1. Principles Of Pharmacokinetics Flashcards
- Be able to compare and contrast the routes of drug administration; know the factors that influence drug bioavailability (objective)
Answer later
- Understand the properties of a drug and the physiologic processes that play a role in drug absorption, distribution, metabolism and elimination (objective)
Answer later
- Understand the concept of apparent volume of distribution (Vd); know how to use the Vd to calculate drug dosing, including the loading dose; have a general sense of the volumes of total body water, extracellular and intracellular water (objective)
Answer later
- Be able to identify the types of chemical reactions and enzymes involved in Phase 1 and Phase 2 drug metabolism; describe first-pass metabolism (objective)
Answer later
- Understand how changes in physiological states or chemical exposures modify the absorption, distribution, metabolism and elimination of drugs (objective)
Answer later
- Understand onset (latency) of response, duration of action and therapeutic window (objective)
Answer later
Pharmacokinetics (definition)
The actions of the body on the drug are called pharmacokinetic processes
What body does!
Pharmacodynamics (definition)
The actions of the drug on the body are termed pharmacodynamic processes
What drugs do to us!
Applications of Pharmacokinetics
Choice of drug, including during changing drugs (drug switching)
Choice of route of drug administration
Calculation of drug dose and dosing interval
Prediction of drug toxicity
Prediction of the effect of a change in patient health or environment on drug therapeutic actions and toxicity
Drug Disposition
Slide 6 Flow Chart
Pharmacokinetic Processes (ADME)
Absorption
Distribution
Metabolism
Elimination
(Depends on chemical properties and patient-related factors)
Routes of Drug Administration
Oral (PO): most convenient; may have significant first-pass metabolism
Intravenous (IV): 100% bioavailability; most rapid onset of action
Intramuscular (IM): may be painful
Subcutaneous (SC): smaller volumes than IM; may be painful
Rectal: less first-pass effect than oral
Inhalation: often rapid onset of action
Sublingual: rapid onset; minimal first-pass effect
Intrathecal: bypass the blood-CSF barrier and blood-brain barrier; risks of infection and headache
Transdermal: slow absorption; longer duration of action; lack of first-pass effect
Bioavailability
Defined as percent of unchanged drug that reaches systemic circulation from a site of administration
Determined: comparing the area under the curve (AUC) for the graph of blood/plasma concentration vs. time for a given route of administration with the AUC for the graph obtained when the drug is administered intravenously.
Bioavailability= AUC(route/oral)/AUC(iv)
Effect of route of administration on drug bioavailability
IV: 100% IM: 75-100% SC: 75-100% Oral: 5 to <100% Rectal (PR): 30 to <100% Inhalation: 5 to <100% Transdermal: 80-100%
Bioavailability (factors)
- Physiological (i.e first-pass metabolism, blood flow)
- Physiochemical (i.e drug solubility)
- Biopharmaceutical (i.e tablet dissolution, particle size)
Drug Permeation (mechanisms)
- Passive diffusion through cell membrane lipid
- Carrier-mediated transport (active transport or facilitated diffusion)
- Passive diffusion through aqueous-filled pores
- Endocytosis and exocytosis
Passive Diffusion through Cell Membrane Lipid
Most lipid-soluble drugs- simple diffusion
Fick’s Law: (dD/dt)= [KA(Cm-Cs)]/X.
(dD/dt)= diffusion rate
K= constant in cm2/min
A=area of membrane exposed to drug
Cm= drug concentration on outer (GI lumen) side of membrane
Cs= drug concentration on inner (blood) side of membrane
X= thickness of membrane
Most drugs are weak acids or weak bases (review)
Acid is proton (H+) donor
HA= H(+)+(A-)
HA is protonated weak acid (uncharged and more lipid-soluble form)
A- is unprotonated weak acid (charged and more water-soluble form)
Base is proton (H+) acceptor
BH(+)=H(+)+B
BH+ is protonated weak base (charged and more water soluble form)
B is unprotonated weak base (uncharged and more lipid-soluble form)
Henderson-Hasselbalch Equation
PKa-pH= log(protonated/unprotonated)
PH is the pH of milieu surrounding drug
When pH less than pKa, protonated (HA and BH+) forms predominate; in stomach
When pH greater than pKa, unprotonated (A- and B) forms predominate
Variations of Henderson-Hasselbalch Equation
For acidic drugs:
pKa-pH=log(Du/Di)
For basic drugs:
pKa-pH=log(Di/Du)
Du is concentration of un-ionized drug
Di is concentration of ionized drug
Partition Coefficient
Ratio of concentrations of a solute in two immiscible or slightly miscible liquids, or in two solids, when it is in equilibrium across the interface between them
If coefficient goes up, % absorbed goes up
Carrier-Mediated Transport (characteristics of active transport)
Movement against concentration gradient
Rate proportional to drug concentration only when carrier is not saturated
Specificity for type of chemical structure
Occurs from specific site in limited segment of small intestine
Competitive inhibition for structurally similar substrates transported by the same transport mechanism
Inhibited non competitively by substances that interfere with cell metabolism
ATP-binding cassette (ABC) family of transporters: permeability glycoprotein (P-glycoprotein, P-gp)
Transmembrane proteins
Transport variety of endogenous and exogenous molecules across intra and extracellular membranes
3 ABC subfamilies (B,C,G) responsible for efflux of foreign chemicals from cells (including xenobiotics)
P-gp transporter (in luminal membrane of epithelial cells in small intestine) responsible for efflux of drugs from enterocytes, limiting their absorption
P-gp role in resistance to cancer chemotherapy agents
Facilitated Diffusion (characteristics)
Not against a concentration gradient
Occurs for drugs that are analogs of endogenous compounds
Passive Diffusion through Aqueous-Filled Pores
Diffusion via aqueous-filled pore or channel
For molecules of Mr<150-200 Da
Endocytosis and Exocytosis
Only occurs for few substances that are very large or impermeant
Physiological Factors Affecting GI Absorption
Surface Area
GI pH
GI motility/gastric emptying
Blood Flow
Drug Distribution
Distributes into various body compartments depending on physiochemical properties
I.e. Only in extracellular fluid, others in extra and intracellular fluid, others bound to extra and intracellular proteins, lipids…
Drug Distribution
Once in plasma, most drugs gain access to interstitial fluid and intracellular water. Rate and extent depends:
- Plasma protein binding of drug
- Physiochemical properties of drug (pKa and partition coefficient)
- Cardiovascular factors
- Tissue-dependent factors (pH gradient, active transport, non-specific binding, dissolution in fat)
Plasma Protein Binding
Once absorbed, drug can exist in both a free (unbound) and bound state in blood.
Unbound drug+proteindrug/protein complex
Only unbound drug in plasma can penetrate cell membranes
Plasma Protein Binding of Drugs
Neutral and acidic drugs bind to albumin; some basic drugs bind to albumin-organic acids and bases bind different sites
Basic drugs bind to globulins (including a1-acid glycoprotein)
Binding usually reversible, nonselective and competitive
Prior to equilibrium, binding reduces free drug concentration in plasma
Effects of drug physiochemical properties on distribution
Rate and extent of distribution of drug out of plasma depends on:
- Lipid solubility (partition coefficient) of drug
- pKa of drug
Cardiovascular Factors (drug distribution)
Cardiac output
Regional blood flow
Tissue-dependent factors: drug reservoirs (drug distribution)
Cellular reservoir:
Accumulation may be result of binding or active transport (binding reversible)
Fat:
Important reservoir for lipid-soluble drugs, may affect onset and duration of action
Volume of Distribution (Vd)
Volume of fluid (blood or plasma) that would be needed to contain the administered amount of drug at the concentration measured in blood or plasma
Equation Defining Vd
Vd=D/C
Vd is apparent volume of distribution
D is total amount of drug administered
C is concentration of drug measured in blood (serum or plasma)
How to determine the apparent volume of a chamber (body)
- Add known amount of drug to chamber
- Let it equilibrate with the chamber contents
- Take sample (blood) from chamber
- Determine drug concentration in sample
- Calculate volume of chamber
Chamber volume=(amount of drug added)/(drug concentration in the sample)
Total Body Water (normal lean 70kg man)
Total body water 42L (60% of total weight)
Extracellular water 14L (interstitial water 11L, plasma water 3L)
Intracellular water 28L (erythrocytes 3L)
Example Vd Values
Aspirin 11L Erythromycin 55L Gabapentin 58L Propranolol 270L Thiopental 293L Quinacrine 50000L
Purpose of Vd
If know Vd and therapeutic concentration of drug, can calculate how much to give (dose).
Vd=D/C
D=Vd*C
Have to Consider Bioavailability For Dose Calculation
For routes other than IV:
FD=VdC
D= (Vd*C)/(F)
Loading Dose (for any route)
Loading dose= (Vd*C)/(F)
Drug Distribution (additional considerations list)
Blood-brain barrier
Placenta
Distribution Across Blood-Brain Barrier
CNS capillaries are not fenestrated (windows/pores)
Tight junctions and basal lamina of cerebral endothelial cells resist movement of water-soluble and ionized drugs into CNS
Brain capillary endothelial cells express ATP-driven drug efflux pumps (P-gp and BCRP) on the luminal (blood-facing) plasma membrane
CSF proteins do not function as drug reservoir***
Distribution Across Placenta
Highly permeable to drugs
Distributed primarily by simple diffusion
Nutrients and drugs of abuse (alcohol/cocaine) readily cross placenta
Drug Metabolism (intro)
Primary site of biotransformation is liver
Products generally have lower biological activity
Products are usually more polar (facilitating renal excretion)
Two categories of reactions (phase 1+2)
First-Pass Effect/Metabolism
Biotransformation (usually to less active compound) of a drug prior to its entry into systemic circulation (definition)
Most common site is liver; drugs absorbed from GI tract are transported via portal blood to the liver (to be metabolized)
Can also happen in intestinal epithelium
Phase 1 and 2 Metabolism
Phase 1: introduce or unmask polar functional group (OH, NH2, SH)
If sufficiently polar will be excreted; if not, then phase 2 reaction
Phase 2: conjugation and synthetic reactions, addition of an acid (glucuronic) or an amino acid
Hepatic Sites of drug metabolism (microsomal)
Microsomes are vesicles enriched in endoplasmic reticulum membranes that are isolated from liver homogenates by differential centrifugation; microsomes contain enzymes catalyzing oxidation reactions and glucorinide conjugation
Hepatic Sites of drug metabolism (non-microsomal)
Primarily in liver; some enzymes (pseudocholinesterase and acetylating enzymes) display important genetic polymophisms
Phase 1 Metabolism (Mixed Function Oxidases- MFOs)
Also called monooxygenases
Require both a reducing agent (NADPH) and molecular oxygen
2 key microsomal enzymes:
NADPH-cytochrome P450 reductase
Cytochrome P450
Cytochrome P450 Cycle
Extra Information
Oxidative Reactions Examples
Hydroxylation (add OH, phenobarbital) Dealkylation (remove alkyl, morphine) Desulfuration (thiopental) Deamination (amphetamine) Sulfoxide Formation (cimetidine)
Principle CYP isozymes involved in drug metabolism
CYP2C9
CYP2C19
CYP2D6
CYP3A4
2C9 and 2C19
2D6
3A4
Major substate class: Xenobiotics
Phase 2 Metabolism (Glucuronidation)
In liver
Catalyzed by microsomal enzyme UDP glucoronosyl-transferase; UDP glucoronic acid serves as donor
Glucoronides eliminated in bile may be hydrolyzed by intestinal (or bacterial) B-glucoronidase and the free drug may be reabsorbed (prolonging duration of drug action)
Enterohepatic Cycling
Drugs excreted into the gut via the bile may be reabsorbed or eliminated in feces
Water-soluble compounds eliminated in feces, while lipid-soluble, unionized drugs reabsorbed
Process of excretion and reabsorption known as enterohepatic cycling
Modification of Microsomal Metabolism
Inhibition: competitive inhibition between drugs
Induction: 2 types
- phenobarbital-like
- polycyclic hydrocarbon-like
Examples of Inducers of CYP
- Phenobarbital (epilepsy)
- Phenytoin (anticonvulsant)
- Polycyclic hydrocarbons (burning fuels)
- Chronic alcohol
- St. John’s wort (depression)
Examples of Inhibitors of CYP
- Cimetidine (reduce acid to treat ulcers and acid reflux, antihistamine)
- Erythromycin (treat infections and acne)
- Ketoconazole (fungal infections)
- Chloramphenicol (bacterial infections)
- Acute Alcohol
- Grapefruit juice (vitamin C)
Diseases Affecting Drug Metabolism
Hepatitis, cirrhosis and liver cancer-impairment of microsomal oxidases
Decreased hepatic flow secondary to cardiac dysfunction reduces metabolism of drugs whose metabolism is flow-limited
Pulmonary disease and thyroid dysfunction may alter drug metabolism
Drug Elimination (intro)
Primary site is kidneys
Several other sites exist; excretion into bile*
Rate of elimination is proportional to free drug concentration in plasma
Use Henderson-Hasselbalch principle to predict drug excretion in the urine
Diagram slide 71
Clearance
Hypothetical volume of body fluid from which a drug is removed per unit of time
CL=Vd*ke
CL=clearance
Vd=volume of distribution
ke= elimination rate constant
Clearance (defined with respect to a particular route of elimination, or total systemic clearance)
CLsystemic=CLrenal + CLextrarenal
Extrarenal clearance is primarily due to hepatic metabolism and biliary excretion
Clearance (and steady-state concentration in blood)
Inversely related to steady-state drug concentration in blood
Css proportional to 1/CL
Clearance Determinants
- Blood flow to the organ that eliminates the drug
2. The efficiency of the organ in extracting the drug from the bloodstream
Renal Clearance of Drugs
Factors:
- Drug properties: water/lipid solubility, degree of ionization, size, protein binding
- Renal processes: filtration, secretion, reabsorption
Clearance (reduction)
Impairments in cardiac, hepatic or renal function
Effect of renal insufficiency on drug clearance
Plasma half-life vs renal function graph
A-Drug cleared only by kidneys
As renal function tanks, half life exponentially goes up
B-Drug not cleared by kidneys
As renal function tanks, half life stays low and a straight line
Plasma drug concentration profile
Slide 79 blank
Effects of differences in the rate of absorption on bloods levels, latency to response and biological action of drugs
Just a bunch of curves that fall between toxic concentration and therapeutic concentration lines, or below and have varying absorption rates and doses.
