Unit 4 Pharmacology: Pharmacokinetics Flashcards
What is the volume of distribution?
Describes the relationship between a drug dose and the drug’s plasma concentration, it is a theoretical measure of how a drug distributes throughout the body.
What 2 things does Vd assume?
- The drug distributes instantaneously (full equilibrium at t=0)
- The drug is not subjected to bio transformation or elimination before it fully distributes
What is the formula for Vd?
Vd = amount of drug / desired plasma concentration
What is the body water distribution?
total body water 60% Intracellular volume 40% Extracellular volume 20% -interstitial fluid 16% - plasma fluid 4%
What is the Vd of a lipophilic drug? What does this mean for distribution and dose?
It exceeds total body water, >0.6 L/kg
This means it distributes into the total body water as well as into the fat.
It will require a higher dose to achieve a given plasma concentration
What is the Vd of a hydrophilic drug? What does this mean for distribution and dose?
It is less than total body water <0.6 L/kg
It distributes into some or all of the total body water, but not the fat.
It will require a lower dose to achieve a given plasma concentration
What affects the volume of distribution?
Drug characteristics:
Molecular size
Ionization
Protein binding
Patient characteristics:
Pregnancy
Burns
What is the formula for loading dose?
Loading dose = Vd x (desired plasma concentration / bioavailability)
What is the bioavailability for an IV drug?
1
Because it is injected right into the bloodstream
What is drug clearance?
The volume of plasma that is clear of drug per unit time
Clearance is directly proportional to what 3 things?
- Blood flow to clearing organ
- Extraction ratio
- Drug dose
Clearance is inversely proportional to what 2 things?
- Half-life
2. Drug concentration in the central compartment
What is steady state?
It occurs when the amount of drug entering the body is equivalent to the amount of the drug being eliminated by the body, there is a stable plasma concentration. Each compartment has equilibrated.
After how many half-times is steady state achieved?
After 5 half-times
In a 2 compartment model what part of the curve correlates with drug elimination from the plasma?
The less steep portion (the second part) represent elimination from the plasma, it is called beta phase
In a 2 compartment model what does the steepest part of the slope represent?
Redistribution from the plasma to the tissues, it is alpha phase
The slope of alpha phase in a 2 compartment model is influenced by a drug’s what?
Volume of distribution
As a general rule, the more lipophilic the drug, the larger the Vd, and the _____ the slope
Steeper
What is another name for the alpha portion of a 2 compartment model
t1/2 alpha
What is another name for the beta portion of the 2 compartment model?
t1/2 beta
What is a rate constant?
The speed at which a reason occurs, or how fast a molecule moves between compartments
Define the 3 rate constants:
k12
k21
ke
k12: rate constant for drug transfer from central to peripheral compartment
k21: rate constant for drug transfer from peripheral to central compartment
ke: rate constant for drug elimination from body
What is the difference between elimination half-life and elimination half-time?
Elimination half-life: the time it takes for 50% of the drug to be removed from the body after a rapid IV injection
Elimination half-time: the time it takes for 50% of the drug to be removed from the plasma during the elimination phase
When are elimination half-life and half-time different?
When the rate of drug removal from the plasma is not the same as the rate of drug removal from the body
By convention we say that a drug has been cleared from the body when what percent of the dose has been eliminated from the plasma? This is how many half-times?
96.9%
5 half-times
Half Time : % of drug eliminated : amount of drug remaining 0 1 2 3 4 5
0 : 0% : 100% 1 : 50 : 50 2 : 75 : 25 3 : 87.5 : 12.5 4 : 93.75 : 6.25 5 : 96.875 : 3.125
The half-times measures a constant fraction not constant amount, what does this mean
It takes the same period of time for the plasma concentration to a drug to fall from 200 to 100 as it does for 50 to 25
What is a context sensitive half-time?
The time required for the plasma concentration to decline by 50% after the infusion is stopped.
An acid donates ____
A base donates _____
Acid donates H+
Base donates OH-
If you put a strong acid or strong base in what it will _____ completely.
Ionize
If you put a weak acid or a weak base in water ______
A fraction will ionize and the remaining will be unionized.
What is ionization?
The process where a molecule gains a positive or negative charge, and this molecular charge affect a molecule’s ability to diffuse through lipid membranes.
What 2 things does the amount of ionization depend on?
pH of the solution
pKa of the drug
What is another name for pKa?
Dissociation constant
When is 50% of a drug ionized and 50% unionized?
When pKa and pH are the same
What is the solubility of ionized and unionized molecules?
Ionized: hydrophilic, lipophobic
Unionized: hydrophobic, lipophilic
Which form of a molecule is the active form, ionized or unionized?
Unionized
When is a drug more likely to undergo hepatic elimination, ionized or unionized?
Unionized
When is a drug more likely to undergo renal elimination, ionized or unionized?
Ionized
What form of the drug crosses lipid bilayers?
Unionized
What happens when you put an acid in a basic solution?
Acidic drug becomes highly ionized in basic pH.
The acidic drug donates its proton to the base and the acid becomes ionized.
What happens when you put an acidic drug into an acidic solution?
Like dissolves like.
The acidic drug will be highly unionized in an acidic pH.
Both want to donate a proton, so neither do and the drug remains unionized.
What happens when you put a base in an acidic solution?
A basic drug will be highly ionized in an acidic pH.
The basic drug wants to accept a proton and the acidic solution wants to donate one.
What happens when you put a base in a basic solution?
Like dissolves like.
A basic drug will be highly unionized in a basic pH.
Both want to accept a proton, but there are no donators so the basic drug remains unionized.
Drugs are usually prepared as a salt that dissociates in solution, a weak acid is paired with:
A positive ion: sodium, calcium, magnesium
Drugs are usually prepared as a salt that dissociates in solution, a weak base is paired with:
A negative ion: chloride, sulfate
The unionized fraction predominates if:
A molecule is a weak base and pH of the solution is _____
A molecules is a weak acid and pH of the solution is _____
> pKa of the drug (a base in a base)
< pKa of the drug (an acid in an acid)
The ionized fraction predominates if:
The molecule is a weak base and the pH is ____
The molecule is a weak acid and the pH is ____
< pKa of the drug (base in an acid)
> pKa of the drug (acid in a base)
Which circumstance creates the strongest gradient for passage of local anesthetic from the mother to the fetus?
Maternal alkalosis and fetal acidosis
Explain ion trapping as an example of local anesthetic and a pregnant woman.
Local is a weak base, the unionized fraction freely diffuses across the placenta. A fetus pH is normally a little lower than a mother’s, creating a greater degree of ionization which can’t diffuse back across the membrane.
Where are plasma proteins synthesized?
The liver
What type of bond do drugs and plasma proteins bind with?
Weak bonds: ionic, hydrogen, van der Waals
What it the most plentiful plasma protein in the body, and therefore the primary determinant of plasma on oncotic pressure?
Albumin
What is the t 1/2 of albumin?
3 weeks
What type of charge does albumin carry?
Negative charge
What type of drugs primarily bind to albumin?
Acidic drugs.
Also can bind some neutral and basic drugs.
Name the 2 other plasma proteins besides albumin
a1-acid glycoprotein
Beta-globulin
What type of drugs does a1-acid glycoprotein primarily bind?
Basic drugs
What type of drug primarily binds to Beta-globulin?
Basic drugs
What conditions decrease albumin level? (5)
Liver disease Renal disease Old age Malnutrition Pregnancy
What conditions increase albumin?
None
What conditions increase a1-acid glycoprotein? (5)
Surgical stress Myocardial infarction Chronic pain Rheumatic arthritis Advanced age
What conditions decrease a1-acid glycoprotein?
Neonates
Pregnancy
What condition increases Beta-globulins?
None
What conditions decrease Beta-globulins?
None
If a drug is 98% protein bound and is reduced to 96% bound, the free fraction has increased by?
100%
Think of it as the free fraction portion has increased from 2% to 4% that’s doubled.
Vd and degree of plasma protein binding have a ______ relationship
Inverse
Highly protein bound drugs typically have what rate of metabolism?
A slower rate
Zero order kinetics metabolizes a constant _____ per time.
Amount
Why is a constant amount of drug per time metabolized in zero order kinetics?
There is more drug than enzyme, the biotransformation process is saturated.
First order kinetics metabolizes a constant ____ per time.
Fraction
Which order of kinetics do almost all the drugs we give follow?
First order kinetics
What are the 3 phases of metabolism?
Modification
Conjugation
Elimination
What is phase 1 of metabolism? What does it do? What carries out most phase 1 biotransformation?
Modification.
Phase 1 reactions results in small molecular changes that increase the polarity (water solubility) of a molecule.
P450 system.
List the 3 phase 1 reactions and what they do
- Oxidation - removes electrons from a compound
- Reduction - adds electrons to a compound
- Hydrolysis - adds water to a compound to split it apart (usually an ester)
What is phase II of metabolism?
Conjugation
What happens in phase II of metabolism?
Phase II reaction conjugated (adds on) an endogenous, highly polar, water soluble substrate to the molecule resulting in a water soluble, biologically inactive molecule ready for excretion.
What is phase III of metabolism?
Elimination
What occurs in phase III of metabolism?
ATP dependent carrier proteins transport drugs across cell membranes
What is the primary role of metabolism?
To change a lipid soluble, pharmacologically active compound into a water soluble, pharmacologically inactive byproduct.
Hepatic clearance depends on what 2 things?
Liver blood flow - how much is delivered to the liver
Hepatic extraction ratio - how much is removed by the liver
What is extraction ratio? Equation?
A measure of how much drug is delivered to clearing organ vs how much drug is removed by that organ.
Extraction ratio = (arterial concentration - venous concentration) / arterial concen.
What does an extraction ratio of 1.0 mean? 0.5?
- 0 : 100% of the drug delivered to the clearing organ is removed
- 5 : 50% of the drug delivered to the clearing organ is removed
What are the 2 categories of hepatic clearance?
Flow limited elimination
Capacity limited elimination
What is the extraction ratio for flow limited elimination? What does this mean?
> 0.7
Clearance is dependent on liver blood flow
What is the extraction ratio of capacity limited elimination? What does this mean?
< 0.3
Clearance is dependent on the ability of the liver to extract drug from the blood, changes in hepatic enzyme activity or protein binding impact clearance.
With capacity limited elimination enzyme induction does what to clearance?
Increases clearance
7 commonly used drugs with low hepatic extraction ratio (ER)
Rocuronium Diazepam Lorazepam Methadone Thiopental Theophylline Phenytoin
4 commonly used drugs with intermediate hepatic extraction ratio (ER)
Midazolam
Vecuronium
Alfentanil
Methohexital
15 commonly used drugs with high hepatic extraction ratio (ER)
Fentanyl Sufentanil Morphine Meperidine Naloxone Ketamine Propofol Lidocaine Bupivacaine Metoprolol Propranolol Alprenolol Nifedipine Dilitazem Verapamil
What it the most important mechanism of biotransformation in the body? What are 2 other names for it?
P450 system
Mixed-function oxidase system
Monooxygenases
What is the most important cytochrome P450 enzyme? It metabolizes nearly what percentage of drugs. Name another variant that is also important.
CYP 3A4
nearly 50%
CYP 2D6
What does an enzyme inducer do to the P450 system? Examples.
It stimulates synthesis of additional enzyme increasing clearance and reducing t 1/2. Tobacco smoke Phenytoin Barbiturates Ethanol Rifampin Carbamazepine
What does enzyme inhibition do to the P450 system? Examples.
It competes for binding sides on an enzyme reducing drug clearance and increasing t 1/2. Grapefruit juice Cimetidine Omeprazole Isoniazid SSRIs Erythromycin Ketoconazole
Name 4 opioids that undergo CYP 3A4
Fentanyl
Alfentanil
Sufentanil
Methadone
Name 2 barbiturates that undergo CYP 3A4
Midazolam
Diazepam
Name 3 local anesthetics that undergo CYP 3A4
Lidocaine
Bupivacaine
Ropivacaine
What 6 drugs induce CYP 3A4
Ethanol Rifampin Barbiturates Tamoxifen Carbamazepine St. John’s Wort
What 5 “drug” inhibit CYP 3A4
Grapefruit juice Cimetidine Erythromycin Azole antifungals SSRIs
What 3 opioids undergo CYP 2D6
Coding -> morphine
Oxycodone
Hydrocodone
What 3 drugs induce CYP 2D6
Phenytoin
Carbamazepine
Dexamethasone
What 3 drugs inhibit CYP 2D6
Isoniazid
SSRIs
Quinidine
What drug undergoes CYP 1A2
Theophylline
What drugs induce CYP 1A2
Tobacco
Cannabis
Ethanol
What 2 drugs inhibit CYP 1A2
Erythromycin
Ciprofloxacin
In renal elimination, what 2 things determine drug elimination?
A drug’s polarity
pH of the glomerular fluid
What happens to hydrophilic drugs in renal elimination?
They are excreted unchanged.
What happens to lipophilic drugs under renal elimination?
They must first undergo biotransformation to increase their water solubility, if they have not undergone biotransformation they will be reabsorbed into the peritubular fluid by diffusion
What 2 processes deliver drug to the urine?
- Glomerular filtration
2. Organic ion transporters
What drugs undergo glomerular filtration?
Drugs not bound to plasma proteins. Those bound to protein are resistant, and only the free fraction is filtered.
What is organic ion transportation?
Transport proteins located in the proximal renal tubules actively secrete organic acids and bases into the urine (anions and cations)
What does urine pH have to do with elimination?
Like dissolves like.
Acidic urine favors: absorption of acidic drugs and excretion of basic drugs
Basic urine favors: absorption of basic drugs and excretion of acidic drugs
What 2 things can be used to acidify urine? What kind of drugs with this help eliminate?
Ammonium chloride
Cranberry juice
Basic drugs
What 2 things can be used to alkalize the urine? What kind of drugs will this help eliminate?
Sodium bicarbonate
Acetazolamide
Acidic drugs
Metabolism in the plasma is performed by which reaction? What does this mean?
Hydrolysis - uses water to cleave an ester linkage
Name the 4 important metabolic pathways in the plasma
Pseudocholinesterase
Nonspecific esterase
Alkaline phosphatase
Hofmann elimination
What drugs are metabolized by pseudocholinesterase?
Succinylcholine
Micavurium
Ester local anesthetics
What drugs are metabolized by nonspecific esterases?
Remifentanil
Esmolol - RBC esterases
Etomidate - plus hepatic
Atracurium - plus Hofmann
What drug is metabolized by alkaline phophatase?
Fospropofol - alkaline phophatase converts it into propofol
What drugs undergo Hofmann elimination?
Cisatracurium
Atracurium - plus nonspecific esterases
What 2 factors affect Hofmann elimination?
pH and temperature
