Chapter 11: Pharmacokinetics and Related Topics Flashcards
What are the three phases involved in drug action?
pharmaceutical phase
pharmacokinetic phase
pharmacodynamic phase
_____ phase for an orally administered drug, this includes the disintegration of a pill or capsule in the gastrointestinal tract (GIT), the release of the drug and its dissolution
pharmaceutical
_____ phase includes absorption from the GIT into the blood supply and the various factors that affect a drug’s survival and progress as it travels to its molecular target
pharmacokinetic
______ phase involves the mechanism by which a drug interacts with its molecular target and the resulting pharmacological effect
pharmacodynamic
What are the four main topics of pharmacokinetics?
absorption, distribution, metabolism and excretion
often abbreviated to ADME
_____ are the basic unit of a biological system
Cells
____ are collections of cells with a common function
Tissues
____ are multiple tissue types that have a common role
Organs
_____ are the highest level of organization
Organ systems
What are the 5 systems?
Circulatory, digestive, nervous, skeletal, urinary
True or False: All drugs must be introduced into the body by some method
True
called route of administration (ROA) or route of delivery
What are the 3 different drug delivery methods?
enteral, parenteral, topical
_____ delivery method is entry into bloodstream by a route other than the digestive system
parenteral
-includes intravenous (IV), intramuscular (IM) and subcutaneous (SC)
_____ delivery method is absorption through the digestive system
enteral
includes oral (PO) and rectal delivery
_____ delivery method is applied directly to site of action
Topical
includes auricular (ear), conjunctival (eye) and cutaneous (skin)
What is the route of orally administered drugs (5 steps)?
mouth, throat, stomach and upper and lower intestines (could be absorbed by mucosal membrane in mouth)
most enters stomach containing digestive juices and HCl (pH 1-3)
if drug survives, it enters upper intestine containing digestive enzymes
has to pass through cells lining the intestines
relatively easy for drug to enter capillaries
When is drug is passed through the intestines, it crosses the ____ membrane from intestinal lumen to cell interior then the cross ______ membrane from cell interior to capillary bed.
Apical, Basal
The ______ contains enzymes that are ready and waiting to intercept foreign chemicals and modify them such that they are more easily excreted. This process is called ______.
Liver, drug metabolism
______ is preferred method of drug delivery
Oral
Why can asprin, ASA be absorbed in the stomach?
has pKa of about 3.5
therefore mostly neutral in stomach and can be absorbed
What are the 3 reasons why the presence of food greatly influences rate of drug absorption?
increases the volume of the stomach
raises pH in stomach
slows drug passage into small intestine
What type of digestion occurs in the small intestine?
primarily with enzymatic digestion of proteins and fats
True or False: PH and length decreases as you go down the small intestine.
False, both increase
_____ have a large surface area they present allows for rapid absorption of digestion products.
Villi
What are the 4 advantages of small intestine absorption over stomach absorption
food is more digested, retains less drug
drug spends much greater time in small intestine
higher pH of small intestine more favourable for drug absorption
has a large surface area due to folds, villi and microvilli
What is the effect of grapefruit juice on certain drugs?
can increase amount of drug that reached the circulation
effect due to bergamottin, a coumarin derivative, in the juice
potent inhibitor of cytochrome P-450 3A4 (CYP3A4)
reduces metabolism of the drug before it enters circulation (first pass
drugs absorbed from stomach and small intestine enter the ______ system. It collects blood from the stomach, small intestine, large intestine, spleen and pancreas and delivers it to the liver, from there can enter the general circulatory system.
Hepatic portal
_____ acts as a protective system against xenobiotics
Liver
first pass metabolism leads to ______ bioavailability.
Low
True or False: Drugs can still be absorbed through the large intestine.
False, drugs are usually absorbed before they reach large intestine, if drug is found in feces it can indicate poor absorption
What is the simplified 4 step pathway of oral drugs.
Tablet disintegrates and is released in stomach
Drug absorbed through SI and transported via portal vein to liver
Liver breaks down active ingredient before it reaches the heart
Heart pumps blood with remainder of active ingredient
For efficient absorption in the GIT you need the correct balance of _______.
of hydrophobicity (i.e., fat vs. water solubility)
too polar (_______) will not pass through membrane and too fatty (______) – poorly soluble in gut (fat globules)
hydrophilic, hydrophobic
What is the pharmacokinetic advantage of drugs having amine functional groups?
They are weak bases and are in equilibrium between the ionized and free base forms
Slightly acidic in upper intestine and slightly alkaline in blood
______ was used to determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans
Lipinski’s rule of five
What is the criteria for Lipinski’s rule?
an orally active drug has no more than one violation of the following criteria:
a molecular weight less than 500 Daltons
not more than 5 hydrogen bond donors (HBD) (nitrogen or oxygen atoms with one or more hydrogen atoms)
not more than 10 hydrogen bond acceptors (HBA)
(nitrogen or oxygen atoms)
an octanol-water partition coefficient log P of less than +5
True or False: compounds with good oral bioavailability tend to have more molecular flexibility, as measured by the number of freely rotatable bonds
False, compounds with good oral bioavailability tend to have reduced molecular flexibility
65% of fairly rigid compounds in the collection (those with seven or fewer rotatable bonds) exhibited good-to-excellent oral bioavailability, independent of molecular weight
more than 75% of floppy compounds (those with more than 10 rotatable bonds) had poor oral bioavailability
True or False: Drugs entering the blood supply are evenly distributed round the blood supply within one minute, but are unevenly distributed to different organs.
True
True or False: Drugs have to leave blood supply to reach target organs and tissues
True
body has an estimated 10^10 capillaries with surface area of ____ m^2
no cell is more than ______ μm away from a capillary
capillaries have pores that are ______ nm in diameter that allow most drugs to escape but retains plasma proteins
200, 20-30, 9 – 15
Drugs such as local anaesthetics, enzyme inhibitors and drugs which act on nucleic acids or intracellular receptors need to enter the individual cells of tissues. Therefore, drugs must be ______ enough to pass through the cell membrane unless they are smuggled through by carrier proteins or taken in by pinocytosis
Hydrophobic
What are 3 other distribution factors involved with drug distribution to cells?
excessively hydrophobic drugs absorbed by fatty tissues
ionized drugs may be bound to macromolecules
may be bound to blood plasma proteins (e.g., serum albumin)
Why is it hard for drugs to cross the blood brain barrier (2 reasons)
the blood capillaries feeding the brain are lined with tight-fitting cells that do not contain pores
the capillaries are also coated with a fatty layer formed from nearby cells, providing an extra fatty barrier through which drugs have to cross
True or False: In order to cross the blood brain barrier, drugs must have a minimum number of polar groups or have these groups masked temporarily (prodrug)
True
What drug crosses the blood brain barrier with the aid of a carrier protein?
Insulin
What is lipinski’s rule of 5 for CNS drugs?
Molecular weight (Da) less than 400
Hydrophobicity (logP)
not greater then 5
Hydrogen bond donors (HBD)
not more than 3
Hydrogen bond acceptors (HBA)
not more than 7
_____ drugs will cross the placental barrier most easily
Fat soluble
drugs such as barbiturates will reach the same levels in fetal blood as in maternal blood
True or False: Orally taken drugs must be sufficiently polar to dissolve in the GIT and blood supply, but sufficiently fatty to pass through cell membranes.
True
Most orally taken drugs obey Lipinski’s rule of five and have no more than _____ rotatable bonds.
7
True or False: Highly polar drugs can be orally active if they are small enough to pass between the cells of the gut wall, are recognized by carrier proteins or are taken across the gut wall by pinocytosis.
True
Distribution to the interstitial fluid surrounding tissues and organs is rapid if what?
if the drug is not bound to plasma proteins
Most drugs undergo some form of metabolic reaction, resulting in structures known as _______.
Metabolites
True or False: Metabolites may have no effect, more active affect, or a different effect from the parent drug
True
True or False: A single drug is usually metabolized by multiple enzymes
True, some reactions faster than others, some reactions are reversible or can be reversed by another enzyme
The metabolite most important for elimination of a drug depends on?
the rate and reversibility of each step
Phase I reactions include _____ and phase II reactions include ______.
oxidation, reduction and hydrolysis
conjugation
Phase ______ add fragments to the original drug in a process called including acetylation, sulfonylation, glucuronidation, conjugation with amino acids and conjugation with glutathione
II
Phase _____ usually fragment the drug into smaller molecules that are eliminated more easily.
I
True or False: newly appended fragments form a metabolite with increased polarity for improved clearance
True
How can phase I and phase II reactions work together?
products of phase I reactions contain functional groups such as carboxylic acids, alcohols and amines
these functional groups may serve as handles for attachment of polar fragments during phase II metabolism
True or False: many drugs are metabolized by only phase I or only phase II processes
True
What type of reactions are catalyzed by cytochrome P450 enzymes?
Oxidation (therefore phase I)
reactions catalyzed by cytochrome P450 enzymes can involve the oxidation of ______, ______, ______, ______ and other atoms
carbon, nitrogen, phosphorus, sulphur
_______enzymes are chiefly responsible for metabolic reactions involving oxidation at nucleophilic nitrogen, sulphur and phosphorus atoms, rather than at carbon atoms
Flavin-containing monooxygenases
True or False: monoamine oxidases are involved in the deamination of catecholamines
True
other important oxidative enzymes include ______ and ______.
alcohol dehydrogenases and aldehyde dehydrogenases
reductive phase I reactions are less common than oxidative reactions, but reductions of ______, ______, ______, and ______ functional groups have been observed in specific drugs.
aldehyde, ketone, azo and nitro
hydrolysis of _____and _____ is a common metabolic reaction, catalyzed by esterases and peptidases, respectively
Esters and amides
Most phase II reactions are conjugation reactions catalyzed by ______ enzymes
Transferase
usually results are inactive, but there are exceptions
True or False: Glucuronic acid conjugation is excreted in the urine, but may also be excreted in the bile if the molecular weight is over 300
True
_____-glucuronides by reaction with UDFP‑glucuronate such that a highly polar glucuronic acid molecule is attached to the drug
sulphonamides, amides, amines and thiols can react to form ____‑ or _____‑glucuronides
_____-glucuronides are also possible in situations where there is an activated carbon centre next to carbonyl groups
O
N or S
C
Sulphate conjugation is less common than glucuronation and is restricted mainly to ______, ______, _______, and _______.
phenols, alcohols, arylamines and N-hydroxy compounds
primary and secondary amines, secondary alcohols and phenols form ______ conjugates, whereas primary alcohols form ______ sulphates, which can act as toxic alkylating agents
stable, unstable
aromatic _______ and ______ also form unstable sulphate conjugates that can be toxic
hydroxylamines and hydroxylamides
In amino acid conjugation, drugs bearing a ______ group can become conjugated to amino acids by the formation of a peptide bond
carboxylic acid
in most animals, ______ conjugates are generally formed, but _______ is the most common amino acid used for conjugation in primates
glycine, glutamine
electrophilic functional groups, such as epoxides, alkyl halides, sulphonates, disulphides and radical species, can react with the nucleophilic thiol group of the tripeptide glutathione (Glu-Cys-Gly) to give _______, which can be subsequently transformed to mercapturic acids
glutathione conjugates
the glutathione conjugation reaction can take place in most cells, especially those in the ____ and _____, and is catalyzed by _______.
Liver, kidney, glutathione transferase
______ is important in detoxifying potentially dangerous environmental toxins or electrophilic alkylating agents formed by phase I reactions
Glutathione conjugation
glutathione conjugates are often excreted in the _____, but are more usually converted to _______ conjugates before excretion
bile, mercapturic acid
Methylation and acetylation are important phase II reactions that ______ drug polarity
decrease
True or False: An ideal drug should be resistant to drug metabolism
True
acetaminophen metabolism produces toxic ______
NAPQI
What is an example of metabolites that bind the same target as the unchanged drug and do not necessarily have the same activity
morphine (and heroin) are metabolized by glucuronidation
morphine-3-glucuronide (M3G) is considered largely inactive (90%)
morphine-6-glucuronide (M6G) is thought to be responsible for pain relief (10%)
Why do significant numbers of women might not receive optimal benefit from tamoxifen treatment?
4-hydroxytamoxifen and endoxifen are 30-100x more potent than tamoxifen and are generated by cytochrome P450 isozymes in the liver
due to genetic polymorphism of CYP2D6, there are large variations among patients in both therapeutic efficacy and side effects
True or False: CYP2D6 interacts with specific selective serotonin reuptake inhibitors (SSRIs), frequently used to prevent the hot flushes experienced by up to 45% of patients taking TAM.
True
In 1966, _____ synthesized tamoxifen
Dora Richardson
What is the metabolic resistance of tamoxifen? (2)
mutation of CYP2D6 to reduce activation of prodrug
administration of SSRIs and other drugs that inhibit CYP2D6
What is the intrinsic resistance of tamoxifen?
much less effective in controlling the growth of tumours that are progesterone-receptor negative and have high levels of membrane growth factor receptors (GFRs) that can activate phosphorylation cascades via Src, Akt and PAK
What is the acquired resistance of tamoxifen?
tumours that initially respond to tamoxifen can acquire resistance to tamoxifen by increasing the level of GFRs that phosphorylate Src and Akt
_____ is any process, typically irreversible, that diminishes the amount of a drug that is distributed throughout the body
Elimination
What are the 5 ways drugs can be eliminated from the body?
Gas through lungs
Blood supply back through intestines in bile produced by liver
10-15% can be lost through sweat
Saliva and breast milk
Kidneys
What is the principal route where drugs are excreted?
Kidneys
_______ increases drug concentration in lumen
_______ decreases drug concentration in lumen
_______ increases drug concentration in lumen
Glomerular filtration
Tubular reabsorption
Tubular secretion
Renal Excretion =
Filtration – Reabsorption + Secretion
What are the 6 routes of drug administration?
oral
sublingual
rectal
epithelial
inhalation
injection
True or False: The oral route places the greatest demands on the chemical and physical properties of the drug
True
drugs taken as pills or capsules are mostly absorbed in the ______.
Upper intesitne
_______ binds strongly to calcium ions, which inhibits absorption, so foods such as milk should be avoided
Tetracycline
Why could there be complications when taking cholestyramine?
binds to warfarin (anticoagulant) and also to levothyroxine sodium (thyroid drug)
What is an advantage of drugs absorbed through mucous membranes?
avoids the digestive and metabolic enzymes encountered during oral administration
What are two examples of drugs absorbed through the mucous membranes?
heart patients take glyceryl trinitrate (nitroglycerin) by placing it under the tongue (sublingual administration)
the opiate analgesic fentanyl has been given to children in the form of a lollipop
Why may a patient receive rectal admission medicine?
unconscious, vomiting or unable to swallow
What are 3 problems associated with rectal admission?
the patient may suffer membrane irritation
interruption of absorption by defecation
lack of patient acceptability
it is also possible for some of the drug to be absorbed through the skin (transdermal absorption ) and to enter the blood supply, especially if the drug is _______.
Lipophilic
ie, nicotine patches, hormone replacement therapies for estrogen
____ are applied topically to treat local skin irritations
Steroids
Advantages of drug inhalation?
drugs administered by inhalation avoid the digestive and metabolic enzymes of the GIT or liver
True or False: assuming the drug is able to pass through the hydrophobic cell membranes, absorption is rapid and efficient because the blood supply is in close contact with the cell membranes of the lungs
True
ie, general anaesthetic gases
anti-asthmatic drugs are administered as ______ allows it to be delivered to the lungs in far greater quantities than if they were given orally or by injection
Aerosols
Why is injection faster than oral administration ?
reaches the blood supply more quickly
What type of drug administration has more accurate absorption
injection, oral route has a level of unpredictability owing to the first pass effect
Why is injection more hazardous
unexpected reaction to a drug and there is little that can be done to reduce the levels once the drug has been injected
What are the two disadvantages of injection?
include potential pain or discomfort for the patient and the requirement of trained staff using aseptic techniques for administration
What are the 4 types of injection?
Intramuscular, subcutaneous, intravenous, intradermal
What are 3 examples of drug implants?
continuous osmotically driven minipumps for insulin
Gliadel is a carmustine wafer that has been implanted into the brain to administer anticancer drugs directly to brain tumours
polymer-coated, drug-releasing stents have been used to keep blood vessels open after angioplasty
______ drugs that are unable to cross cell membranes are given by injection
Polar
What is the range within maximum and minimum concentrations known as?
Therapeutic window
What are the factors that can alter dosage ?
differences of age, sex and race
diet, environment and altitude
obesity – it can be very difficult to estimate how much of a drug will be stored in fat tissue and how much will remain free in the blood supply
the precise time when drugs are taken may be important because metabolic reaction rates can vary throughout the day
True or False: if a drug has a half-life of 1 h it takes 7 h for the level to fall below 1%
True, not linear with time
Why is it important to know the half life of a drug?
to calculate the frequency of dosing required to reach and maintain these levels
In general, the time taken to reach a steady state concentration is _______ the drug’s half-life
6 times
What are the four factors that effect bioavailability?
absorption –bioavailability is directly related to absorbance
first-pass metabolism – first-pass metabolism lowers bioavailability
chemical instability – may be destroyed by the HCl or enzymes in the GIT
manufacturing methods – particle size, excipients, compression pressure, moisture content, drug polymorphism all affect bioavailability
