Chapter 1 Flashcards
What are the four basic processes of pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Elimination
What determines the bioavailibility of a drug?
ADME (Absorption, Distribution, Metabolism, Elimination)
What is bioavailibility?
how much of the drug that is administered actually reaches its target
what does the kinetics part of ‘pharmacokinetics’ refer to?
movement and time
What are the three ranges that drug concentrations in blood can be?
- ineffective range
- therapeutic range
- toxic range
What does drug absorption refer to?
Processes and mechanisms by which drugs pass from the external world into the bloodstream
What are the two categories of ways that drugs can be administered?
- Enteral routes (administration involving the GI tract)
2. Parenteral (routes of administration that do NOT involve the GI tract)
List the 2 enteral routes
- Orally
2. Rectally
List the 4 parenteral routes
- Injected
- Inhaled
- Absorbed through the skin
- Absorbed through mucous membranes
What is insufflation
“snorting,” or sniffing, the drug, with the drug depositing on the oral or nasal mucosa (note to review this because I feel like it might be more broad)
Drugs administered orally in liquid form absorb faster than tablet (true or false)
true
by which process are drug molecules absorbed across the intestinal mucosa?
passive diffusion: they pass from an area of high concentration to one of lower concentration
In order to be absorbed through the intestinal mucosa a drug must be
lipid soluble (at least to a small degree)
What is pharmacokinetics?
What is pharmacodynamics?
What is pharmacokinetics = how drugs move through the body.
What is pharmacodynamics = ow drugs exert their effects in the body (mechanisms of action)
What is first pass metabolism?
Class explanation: A majority of the blood supply leaving the area of the stomach and upper intestines goes directly to the liver (enterohepatic circulation) where many drug molecules (up to 60% of those absorbed) are metabolized before they can be distributed to the body and the brain (hepatic first pass).
Textbook explanation: The process by which nutrients (and drugs) from the intestines are absorbed into veins, which collect into the hapatic vein, which transports them to the liver as a first stop before going to other organs
Why should caution be taken when having grapefruit juice with a drug taken orally?
Because over 85 drugs have an interaction with a component of grapefruit juice (furanocoumarin), which inhibits an enzyme that metabolizes the drug
What are some of the disadvantages of oral administration?
- Can lead to vomiting/stomach distress
- difficult to predict how much drug will be absorbed because of (1) differences across people (2) differences in manufacturing
- some drugs cannot be administered this way because they are destroyed by stomach acid
What are some of the disadvantages to rectal administration?
Absorption, is irregular, unpredictable, and incomplete
can irritate the membranes that line the rectum
Why is inhalation a popular route of administration for recreational drugs?
- Large surface area of lungs with lots of blood flow mean rapid absorbtion
- The blood flow from the lungs goes almost directly to (left side of heart then into aorta and arteries carring blood to the brain) the brain, which makes onset even faster than intravenous administration
- This rapid effect on the brain is highly reinforcing
What is a benefit of transdermal administration?
It allows for slow, continuous absorption over many hours (or days), which may limit side effects associated with rapid rise and fall of drug concentrations in blood plasma
What are the 4 types of administration by injection?
- Intravenous (vein)
- Intramuscular (muscle)
- Subcutaneous (just under skin)
- Spinally
What features are shared by all injection methods?
more rapid repsonse than oral, easier to control dosage than oral
What are the advantages and disadvantges of Intravenous
Advantages:
- Valuable for emergency use
- Permits titration of dosage (start low and increase)
- Can administer large volumes and irritating substances when diluted
Disadvantages:
- Increased risk of adverse effects
- Must inject solutions slowly as a rule
- Not suitable for oily solutions or insoluble substances (could result in embolism)
What are the advantages and disadvantges of Intramuscular
Advatanges:
1. Suitable for moderate volumes, oily vehicles, and some irritating substances
Disadvantages:
- Precluded during anticoagulant medication
- May interfere with interpretation of certain diagnostic tests (for example, creatine phosphokinase)
What are the advantages and disadvantges of Subcutaneous
Advatnages:
1. Suitable for some insoluble suspensions and for implantation of solid pellets
Disadvantages
- Not suitable for large volumes
- Possible pain or necrosis from irritating substance
What are the advantages and disadvantges of Epidural
Advantages
1. Limited exposure of brain (localized effect)
Disadvantages
1. Dural puncture or nerve damage, bleeding, or infection
How quickly does a drug given intramuscularly take action?
- Prompt action from aqueous solution
2. Slow and sustained action from repository preparations
How quickly does a drug given subcutaneously take action?
- Prompt action from aqueous solution
2. Slow and sustained action from repository (depot) preparations
Why are epidural injections called epidurals?
Because they are injected into a space between the dura mater and the surrounding bones of the vertebra called the ‘epidural space’
What are the spinal meninges and what are they called?
They are 3 layers of tissue membranes that protect the brain and spinal cord
- Pia mater (innermost)
- Arachnoid mater (middle)
- Dura mater (outermost)
Where are intrathecal injections injected into?
subarachnoid space
where is cerebrospinal fluid (CSF) found?
subarachnoid space (between the arachnoid mater and the pia mater) and the ventricular system around and inside the brain and spinal cord
How often does an average-size adult pumps a volume of blood that is roughly equal to the total amount of blood in the circulatory system?
every minute
Where is cerebrospinal fluid produced
Most of the CSF is produced by the choroid plexus (lining) of the lateral, third, and fourth ventricles and circulates through the subarachnoid space (between the arachnoid mater and the pia mater) and around the brain, and is absorbed into the superior sagittal sinus of the peripheral bloodstream across the arachnoid villi.
How much CSF is in the brain?
approximately 140 milliliters
What is the function of CSF?
- Reduced pressure at base of brain
- protective cushion against impact
- circulates nutrients/chemical substances
- removes waste products
- transports hormones
How often is the entire CSF volume is produced and excreted into the blood
every 4-5 hours
What does a drug need to cross in order to to enter CSF?
choroid plexus, which forms the blood–CSF barrier
What are the four types of membranes in the body affect drug distribution?
- cell membranes
- walls of the capillary vessels in the circulatory system
- the blood–brain barrier
- the placental barrier.
Cell membranes are an important barrier for the passage of drugs in which 4 situations?
- from the stomach and intestine into the bloodstream
- from the fluid that closely surrounds tissue cells into the interior of cells
- from the interior of cells back into the body water, and
- from the kidneys back into the bloodstream.
How do drugs pass from the blood into body tissue?
Through Capillaries which has small pores between
cells (cle s or fenestra) that allow passage of small molecules
How large are the poresin capillaries?
between 90 and 150 angstroms
Why is the transport of drug molecules between plasma and body tissues independent of lipid solubility?
because the capillary cell membrane pores are large enough for even fat-insoluble drug molecules to penetrate
What are the only type of drugs that do not readily penetrate capillary pores and why?
drugs that bind to plasma proteins because red blood cells and plasma proteins are too large to travel through the capillary pores
What does the rate at which drug molecules enter body tissue depend on?
- rate of blood flow
2. the ease with which drug molecules pass through the capillary membranes
Do all capillary walls have pores?
No, the ones in the blood brain barrier do not.
The rate of passage of a drug into the brain is generally determined by
- the size of the drug molecule
2. its lipid (fat) solubility.
To penetrate the blood brain barrier a drug must pass through
The wall of the capillary
The membranes of the astrocytes of the glial sheath
How do larger substances (e.g., iron, insulin) cross the blood brain barrier?
Transcytosis:
attach to a receptor which forms a vesicle and transports it across
drugs primarily cross the placenta through?
passive diffusion
True or false: the placenta is a barrier to drugs?
False they are generally present in levels similar to the mother
List 4 main routes through which drugs can leave the body (routes of elimination)?
- Kidneys (renal/uniary)
- Lungs
- Bile
- Skin
What is the main route of drug elimination?
Kidneys: Renal (urinary) excretion of drug metabolites produced by the hepatic (liver) biodegradation of the drug
What needs to happen for lipid soluble drugs to be passively excreeted?
biotransformation: they are metabolically transformed into a form that can be excreted by enzymes in the liver:
- more water soluble
- bulkier
- less biologically active
What are the 2 steps involved in biotransformation?
- Phase I reactions: the P450 System
2. Phase II reactions, or conjugation
What is the P450 system?
A system of enzymes (cytochrome P450 enzymes) in the liver that are responsible for phase 1 biotransformation
Where are the P450 enzymes located?
they are located on hepatocytes (liver cells) on
their smooth endoplasmic reticulum
What is the main function of P450 enzymes?
How is this function executed?
to turn lipophilic fat-soluble drugs into more water-soluble compounds
this is done by changing the drug molecule into a ‘polar’ compound - that is one that is positively charged at one end and negatively charged at the othe other
Why are polar molecules attracted to water?
because water is also polar
What are the 3 primary reactions (forms of biotransformation) catalyzed by P450 enzymes?
- Oxydation
- Reduction
- Hydrolysis
What is oxidation?
removing (negative) electrons, causing the compound to have a net positive charge
What is reduction?
adding electrons by adding a hydrogen atom
What is hydrolysis?
adding H2O, that is, water, which causes a molecule to split up into two polar molecules
What is the primary way that P450 enzymes biotransform psychotropic medication?
oxidation
What is Phase 2 Conjugation?
Phase 2 means that it is a reaction that generally occurs after phase 1 reactions fail to make a drug hydrophilic enough to be eliminated
Conjucation means combining a drug with another molecule
What is the most common type of conjugation reaction?
glucuronidation (combining drug with glucuronic acid)
prof referred to as: Glucuronide conjugation
What are the 4 main factors that affect biotransformation?
- Genetic
- Environmental
- Cultural
- Physiological
what does kinetics mean
the rate of a chemical reaction
What do structure activity relationships helps us do?
Look at how the chemical structure of drugs interacts in a specific way with receptors in and we can use the knoweldge of this relationship (structure activity relationship) in order to predict what the drugs effect will be
What are the factors that affect oral absorption? (5)
- Rate of dissolution of drug
- Phospholipid bilayer (how well a drug can pass through this)
- water/lipid solubility - Drug and Environment Acid/Base relationship
- > Ionized drug/non-ionized drug
- > Ion trapping - Size of drug molecules
- ‘First-pass’ metabolism
Describe the aspects of the phospholipid bilayer that affect drug absorption
Fatty component of the membrane, anything needs to pass through this fatty layer, only certain types of molecules can get through
but there are also specialized transporter receptors that can either bring medications across or expell medications
An acid is?
a substance that can release a proton (H+)
A base is?
a substance that can accept a proton (H+)
What is the pH scale
a logarithmic scale used to measure the acidity and bascity of a substance
What is pH a proprty of?
pH is a property of the environment (representing how many hydrogen atoms there are - more = more acidic)
What is pKa?
property of the substance
a measure of what pH the environment needs to be to have half the substance turned into an ion/ionized (have a charge)
helps us match a medication with its environment
which are able to be absorbed through the lipid bilayer ionized or non ionized substanced
non ionized
if they are ionized they have a charge and are repelled from the lipid bilayer (which is charged)
substances with what range of pKa values are best absorbed by the GI tract
Weak acids or weak bases with pKa values below 7
This is because the stomach is very acidic so drugs with a pH below 7 ionize less in the GI tract (above seven too much ionized and would not absorb)
More detail:
A weak acid with pKa= 6.5 in an acidic environment (pH = 1.5)
• Environment has lots of extra H+ because it is acidic
• A weak acid is a proton donor but in an environment with lots of extra H+ there is no proton acceptor around
- Under these conditions, the weak acid will be non-ionized and lipid soluble
Drug molecules in the GI tract exist in which two interchangeable forms
– ionized (electrically charged; water soluble), or
– non-ionized (non-electrically charged; lipid
soluble).
Which type of drug molecules can be absorbed into the lining of the GI tract?
Only non-ionized molecules can be absorbed
and reach concentration equilibrium across the lining of the GI tract and the blood.
The number of ionized molecules depends on which 3 things?
- If the drug is a weak acid or a weak base,
- If it is dissolved in an acidic or basic environment (pH of location within the GI tract or blood), and
- pKa of the drug
The ratio of non-ionized to ionized molecules determines what?
which types of drugs have poor rates of absorption?
the rate of absorption
Highly ionized drugs have poor rates of absorption
As you move through the GI tract the pH…
goes up (closer to 7)
What is the pH of blood
7.4
What is ion trapping
when a drug moves from the GI tract (acidic) into the blood (much more neutral) this change in environment results in the drug molecules becoming ionized and therefore ‘trapped’ in the blood (unable to cross back through the lipid bylayer because they are now ionized and not lipid soluble)
True or false: most drugs that can cross the blood brain barrier can cross the placental barrier?
True
What is plasma protein binding?
when medication enters the blood it will bind to certain proteins in the blood and prevent them from being active (prevents them from acting at their site)
What are 4 factors that can influence distribution of a drug?
- Ionization status of drug
- ability to cross BBB (for psychotropic drugs)
- Disease states
- Plasma protein binding
What are the consequences of first pass metabolism?
Since there is removal of and metablism of a portion of the drug by the liver before it can reach other areas (including its target) it means that there is a reduction of the amount of drug reaching that target and require a larger dose
What is a pro drug?
a type of drug that requires passing through first pass metablism and being converted to a metabolite prior to beign active
What is metabolic tolerance?
What is a consequence of this?
When a drug causes enzyme induction (increases the presence of the enzymes that metabolize it)
A consequence of this is cross-tolerance:
- any other drug that is metabolized by the same enzyme will also be broken down more rapidly.
What is metabolic sensitization
What is a consequence of this?
The oposite of metabolic tolerence:
When a drug causes Enzyme inhibition (decreases the presence of the enzymes that metabolize it)
A consequence of this is cross sensitization
- any other drug that is metabolized by the same enzyme will also be broken down more slowly
Describe Enzyme Induction
A drug causes an increase in the production of the enzymes that metabolize it in the liver
Which cytochrome p450 enzymes are involved in the metabolism of the most drugs?
CYP-3A4/5
What 3 factors affect drug metabolism?
- Genetic, environmental and various physiological factors (e.g., health status like if liver is functioning properly)
- Enzyme induction – metabolic tolerance and cross-tolerance
- Enzyme inhibition – metabolic sensitization and cross-sensitization
Which is more common: enzyme induction or enzyme inhibition?
enzyme induction is more common
Where does Glucuronide conjugation occur and extrete metabolites?
occurs in liver
excretes metabolites in bile
Why is estimation of the time course of distribution and elimination of drugs important? (3)
- Can predict optimal dosages and dosing intervals needed to reach a therapeutic
effect - Can maintain a therapeutic drug level for the desired period of time, and
- Can determine the time needed to eliminate the drug completely
Explain the difference between first order and zero order elimination
First order: The drug is eliminated according to half life (so it takes the body a certain amount of time to eliminate half the drug, and then the same amount of time to eliminate half of the remaining drug and so on) e.g., 100 units, half life is one hour 1 hour: 50 units 2: hours: 25 units 3 hours: 12.5 units and so on based on proportion VS Zero order: the drug is eliminated at a constant rate. e.g., 100 units eliminated at a rate of 10 per hour 1 hour: 90 2 hours: 80 3 hours: 70 and so on
what is an example of a drug with zero order elimination?
alcohol
What is Elimination half-life?
time required to detoxify the drug by hepatic metabolism to 50% of the total drug in the blood.
what is First order half life independent of?
Independent of the absolute concentration of the drug. Always decrease by the same proportion (50%) in the specified time frame
e.g., if you have 1000 units and the half life is 1 hour you will have 500 units after an hour
versus if you have 100 units and the same laf life, you would have 50 units after 1 hour
proportion eliminated is constant not the absolute amount eliminated
What is steady-state concentration?
The steady-state concentration is when the amount administered per unit of time equals the amount eliminated per unit of time.
i.e. the drug is being eliminated at the same rate that it is being administered
The time to reach steady state concentration is?
The time to reach steady-state concentration, following repeated, regular-interval dosing, is about SIX times the drug’s elimination half-life, and is independent of the actual dosage of the drug.
Describe the process of reaching steady-state concentration
Only 50 percent of each dose is eliminated before the next dose is given, the drug accumulates, reaching steady-state concentration in five to six half-lives
KT explanation: So you start with 1 unit and the half life if 1 hour. After 1 hour you have .5 units left and you administer an additional 1 unit so you have a total of 1.5 units. After 1 hour, half of this concentration is gone leaving you with .75 units, then you add another unit bringing you to 1.75, after another hour this would drop to half so .875, and this process continues until you reach a concentration of .984, at which point it would stabalize (after about 5-6 half lives)
this is the point where the rate of absorption and elimination are the same
What are the interdependent variables that determine the ultimate concentration (or steady- state blood level of drug)
- Dose (which determines the blood level but not the time to steady state)
- Dose interval
- Drug half life
- Various other more complex factors
What are the 3 main goals of therapeutic drug monitoring?
- Assess whether a patient is taking medications as prescribed and that blood levels are sufficiently high to exert a therapeutic effect.
- Maximize therapeutic effectiveness by elevating blood levels slowly.
- Avoid toxicity, especially serious or potentially fatal side effects by careful monitoring.
What is Metabolic tolerance?
Physiological, cellular-adaptive or pharmacodynamic tolerance
– due to cellular compensatory mechanisms which occur in response to the drug’s specific effect
(e.g., receptor up- or down-regulation) – typically leads to “physical dependence” which accounts for withdrawal symptoms (abstinence syndrome).
What is Behavioral Tolerance?
learning to decrease or compensate for the effect(s) of the drug.
What is Behavioral (or psychological) Dependence
repeated re- administration of the drug, not because of withdrawal symptoms, but because it promotes a sense of well being.
What are the 2 basic premises of therapeutic drug monitoring
- Blood concentrations of psychotropic drugs correlate well with concentrations at sites of action.
- Bio-availability of a drug (concentration at the site of action) must be at threshold or above in order to induce and maintain a pharmacological response (or therapeutic effect).
What is the therapeutic window?
A well-defined range of blood levels associated with optimal clinical response
