Lecture 2-3: General Principles of Pharmacokinetics Flashcards
What is pharmacokinetics
Describes the process by which the body handles the drugs presented to it
What are 4 the pharmacokinetic processes
- Absorption
- Distribution
- Metabolism
- Excretion
What are ways drugs can be absorbed
- Oral intake
- Inhalation
- Injection
Drugs enter the bloodstream and interact/bind with ___
Proteins
Do bound or free drugs leave bloodstream and go to site of action
Free
Size of ____ determines what size of molecules can get in and out of bloostream
Fenestrated capillaries
What is the distribution process of drugs
- Enter liver or other sites of bio transformation
- Either enter bile to be eliminated or can be reabsorbed or enter circulation
- Free drug when migrates to site of action or inactive tissues
How are drugs eliminated
- Transported in Bile and eliminated in feces
- Air
- Urine via kidney
What is the major site of elimination/excretion
Kidney—> urine
What are the 3 kinds of passive transported
- Simple diffusion
- Channel mediated
- Transporter mediated
What is passive/simple diffusion
Water soluble and lipid soluble drugs penetrate membrane
What does carrier mediated transport depend on
- Structure specifics- # of transporter molecules
- Competition for binding
- Tmax- # of transporters finite
What are the 2 types of carrier mediated transport
- Facilitated diffusion
- Active transport (ATP)
What is filtration
Glomerular filtration in kidney
What is transcytosis (pinocytosis)
Drug molecules and fluid get engulfed by vesiculation of cell membrane
Mechanisms of membrane penetration follow ____ gradient
Concentration gradient
Are most drugs in clinical use weak or strong acids/bases
Weak
The extent of ionization is described by what equation
Henderson hasselbachs
In order for a drug to be lipid soluble does it need to be ionized or non-ionized and why
Non-ionized, if it is ionized it will bind H20 and become large and charged therefore will not be able to go through membrane and will be eliminated
Do acidic drugs have lower or higher pKa’s
Lower
Do basic drugs have lower or higher PKa’s
Higher
What is the ionized form of an acid
A-
What is the unionized form of an acid
HA
What is the ionized and unionized form of basic drug
Unionized form: B
Ionized form: BH+
What is the Henderson hassalbach equation
PH-pka=log (A-)/(HA)
*B and BH basic
Is a weak acid LESS ionized in an acidic or basic medium
Acidic medium and therefore more lipid soluble and readily absorbed
If you have a weak acid and want it to be eliminated and not absorbed what type of medium should be created
Basic medium, will ionize acid and therefore no longer lipid soluble
Is a weak basic drug LESS ionized in an acidic or basic medium
Basic medium and therefore rapidly absorbed
If you have a weak basic drug that you want to be eliminated and not absorbed should the medium be acidic or basic
Acidic- will ionize the drug and therefore no longer lipid soluble and will be eliminated
What is ion trapping
When a weak base or acid diffuses into an acidic or basic medium, respectively and becomes ionized and will accumulate in that environment- trapped and will get eliminated
Are strong or weak acids/bases always ionized in the body and therefore not lipid soluble
Strong
Are mineral acids and quaternary ammonium compounds like methylnaltrexone and mineral bases strong or weak acids/bases
Strong
If a drug is non-ionized what is the concentration of that drug in 2 separate “compartments”
Concentration is equal on both sides because the drug is lipid soluble and will therefore diffuse across the membrane via a concentration gradient until equilibrium is reached
What is the concentration of an ionized form dependent on
Environmental pH (increase acidity, increase ionized bases and vice versa) and pKa
The total concentration on each side of the compartment is the sum of what
Concentrations of the ionized and non-ionized form of the drug
Compartment example: Weak acid
- compartment #1: pH=3, pka=4 nonionized=1, ionized=0.1 and total= 1.1
-compartment #2: pH=7, pka=4
What do you expect the concentration of nonionized and ionized to be in compartment #2?
Nonionized=1–> will be equal to compartment #1 because non-ionized form is freely diffusible regardless of different pH
Ionized form: greater in compartment 2 because the weak acid will become ionized in the more basic pH of 7 in compartment #2
Acids are accumulated in a ___ environment
Basic
Bases are accumulated in a ___ environment
Acidic
What can be used to make the urine more acidic and increase the elimination of bases
Ammonium chloride
What can be used to make the urine more basic and increase elimination of acids
Sodium bicarbonate
Ex: dog eats a lot of phenobarbital which is a barbiturate acid. What can you give in order to excrete the acid to maintain homeostatic pH
Sodium bicarbonate- basic which will ionize acid no longer lipid soluble so won’t be absorbed into bloodstream
Are uniports, symports, and antiports forms of active or passive transport
Active
What type of active transport is an H+ pump
Uniport
What type of active transport does glucose uptake use
Symport
What type of active transport does Na+/K+ ATPase use
Antiport
What is permeability glycoprotein (P-gp) also known as
multi drug resistant protein (MDR1) or ATP binding cassette subfamily B membrane 1 (ABCB1)
What does P-gp do
Utilizes ATP as energy to pump out a wide variety of substrates across extra- and intracellular membranes
Utilized to excrete toxins
Where is P-gp distributed in body
Widely distributed- found in intestinal mucosa, hepatocytes, renal proximal tubular cells, adrenal gland, and capillary endothelial cells making BBB
What is absorption
The process whereby a drug gains entry into body fluids, usually blood that distribute throughout the organism
What factors modify absorption
- Solubility
- Dissolution
- Concentration
- Blood flow
- Absorbing surface
- PH
- Contact time
How does pH modify absorption
Weak Acid drug in basic environment will decrease absorption because ionized Weak acid in acidic environment is lipid soluble
**same concept applies to bases
What is bioavailability
Amount of active drug available at the site of action
Which form of drug administration has 100% bioavailability
IV- directly into circulation
What is the equation that represents the relationship between IV and oral administration of the same drug
Dose-IV= Dose-PO(F)
F=bioavailability
Helps convert IV to PO dose
Bioavailability is the summary result of what 4 things
- Decomposition /inactivation of drugs in the intestine
- Degree of absorption
- Metabolism in the wall of the gut or in the liver
- Transport of drug by P-gp back to lumen of the gut
What is the first pass effect
Initial metabolism of a drug while passing through the wall of the gut and liver
If there is little first pass effect does a small or large amount of the drug get into the system
Large (vice versa)
Which form of drug administration would have a large first pass effect and therefore a smaller % gets into blood
Orally
if unable to increase amount entering blood, drug must be given IV
What are the three main routes of administration
- Oral
- Parenteral
- Topical
What are the 7 forms of parenteral administration
- IV
- IM
- SQ
- Intraperitoneal
- Intraarterial
- Intrathecal
- Inhalation
What are the four forms of topical administration
- Skin/transdermal
- Eye
- Buccal/sublingual
- Rectal
What are some disadvantages of oral administration
- Emesis
- Destruction of drug by enzymes or by low pH
- Metabolism by the intestinal flora
- Absorbed drug is exposed to the liver
- Gastric emptying time
- Binding to food
What is slow release formulation
Designed to produce slow uniform absorption of the drug for several hours
What is a negative side effect of slow release formulation
Absorption is often irregular and erratic
Which form of parenteral route has no absorption phase
IV-directly injected into systemic circulation
What form of parenteral route is important route of entry for toxic substances
Inhalation
Topical application of drugs includes to what areas
Skin, eye, nose throat (usually for local effects) and systemic absorption
Under normal conditions the ___binding capacity is much larger than the drug concentration. Consequently the free fraction of drug is generally ____
Protein, constant
How do storage depots of drugs affect plasma levels and 1/2 lives
Decreasing plasma levels and prolongs 1/2 life by accumulating in body
What are some storage depots of drugs
Fat, tissues, bone
What are some common sites of drug exclusion
- CSF (no fenestrated membranes- only lipid soluble can pass)
- Ocular fluid
- Endolymph fluid
- Fetal fluid
- Pleural fluid
When drugs enter the body and bloodstream where are they redistributed first
1st (most) goes to the brain quickly
Then slowly makes its way to affected tissues
What is the initial and secondary redistribution/effect of thiobarbiturates and benzodiazepines)
Initial effect: anesthetic
Then goes to fatty tissue
What is the apparent volume distribution (Vd) equation
D-IV/C0
Vd= Total amount of drug in the body/concentration in plasma
What is C0 (mg/L)
Plasma concentration of the drug at time zero
What is D-IV (mg)
Intravenous dose
Sample problem: 200mg of drug A is administered IV. Plasma concentration was found to be 5mg/mL at time zero. Calculate Vd
Vd= dose of drug administered/plasma concentration
= (200mg)/(5mg/L)= 40L
What is the standard value of plasma compartment fluid
3L
What is the standard value of extracellular fluid compartment
12L
What is the standard value of total body water
41L
What is the distribution and binding of drugs that show a large Vd
Extensive distribution and bind extensively in peripheral tissues
*vice versa
Would Vd be low or high if the drug is mostly present in the plasma
Low
Drugs with a very high plasma protein binding have low or high Vd
Low
What is the principal goal of metabolism or biotransformation of drugs and xenobiotics
Elimination
What are some characteristics of most pharmacologically active drugs
- Lipid soluble
- Unionized or partially ionized
- Strongly bound to plasma proteins or other tissues
- Not readily excreted by the kidney
- Tend to remain in body for a long time
What happens during phase I metabolism of drugs
Form drug metabolite with modified activity and inactive drug metabolite
Decrease lipid solubility
What happens during phase II metabolism
Add conjugate- large charged molecule that will promote elimination and form hydrophilic, polar molecules
Absorbed drugs are initially lipophilic and transform to ____ to be eliminated
Hydrophilic
Phase I reactions usually convert lipid soluble parent to more __ metabolites
Polar
What functional groups are introduced or unmasked during phase I reactions that will decrease lipid solubility
OH, SH, NH2
What are the two classes of metabolism enzymes in phase I reactions
- Nonmicrosomal
- Microsomal
Are nonmicrosomal inducible or non-inducible
Non-inducible
What are the three nonmicrosomal enzymes
- Esterases and amidases
- Monoamine oxidases
- Alcohol and aldehyde dehydrogenases
What do esterases and amidases metabolize
Pseudocholinesterases- genetic polymorphism
Important for elimination of local anesthetics, succinylcholine
What do monoamine oxidases metabolize
Endogenous amines- catecholamines, serotonin
What does alcohol and aldehyde dehydrogenases
Ethylene glycol metabolism (toxicology)
Are microsomal reactions inducible or non-inducible
Inducible
Where do microsomal metabolic enzymes come from and what are they made of
Come from endoplasmic reticulum- layers of enzyme and lipid layers- so can metabolize lipid soluble drugs
What is the mechanism of drug oxidation for microsomal reactions
P450
What are the inducers of P450
- Rifampin
- Barbiturates
- Phenytoin
- Glucocorticoids
- St. John’s wort
What are the inhibitors of P450 microsomal reactions
- Cimetidine
- Ketoconazole
- Diltiazem
- Erythromycin
- Verapamil
- Fluoxetine
What is the result of phase II synthetic reactions
Large molecular weight, increased polarity, diminished biological activity
What is the only phase II reaction that is microsomal and inducible
Glucuronidation
What are the 7 types of Phase II reaction conjugations
- Glucuronidation
- Acetylation
- Glutathione
- Glycine
- Sulfate on
- Methylation
- Water
What is the process of enterohepatic circulation
- Drug enters liver, becomes conjugated
- Conjugated drug enters bile to small intestines
- Drug conjugate is cleaved from drug- smaller, lipophilic and therefore can get reabsorbed back into circulation
How does enterohepatic circulation effect the 1/2 of a drug
Increases
How do antibiotics effect enterohepatic circulation
Get rid of bacteria/enzymes that cleave drug conjugate therefore drug remains large and doesn’t get reabsorbed- is eliminated
What are some common enterohepatic circulation drugs
Opioids, benzodiazepines
What are the three ways in which the renal system excretes drugs and drug metabolites
- Glomerular filtration
- Active tubular secretion or reabsorption (especially in PT)
- Passive diffusion across tubular epithelium
How does the proximal tubule affect drug concentration
Increases it because 65% of Na+ and H20 are reabsorbed
How does the proximal tubule reabsorption of Na+ and H2O effect the concentration gradient for the drug
Will generate strong concentration gradient if the drug is capable of diffusion and it will go back into blood stream
If we want to eliminate of a weak acid drug via the tubular system what can we do the tubular fluid
Can make tubular fluid more basic by adding sodium bicarbonate to ionize the weak acid therefore making it not lipophilic and can’t be reabsorbed
If we have a weak base drug that we want to eliminate via the tubular system what can we do to tubular fluid
Make tubular fluid more acidic by adding ammonium chloride therefore ionizing the drug and making it less lipophilic so its not absorbed
Are the following drugs acid or base drugs: Penicillin, ampicillin, cephalosporins, furosemide, thiazide diuretics, probenecid, salicylate, phenylbutazone
Acid
Are the following drugs acid or base drugs: histamine, amiloride, cimetidine, procainamide, neostigmine, trimpethoprim, atropine
Basic
What is clearance
Measure of the capacity to remove the drug
Proportionality constant that relates the rate of drug elimination to its plasma concentration
What is the equation for systemic clearance
CL=CL(renal) +CL (hepatic) +CL (lung) + CL (others)
What is the rate of elimination equation
Rate of elimination= CL(c)
What is the equation for 1/2 life
T 1/2= ln2(Vd)/CL
what is the equation for elimination rate constant
Kel=CL/Vd
Describe the two compartment model
Dose is administered and enters central compartment then travels to peripheral compartments. It must then travel back to central compartment where it is excreted into Bowmans’ capsule
What is first order elimination
Constant proportion of the drug is eliminated in a unit time
First order elimination follows ___ kinetics
Exponential
First order elimination example: 100mg unit of drug is given. 50% of the drug is eliminated at each 1/2 life . How many units are eliminated in first half life and then second half life
1st 1/2 life eliminate 50 units
2nd 1/2 life= 25 units
First order elimination gets ride of drugs at ___proportion but ____ rate
Same proportion but different rate
What is half life
Time required to change the amount of the drug in the body by 1/2 of 50%
What are the assumptions regarding 1/2 life
Body is a single compartment, size is the volume distribution (Vd), the drug is distributed equally, the drug in the plasma is in equilibrium with total volume
What is zero order elimination
Elimination process gets saturated after a high dose and only a constant amount is eliminated in urine
What are some examples of drugs that follow zero order elimination
Aspirin, fentanyl, and phenytoin
What order of elimination is followed when >Vmax
Zero order
What is repeated administration
Same doses at the same dosing intervals
Which order of elimination is repeated administration for
1st order
How many half lives must a drug go through to develop a steady state
5
Plasma concentration at a steady state is directly proportional to the ___ and indirectly proportional to ___
Directly proportional to dose and inversely proportional to clearance
Would you want to shorten or lengthen the dosing interval to result in a higher steady state concentration
Shorten
What would have to the steady state if you lengthen dose interval
Gradual decrease of the plasma level and a new lower steady state
What is the purpose of a loading dose
To reach immediate therapeutic concentration, immediate biological effect
What is the loading dose equation
Loading dose= Vd(TC)
What is the loading dose dependent on
Volume distribution and target concentration
What is the loading dose not dependent on
1/2 life and clearance of the drug
Dosing rate= elimination rate- what is the equation
CL (TC)/F
What is the equation for maintenance dose
Maintenance dose= CL(TC)/(F) x dosing interval
