
What 2 factors does the rate of metabolism for most drugs depend on
- The concentration of a drug at the site of metabolism
2. The intrinsic rate of the metabolic process
What influences the concentration of a drug at the site of metabolism
Blood flow to the site of metabolism
What influences the intrinsic rate of the metabolic process
Genetic and enzyme activity
What does Zero order kinetics describe
Situations where there is more drug than enzyme
So the drug metabolizes at a constant AMOUNT per unit time
drug > enzyme (saturation)
What are examples of drugs following zero order kinetics
aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
What does first order kinetics describe
Situations where there is less drug than enzyme
The enzyme will metabolize a constant FRACTION per unit time
drug < enzyme (non-saturation)
What are the 3 phases of drug metabolism
Phase 1 = modification (oxidation, reduction, hydrolysis)
Phase 2 = conjugation
Phase 3 = excretion
Define metabolism and what is the primary metabolic organ
Biotransformation via an enzymatic process that alters the drugs chemical structure allowing it to be eliminated or active
Primary organ = liver
What hepatic system metabolizes molecules
Hepatic microsomal enzymes of the P450 system
What are 4 lesser sites of metabolism
Kidneys, plasma, lung, intestines
What is the purpose of drug metabolism
To change a lipid-soluble, pharmacologically active compound into a water-soluble, pharmacologically inactive byproduct for elimination
Define the 3 examples of phase 1 reactions.
- Oxidation = removal of electron from compound
- Reduction = addition of electron to compound
- Hydrolysis = adds H2O to a compound to split it apart (usually an ester)
What is the purpose of phase 1 reaction
modification of a compound (via oxidation, reduction, or hydrolysis) preparing it for phase 2 reaction
What occurs during a phase 2 reaction and how
Conjugation of a highly polar, water-soluble substrate to the molecule
This makes the drug inactive and ready for elimination
What occurs during a phase 3 reaction
Involvement of ATP dependent carrier proteins that transport a drug across a cell membrane
These proteins are present in the kidney, liver, and GI tract
Where are microsomal enzymes of the P450 system located
In smooth endoplasmic reticulum of the liver. Some are present in the kidney and GI tract
What metabolic reactions occur in the plasma
Hofmann elimination (pH & temperature dependent) Hydrolysis via non-specific plasma esterases and pseudocholinesterase
Describe how water solubility affects a molecules ability to be eliminated
- Molecules that are more water soluble increases ionization
- Ionization decreases the Vd
- This increases delivery to kidneys for elimination.
- Since the molecule is ionized, it will be eliminated in the urine instead of being reabsorbed from the renal tubule.
What happens to lipid-soluble drugs in the renal tubules
They are reabsorbed and continually circulated until metabolized into water-soluble compounds
How are prodrugs treated by metabolism
Prodrugs are inactive molecules that are converted into pharmacologically active molecules via metabolism
Where do most phase 1 biotransformation’s occur
By hepatic microsomal enzymes of the P450 system
What are 5 common substrates for phase 2 conjugation
Glucuronic acid Glycine Acetic acid Sulfuric acid Methyl group
What is significance of enterohepatic circulation.
Name 2 drugs that can undergo enterohepatic circulation.
Some conjugated compounds are excreted in the bile and become REACTIVATED in the intestines. They are then reabsorbed into the systemic circulation
i.e. diazepam and warfarin
Define perfusion-dependent hepatic eliminiation
Drugs with high extraction ratios are dependent on liver blood flow for extraction
Hepatic BF»_space; enzymatic activity
therefore, increased BF = increased clearance
decreased BF = decreased clearance
Define capacity-dependent hepatic elimination
Drugs with low extraction ratios (< 0.3) clearance is dependent on the liver’s ability to extract the drug from the blood
Blood flow minimally affects clearance
Amount of enzyme influences the liver’s ability to remove drug. Enzyme dependent
What is an extraction ratio
The measure of how much drug is delivered to the clearing organ vs how much drug is removed by that organ
What is an extraction ratio
The measure of how much drug is delivered to the clearing organ vs how much drug is removed by that organ
What does an extraction ratio (ER) of 1.0 vs 0.5 mean
ER 1.0 = 100% of the drug delivered to the clearing organ is removed
ER 0.5 = 50% of the drug delivered to the clearing organ is removed
For drugs with a high hepatic extraction ratio (>0.7), what is clearance dependent on?
Examples of drugs with high ER?
Liver blood flow (PERFUSION dependent)
Fentanyl, sufentanil, morphine, ketamine, propofol
For drugs with a low hepatic extraction ratio (<0.3), what is clearance dependent on?
Examples of drugs with low ER?
The ability of the liver to extract the drug from the blood (CAPACITY dependent)
Rocuronium, diazepam, methadone
What are orally administered drugs with a high extraction ratio subjected to?
First-pass metabolism
How is capacity-dependent hepatic clearance altered
Enzyme induction = increased clearance
Enzyme inhibition = decreased clearance
Examples of drugs that have low hepatic ER
ENZYME DEPENDENT Rocuronium Diazepam Lorazepam Methadone Thiopental Theophylline Phenytoin
Examples of drugs that have intermediate hepatic ER
Midazolam
Vecuronium
Alfentanil
Methohexital
Examples of drugs with high hepatic ER
FLOW DEPENDENT Fentanyl Sufentanil Morphine Meperidine Naloxone Ketamine Propofol Lidocaine Bupivacaine Metoprolol Propranolol Nifedipine Diltiazem Verapamil
Describe the effect of drugs that undergo enterohepatic circulation
Prolong duration of effect
What is the most important cytochrome P450 enzyme. Why?
CYP 3A4
It metabolized 50% of drugs we administer
What is an enzyme inducer? Why is it significant?
Exogenous chemical that can stimulate the synthesis of additional enzymes
This increases drug clearance reducing t1/2. Less circulating drug available and increased dose may be required
Examples of enzyme inducers
Ethanol Tobacco Phenytoin Barbiturates Rifampin Carbamazepine
What is an enzyme inhibitor?
Why is it significant?
Exogenous chemicals that compete for binding sites on the enzyme
This reduces drug clearance, increasing drug plasma levels. Decreased doses may be required
Examples of common enzyme inhibitors
SSRIs Omeprazole Grapefruit Cimetidine Erythromycin Ketoconazole
List 6 inducers of CYP 3A4
(increase clearance) Ethanol Rifampin Barbiturates Tamoxifen Carbamazepine St. John's Wort
List 6 inhibitors of CYP 3A4
(decrease clearance) Grapefruit juice Cimetidine Erythromycin Erythromycin Azole antifungals SSRIs
Which opioid substrates are cleared by CYP3A4
Fentanyl
Alfentanil
Sufentanil
Methadone
Which benzodiazepine substrates are cleared by CYP 3A4
Midazolam
Diazepam
Which local anesthetics are cleared by CYP 3A4
Lidocaine
Bupivacaine
Ropivacaine
Which drug is an important CYP 2D6 inducer
(increased clearance)
Disulfiram
Which drugs are CRP 2D6 inhibitor
(decreased clearance)
Isoniazid
SSRIs
Quinidine
What are examples of drugs utilizing CYP 2D6 clearance
Codeine = morphine
Oxycodone
Hydrocodone
Which compounds are CYP 1A2 inducers
(increased clearance)
Tobacco
Cannabis
Ethanol
Which drugs are CYP 1A2 inhibitors
(decrease clearance)
Erythromycin
Ciprofloxacin
What 2 factors determine the renal clearance of a drug
Drug polarity
pH of the ultrafiltrate
How is glomerular filtration affected by highly protein-bound drugs
It isn’t
These protein-bound drugs are resistant to glomerular filtration
Only free fraction is filtered
What 2 processes deliver a drug to the renal tubule
- Glomerular filtration
2. Organ ion transporters
What type of drugs in the ultrafiltrate tend to be eliminated in urine
Hydrophilic drugs
What type of drugs in the ultrafiltrate tend to be reabsorbed
Lipophilic drugs
3 examples of drugs that rely on organic ion transporters for renal clearance.
Where are these located?
Drugs = furosemide, morphine, dopamine
location = proximal renal tubules
Describe how urine pH influences whether drugs are excreted in urine or reabsorbed into peritubular capillaries
Acidity vs alkalinity
like dissolves like
Acidic urine favors REABSORPTION of acidic drugs and EXCRETION of basic drugs
Basic urine favors REABSORPTION of basic drugs and EXCRETION of acidic drugs
What happens to hydrophilic drugs excreted in urine
Unchanged
How are lipophilic drugs excreted in urine
by undergoing biotransformation reaction to increase their water solubility
What happens to lipophilic drugs in the kidneys
It is reabsorbed into the peritubular fluid by diffusion
How does organic ion transporter elimination work in the kidneys
Active secretion or organic acids and bases at the proximal renal tubules
Where are organic ion transporters in the kidneys and what is excreted
proximal renal tubules
secretes organic acids and bases
Describe the 2 types of organic ion transporters and what they eliminate
Organic ANION transporters (OAT) = furosemide, thiazide diuretics, PCN
Organic cation transporters (OCT) = morphine, meperidine, dopamine
Describe the types of drugs reabsorbed and excreted when acidic urine is present
Reabsorb acidic drugs
Excrete basic drugs
AAA = ACIDIC drugs are better ABSORBED in ACIDIC urine
Describe the types of drugs reabsorbed and excreted when basic urine is present
Reabsorb basic drugs
Excrete acidic drugs
BBB = BASIC drugs are BETTER absorbed in BASIC urine
How can urine pH be altered to become more acidic?
What will be eliminated?
Altered with ammonium chloride or cranberry juice
Eliminates BASIC drugs
how can urine pH be altered to become more basic?
What will be eliminiated?
Altered with sodium bicarbonate or acetazolamide
Eliminates ACIDIC drugs
What drugs are metabolized by pseudocholinesterases
Succinylcholine Cocaine (+liver) Tetracaine Procaine Chloroprocaine Mivacurium
What drugs are metabolized by nonspecific plasma esterases
Esmolol Remifentanil Atracurium (+hofmann) Etomidate (+hepatic) Clevidpine
What are 4 metabolic pathways in plasma
Pseudocholinesterase
Nonspecific esterases
Alkaline phosphatase
Hofmann elimination
How does enzymatic metabolism occur in the plasma
Hydrolysis via water to cleave an ester linkage
What drugs are metabolized via Hofmann elimination
Cisatracurium
Atracurium (+nonspecific esterases)
What drug is metabolized via alkaline phosphatase
Fospropofol
How does pseudocholinesterase deficiency affect metabolism? Which drugs are impacted?
Extends the duration of action of succinylcholine, mivacurium, cocaine, and ester LA
