Exam IV: Pharmacokinetics Flashcards
Metabolism
Biotransformation, may change the substance to a more active form or inactive form
Changing to another form of the drug so it could be excreted
NOT breaking drug done/degradation
Biotransformation
Humans are exposed to a wide variety of foreign compounds called xenobiotics
Environmental chemicals, food toxins, therapeutic drugs, “recreational” drugs
Biotransformation: the body needs to process xenobiotics for elimination
Drug Characteristics
Most drugs are HYDROPHOBIC- when they are ionized, they do not favor movement past barriers and are excreted, therefore eliciting no effects
Short half like means no efficacy
Most drugs are lipophilic because this characteristic helps them cross the membrane and get to the site of action
Characteristic also makes drugs hard to eliminate
If lipophilic drugs are not processed, drugs will “stick” around (to plasma proteins, membranes, brush border of the kidney) and accumulate = drug toxicity
Biotransformation: 2 Functions and 2 Phases
Biotransformation has two functions:
Metabolize the drug, detoxify the drug, and render it less toxic (metabolism)
Eliminate the drug from the body (disposition)
Biotransformation is carried out by enzymes, grouped into two phases:
Phase I, takes care of metabolism and some detoxification; makes drug more polar
Phase II, takes care of elimination by making the drug more readily excreted (primarily by the kidney)
Sites of Metabolism
Liver is the main organ and the most active, but not the only one: kidney, lungs, skin, intestines
First-pass effect:
Good-prevention of a disease with short systemic effect; ie. aspirin for preventing cardiovascular disease
Bad-reduce bioavailability of the drug if given orally; Don’t give orally; design a prodrug
Drug Recycling
Some drugs are conjugated by the liver, released into the bile system, absorbed by the intestine where it undergoes hydrolysis (to remove conjugate), and reabsorbed back into the system
Enhance drug effectiveness
Increase toxicity
Can calibrate dose to reduce drug toxicity
Phase I Reactions
Enzymes that put a polar group onto the drug to make the drug more polar (hydrophilic) and allow the drug to be conjugated
Includes oxidation, reduction, and hydrolysis reactions
Majority of the enzymes are heme protein mono-oxygenases of the cytochrome P450 (CYP) gene family
CYP enzymes are responsible for ~75% of all drugs used today
P450 refers to the 450nm absorption peak of these enzymes when they bind carbon monoxide
Cytochrome P450
Heme-containing membrane proteins that localize to the endoplasmic reticulum
Closely associated with NADPH-cytochrome P450 reductase- required for CYP to work
Reductase is a flavoprotein that donates electrons for CYP oxidation-reduction reaction facilitated by lipid bilayer of membrane
Cytochrome P450 Pathway
- Oxidized CYP combines with drug (RH) to form binary complex
- NADPH donates electron via reductase and reduces CYP
- NADPH donates electron via reductase to reduce O2 to form “activated oxygen”-CYP complex
- CYP breaks molecular oxygen into two atoms and transfers activated oxygen to the drug substrate to form the oxidized product
RH + O2 + NADPH + H+ results in ROH + H2O + NADP+
Cytochrome P450 Classification
Classification of P450 enzymes is based on sequence homology
Same family if sequence homology >40%
Most important families are: CYP1, CYP2, CYP3, CYP4
Each family is subdivided into subfamilies by letter ie. CYP3A
Each enzyme is given a number
3A4 alone is responsible for >50% of the prescription drugs metabolized by the liver
Others of importance: 2D6, 2C, 1A2, 2E1
CYP Induction and Inhibition
CYP enzymes can be induced or inhibited by drugs
Drugs can be the same ones that the CYP enzymes metabolize
Induction is transcriptional activation of the enzyme
Inducers are usually CYP specific ie. increase CYP2E1 but not CYP2C
Accelerate drug metabolism:
If metabolize active drug to pro drug, reduce bioavailability and reduce efficacy
If metabolize pro-drug to active drug, increase bioavailability and increase toxicity
Cytochrome P450 Inducers
Tobacco smoke, charcoal broiled meat Barbiturates (anxiolytics) Ethanol Steroids Fibrates (LDL lowering drugs)
Cytochrome P450 Inhibitors
Some drugs inhibit the enzyme primarily by binding to the heme moiety of the enzyme
Some substrates are suicide inhibitors and irreversibly inhibit CYP via covalent binding to the heme or protein portion of the enzyme
Suicide inhibitors: bind and will not go off
Cytochrome P450 Inhibitor Examples
Cimetidine (gastric ulcer medication) and ketoconazole (anti-fungal medication) bind tightly to heme and reduce metabolism of endogenous substrates
Macrolides (one class of antibiotic) are metabolized to reactive species, complex with heme iron and rend it catalytically inactive
Phase II Reactions
Parent drugs or drugs that have undergone phase I biotransformation may contain chemical groups that allow them to undergo conjugation reactions with endogenous substances
Hydroxyl (-OH), amine (-NH2), carboxyl (-COOH)
Conjugates are polar molecules that are often inactive and readily excreted
Phase II are very polar molecules and are made into very hydrophilic
Phase II Conjugation Formation
Conjugate formation involves high energy intermediates and transfer enzymes in the cytosol or microsomes
Conjugation reactions may lead to formation of reactive species responsible for drug toxicity
Most of the time the conjugation reactions are safe and elicit excretion
Conjugation: glucoronidation, acetylation, glutathione conjugation, glycine conjugation, sulfation, methylation, water conjugation
Drug Toxicity Example
95% of acetaminophen (Tylenol) goes through conjugation: glucuronidation and sulfation (phase II first)
5% of acetaminophen goes through P450 metabolism into a very reactive agent (NAPQI) (phase I first)
Normally, GSH conjugates NAPQI for excretion
During overdose, conjugation reaction is saturated, more acetaminophen goes through P450 metabolism and eventually saturates GSH conjugation
NAPQI accumulates and forms protein adducts in the liver, leads to hepatic necrosis and eventually death
Alcoholics more susceptible because ethanol induces the same P450 and shifts the reaction to P450 metabolism
Tylenol Overdose Treatment
Glucuronidation, sulfation, and glutathione conjugation are saturated during overdose
Give N-acetylcysteine (NAC), provides –SH group to bind toxic protein, create cysteine conjugates for excretion
If NAC given within 8-16 hours of OD, patient is saved
GSH administration not effective because it does not cross cell membrane
Factors that Alter Biotransformation
To achieve effective therapeutic levels, dose and frequency of drug administration vary between individuals
Factors that affect drug metabolism and elimination
Genetic Factors (Race and Ethnicity)
Age and Sex
Diet and Environment
Metabolic Drug Interactions
Diseases Affecting Drug Metabolism
Genetic Factors
Genetic polymorphisms exist in individuals that alter their ability to metabolize drugs
Phase I enzyme polymorphisms
2D6, 2C19, 2C9
Phase II enzyme polymorphisms
Slow acetylator phenotype
Genetics of race and ethnicity affect drug metabolism
Phase I 2D6 Polymorphism: UM Phenotype
Ultrarapid metabolizers (UM) phenotype displays in 1/3 of Ethiopians and Saudi Arabians Patients require 2x-3x dose of nortriptyline (antidepressant) Poor response to nortriptyline correlates with higher incidence of suicides In UM phenotype, prodrug codeine is metabolized much faster to morphine (sedative), resulting in faster sedation and more abdominal pain
Phase I 2D6 Polymorphism: Phenotypes & PM
4 different phenotypes: ultrarapid metabolizers, extensive metaboilizers, intermediate metabolizers, and poor metabolizers
Tamoxifen: some people respond well to it, but because it is inactive when entering the body, the active drug can prevent and treat breast cancer.. But in some people they can have a relapse in poor metabolizers; efficacy relies on 2D6 metabolism of tamoxifen to endoxifen
Phase I 2C19 Polymorphism: Mephenytoin in EM and PM
Poor metabolizer (PM) phenotype occurs in 3-5% of Caucasians and 18-23% Japanese population Mephenytoin is synthesized as racemic mixture of 50% R-form and 50% S-form
Extensive metabolizers (EM), S-form is hydroxylated by 2C19, conjugated by glucuronidation, and excreted into the urine R-form is slowly demethylated into the active nirvanol
Poor metabolizers (PM) totally lack hydroxylation activity (2C19) and both S- and R-form accumulate to cause profound sedation and ataxia
Phase I: 2C9 Polymorphism
Two types of mutation:
1. Impaired formation, 2. Inactive protein
Occur in 6-13% of Caucasians
2C9 polymorphism increases patient sensitivity to warfarin, can lead to excessive bleeding and death
Phase I 2C9 Polymorphism: Warfarin
Warfarin: anticoagulant that inhibits vitamin K repoxide reductase
Warfarin is formed into S and R forms
R form enzymes CYP2C19, CYP1A2, and CYP3A4 make the metabolites inactive- good thing
S form is 3-4x more potent than R form
When you have the CYP2C9 mutation, the drug will go through the negative effect pathway more than the metabolite pathway, so they will not clot and have overdose; a big portion of the Chinese population has this polymorphism
Phase II: Slow Acetylator Phenotype
Occur in 50% of white and blacks
More frequent in Northern Europe
Less frequent in Asians and Inuit (Eskimos)
Slow acetylator phenotype is associated with higher incidence of isoniazid-induced peripheral neuritis, autoimmune disorders, and bicyclic aromatic amine-induced bladder cancer
50% are rapid and 50% are slow inactivators
Isoniazid goes through Phase II before I
Phase I to acetylation is non toxic, but P450 oxidation forms a lot of reactive metabolites and cause many side effects
Drug Metabolism: Infants
A newborn child is capable of carrying out many, but not all, biotransformation reactions
Infants are still developing and have intact Phase I reactions, but Phase II is not so good
Chloramphenicol (antibacterial) excretion requires oxidative transformation followed by conjugation
Oxidative metabolite is toxic, if not conjugated, can accumulate and cause gray baby syndrome
Liver is still developing so get accumulation of oxidative metabolite because they have phase I but not phase II = causes gray baby syndrome; no longer used for infants
Drug Metabolism: Elderly
Elderly have reduced metabolic capacity due to decline in liver mass, hepatic blood flow, and reduced renal function
Elderly also are most likely to be taking multiple medications that may contribute to drug-drug interactions
Liver is major organ for phase I and II, but since loss of function, the drug can accumulate in the body and more likely to have an overdose of meds especially because multiple meds taken
Drug Metabolism: Men vs. Women
Men can metabolize drugs more easily than women
Androgenic hormone levels are associated with sex-dependent differences in drug metabolism
Women when pregnant, fetus is susceptible to overdose because many drugs are teratogenic
Drug Metabolism: Diet & Environment
Diet and environment can alter drug metabolism by inducing or inhibiting P450 enzymes
Grapefruit juice inhibits 3A4
St. John’s wort (herbal medication for mood stabilization) induces 3A4
Polycyclic aromatic hydrocarbons in cigarette smoke or eat smoked meat (BBQ) induces 1A1, 1A2, 2E1
Lead induces heme-oxygenase enzyme that breaks down P450 (in houses built before 1978)
Metabolic Drug Interactions
May happen when a patient is taking multiple medication
Possible scenarios:
1. Two drugs metabolized by the same enzyme, one with lower affinity for the enzyme accumulates and can cause toxicity
2. One drug is an inducer of the enzyme and can increase or decrease efficacy of the other drug
3. One drug is an inhibitor of the enzyme and can reduce metabolism of the other drug
Examples of Drug Interactions
Rifampin (antibacterial/for TB) induces 3A4- metabolizes estrogenic component of estrogen-based contraception
3A4 metabolizes erythromycin (macrolide antibiotic)- metabolite complexes with and inhibits 3A4
Interaction inhibits metabolism of other drugs metabolized by 3A4
Methanol intoxication results in blindness or death because its metabolite formaldehyde is highly toxic
Ethanol competes with methanol for oxidation by alcohol dehydrogenase
Delayed methanol oxidation reduces toxic metabolite and allows enough time for renal excretion
Diseases Affecting Drug Metabolism: Liver, Heart, Thyroid, and Kidney Diseases
Liver is the main site of biotransformation Liver diseases (hepatitis, cirrhosis, cancer) will decrease enzymes required for metabolism
Cardiac diseases can compromise blood flow to reduce drug delivery to the heart for effect and to the liver for metabolism
Thyroid hormone regulates rate of metabolism in the body
Hyperthyroidism increases drug metabolism
Hypothyroidism decreases drug metabolism
Kidney diseases decrease drug excretion
Excretion
Removal from the body
Oxidation/reduction and conjugation/ hydrolysis reactions enhance the hydrophilicity of a hydrophobic drug and its metabolites =enable drugs to be excreted as hydrophilic drugs
Most drugs and metabolites are cleared from the blood circulation and eliminated from the body through renal and biliary excretion
Major through renal and minor through bile
Many oral drugs are incompletely absorbed and the drug is eliminated in the feces
Renal Excretion Pathways
Drugs may be:
1. Filtered at the glomerulus
2. Secreted by the proximal tubules
3. Reabsorbed from tubules back into the blood
4. Excreted in the urine
Some tubules have a secretion function and can go into the blood, others have absorption functions
Renal Excretion: Rate of Elimination
Rate of drug elimination through the kidneys depends on the balance of drug filtration, secretion, and reabsorption rates
Only the free form of drug is filtered into the renal tubules
Amount of drug filtered is affected by renal blood flow, glomerular filtration rate, and plasma protein binding
Increased renal blood flow, increased glomerular filtration rate, and reduced plasma protein binding will cause drug to be excreted more quickly
Elderly individuals or individuals with reduced kidney function will reduce drug excretion and increase drug accumulation= toxicity!
Organic Acid Excretion
Organic acids/anions (OA) enter the cell from the blood through OAT’s (organic acid transporter)
OA leave the cell across the apical membrane (tubular side), most likely by OATs
Alpha-KG enters the cell from the blood with Na+ via the NaDC, as well as in exchange for OA on the tubular side
Alpha-KG exits the cell due to the accumulation of OA within the cells, so keeps exchanging alpha-KG on the blood side
Organic Base Excretion
Organic cations (organic bases, OC) enter the cell from the blood through OCT’s
OC leave the cell across the apical membrane (tubular side) by OCTN
Bases allow for transportation outside the tubules
Cells in kidneys have select transporters for cations and they secrete weak acids or bases
Renal Excretion: pH Trapping
Urinary excretion of a drug may fall as the drug is reabsorbed in the proximal and distal tubules
Reabsorption is limited primarily by pH trapping
Renal tubular fluid is acidic beyond the proximal tubule, which favors trapping of ionic form of weak bases
Modify urine pH to increase ionized form of the drug so it cannot be reabsorbed by the renal tubules (ionized drug is trapped in the lumen and excreted into the urine)
If you have reabsorption of the drug it goes back to the systemic circulation
If you make the drug more ionized it will stay in the tubules and urine and not get reabsorbed and enhance elimination
Pharmacokinetics of Excretion
Plasma concentration of the drug dictates the ability of the drug to reach its target organ in an effective concentration
Drug clearance is what is clinically relevant
Clearance of a drug (from the blood) is the parameter that most significantly limits the time course of action of the drug at its target site
Defined as rate of elimination of the drug from the body relative to the concentration of the drug in the plasma
To reach the target organ at certain concentration
Clearance: different from excretion (elimination from the body) but clearance is elimination of drug from the blood
The blood is the distribution system
Kinetics of Elimination
Most drugs follow a 1st order elimination
Constant percentage of drugs eliminated per unit time
A small number of drugs follow a 0th order elimination
Constant amount of drugs eliminated per unit time
Alcohol, aspirin
1st Order Elimination
Can be used to determine elimination half-life of a drug
Elimination half-life is defined as the amount of time over which the drug concentration in the plasma decreases to one-half of its original value
Allows clinicians to estimate the frequency of dosing required to maintain the plasma concentration of the drug in the therapeutic range
After drug infusion, drugs are eliminated from the body after five elimination half-lives via 1st order kinetics
Altering Half Life
Factors that can alter half-life:
1. Changes to volume of distribution, such as age, muscle mass, adipose tissue (fat deposition)
2. CYP enzyme induction or inhibition by diets or drugs
3. Organ failures:
Liver failure reduces enzyme function and biliary excretion
Heart failure reduces drug delivery to organs for clearance
Kidney failure reduces drug filtration, secretion, and excretion
Organ Failures: reduced clearance
Half Life Equation
t1/2 = (0.693 x Vd) / Clearance
Clearance is determined by excretion, metabolism, and filtration
Reduced excretion will reduce clearance
Therapeutic Dosing
Maintain the peak (highest) plasma drug concentration below the toxic concentration, and the trough (lowest) drug concentration above the minimally effective level
Whether maximal or minimal, doesn’t matter as long as in range
Dosing Frequency
Continuous infusion is the most efficient (IV, SC pump, oral sustained-release)
Small frequent doses are more efficacious, but are inconvenient
Large infrequent doses are more likely to cause drug toxicities and reach sub-therapeutic drug levels but patients are more likely to be compliant
Optimal Dose: typically maintain steady-state plasma drug concentration within the therapeutic window of drug
Steady State
Steady-state is reached when rate of drug input equals to its output
Affected by bioavailability, clearance, dose, and dosing interval (frequency of administration)
Steady-state is reached after 4-5 half-lives
Time to reach steady-state is dependent on T1/2- if you have a higher T1/2, it takes longer to reach steady state
Steady State Equation
Steady State (Css) = (bioavailability x dose) / (interval of dose x clearance)
Css= target concentration
Since T1/2 = (0.693 * Vd) / Clearance
If you have a higher T1/2, it takes longer to reach steady state
Loading Dose & Vd
Plasma drug concentration initially increases due to administration and then drops due to tissue distribution
If initial dose fails to take account of volume of distribution, therapeutic levels may not be reached promptly
Initial loading dose of drug may be administered to compensate for distribution- usually one or two high bolus dose
Loading Dose
In the absence of loading dose, requires four to five elimination half-lives for tissue distribution and drug concentration to reach steady-state in the plasma
Loading dose provides sufficient amount of drug in the beginning to attain a therapeutic drug concentration in the blood and tissue after one or two doses (IV doses usually)
Loading Dose Formula
Loading Dose = Vd x C steady state
Maintenance Dose
Once steady-state drug concentration is achieved in the plasma and tissue, dose needs to be adjusted to only replace the amount of drug that is lost through metabolism and excretion
Maintenance dose is dependent on drug clearance
Administration of a dose rate greater than the maintenance dose rate will yield greater input than output
Drug accumulation and toxicity
May lead to saturation kinetics (1st order becomes 0th order due to saturation of metabolic enzymes)
Maintenance dose is usually given orally, but loading dose is IV
INCLUDE bioavailability in the maintenance dose
