Chapter 1: Pharmacokinetics (How Drugs Are Handled by the Body) Flashcards
Four types of membranes in the body affect drug distribution
(1) cell membranes, (2) walls of the capillary vessels in the circulatory system, (3) the blood–brain barrier, and (4) the placental barrier.
What is Pharmacology?
Science of how drugs affect body
What is Psychopharmacology?
Study of how drugs specifically affect brain and behavior
What is Pharmacokinetics?
What does it refer to?
How does it relate to the concentration of a drug?
Study of drug molecules into, through, and out of the body
Refers to the time course of a particular drug’s action
Along with knowledge of the dosage taken, allows determination of concentration of a drug at its receptors and intensity of drug effect on the receptors over time
What is Pharmacodynamics?
Study of interactions of a drug with the structure with which it interacts to produce its effects
Together these processes determine the bioavailability of a drug:
(ADME)
1. Absorption
-Movement of drug from site of administration to the blood
- Distribution
-Movement of drug from blood to rest of body - Metabolism
-Breakdown of drug into metabolites - Elimination
-Removal of drug’s metabolic waste products from the body
For each, talk about where it is administered, what angle, and at what rate?
IM = intramuscular
IV = intravenous
TM = transmembrane
SC = subcutaneous
TD = transdermal
IH = inhalational
Intramuscular (IM): vertical angle, into the muscular tissue, slow sustained absorption, typically you want a LARGE mucles like glutes, hamstrings, etc..
Intraveneous (IV): 45 degree angle, straight into blood supply, very rapid distribution
Transmembrane (TM): through a particular membrane
Subcutaneous: under the skin, almost parallel angle to body surface, ex. insulin, faster than instramuscular but slower than intraveneous
Transdermal (TD): through the skin, using a patch
Inhalation (IH): the fastest way to administer a drug
most common route of administration?
why is it not the best way?
oral
it complicates the absorption of drugs and limits their absorption. the gastrointestinal track gets in the way
depends on how well it is absorbed in a alkaline vs. acidic environment
Enteral routes vs. Parenteral routes?
Enteral routes – Gastrointestinal tract (GI) involvement
*Oral administration
*Rectal administration
Parenteral routes - No GI tract involvement, they bypass the complicated GI environment
*Injection
*Inhalation
*Absorption through the skin
*Absorption through mucous membranes
For a drug to be orally administered, it must be…
Soluble and stable in stomach fluid
Absorbed through upper intestine through passive diffusion
Must generally be somewhat lipid soluble
Food in stomach may increase or decrease absorption
Disadvantages of oral administration?
Vomiting and stomach distress
Hard to know how much of drug will be absorbed due to genetic differences
Stomach acid destroys some drugs
Drug enters bloodstream through a process called…
Passive Diffusion
About 75 percent of orally administered psychoactive drug is absorbed into bloodstream within how many hours?
about 1 to 3 hours after administration
everything absorbed through GI tract also goes into which organ? why?
the circulation of the liver
it breaks and metabolizes the compounds down
When do we use rectal administration with a tube?
The rectal region is somewhat LESS acidic than the stomach, which can facilitate the absorbtion of drugs which are BASIC (aka alkaloids)
Used if patient is vomiting, unconscious, or unable to swallow
Often involves irregular, unpredictable, and incomplete absorption
what are the benefits of drug administration through inhalation?
Lung tissues’ large surface area allows for rapid absorption into blood (even faster than injection)
transdermal patches provide…
continuous, controlled release and absorbtion over hours or days which minimizes side effects
How does Intravenous Administration work?
Drug introduced directly into bloodstream via vein
Dosage can be extremely precise
Fastest pharmacological action onset (most dangerous route)
MAY RIS allergic reactions; blood clots from incomplete solubilization
what route of administration is Injected under the skin
Subcutaneous
two types of Intramuscular Administration
Type 1: Rapid onset/short duration of action
Drug dissolved into aqueous solution
Type 2: Slow onset/prolonged duration
Drug suspended in oily solution (Risperdal Consta; Vivitrol)
Effect not easily reversible
where are drugs administered into the spine?
Subarachnoid space
Specifically, Cerebrospinal fluid (CDF)
how often does blood circulate in average adult?
once every minute
how fast are psychoactive drugs taken into the bloodstream?
Psychoactive drugs are quickly and evenly diluted and distributed by blood through bloodstream
how can we tell how much drug has entered the person’s nervous system?
through measuring the blood
-once it reaches the bloodstream, it can reach the nervous system by passing through membranes
when administering a drug, you must not only consider the dosage but also…
the size of the person taking it
because they have different amounts of blood in their bloodstream
Before blood goes to rest of body from the GI tract, it passes through….
known as…
the liver
known as “first-pass”
what does the liver do for drugs?
the major organ that breaks down drugs
Certain amount of the drug will be inactivated or metabolized as it goes through the liver
Membrane Types?
- Cell membranes
- Capillary walls
- Blood–brain barrier
- Placental barrier
as the drug moves throughout the body, it is essentially moving through what is called…?
cell membranes
Describe the functions of cell membranes?
Only permeable to small, lipid-soluble molecules
*the only way through it is to dissolve into it
-Important as a barrier to absorption and distribution of drugs
EXAMPLES:
Stomach to intestine into bloodstream
Fluid surrounding tissues cells into cell interior
Interior of cells back into body water
Kidney back into bloodstream
how is a cell membrane structured?
made up of phospholipid bilayers with molecules suspended in the phospholipids
-both the top and bottom have a phospholipid head and a phospholipid tail (which is the lipid) the quality of the fat molecules inside make them impermeable to substances passing through which means molecules must be lipid-soluble to pass through.
what are Capillaries?
-the exchange between the circulatory system And central nervous system
-tiny, cylindrical blood vessels formed by single cell layer (a single line can pass through)
-contains small pores (clefts or fenestra between 90 and 150 angstroms) larger than most drugs which allows them to enter into the tissues from high concentration to low concentration
-allow transport of drugs regardless oflipid-solubility
-blood and protein are too large for pores; drugs that bind to plasma proteins cannot pass through
why does drug distribution generally follow a similar pattern?
Because blood flow is greatest to the brain and much less to the bones, joints, and fat deposits
what can the small pores in capillaries allow to pass through them? what can they not allow?
-allows drugs circulating in the blood to enter into tissues
-does not allow blood and proteins through, such that any drug attached to a protein molecule cannot pass through
capillaries that surround the central nervous system are actually quite different… they comprise what is known as…
the blood-brain barrier
what are tight junctions in the blood brain barrier?
what is an example of this?
the cells of the capillaries are overlapping eachother
-this also means they cant pass substances through eachother since they do not have pores
example: shingles on a roof that overlap eachother such that water falls off and cannot get in
the only way molecules can pass through the blood brain barrier?
examples?
- actively transported
- dissolve through it
-oxygen and CO2 can dissolve through it, but everything else which requires sugars, fats, amino acids has to be transported in
so how do drugs get into the brain?
they get in because they are soluble in fat and can therefore diffuse through the membranes of these capillaries
immune systems major defense against toxins?
to keep them out by the blood brain barrier
what is the blood brain barrier?
-protects the brain from toxins since the brain has a great need for nutrients and oxygen (high blood flow) that increases risk of toxic danger
-the capilliaries in the barrier help protect the brain but also do not allow drugs to pass through them as easily as they do in the capillaries of the body- known as the glial sheath
the blood brain barrier prevents the easy passage of…
molecules from the blood to the central nervous system
explain the journey to the neuron from brain capillaries?
they must traverse capillary wall and astrocyte membrane
transporters bring in drugs and protect the brain
explain large vs small drugs entering into the blood brain barrier.
-large drugs do not pass through
-small drugs which are lipid soluble pass through rapidly
what is the placental barrier?
it is a membrane system which is genetically unique
has drug sensitivities
does not have a barrier which means that the fetus is exposed to all the toxins and psychoactive drugs that the mother takes
drugs cross primarily by passive diffusion
Lipid-soluble drugs can pass through cell membranes by…
passive diffusion
the movement is in a direction of higher to lower concentration
as the concentration of the drug in the blood rises to a higher concentration, the main concern is what?
the movement into the central nervous system is more rapid
what is the Partition coefficient?
how do you create it?
a measure of lipid solubility
The drug is mixed with equal volumes of water and oil or a lipid solvent. The ratio of amount of drug in the oil to amount in the water is the partition coefficient.
Extent of ionization determines the oil/water solubility of the drug.
what does ionization do to a drug?
a drug that is ionized has an electric charge to it which makes it water soluble and not lipid soluble
whats an example of a drug which has a partition coefficent?
alcohol
it can become a water soluble form (which is the kind that we drink)
but it is also lipid soluble because it can pass through cell membranes into the central nervous system
Most drugs are not lipid-soluble because…
they are weak acids or bases that ionize in water
what determines how water soluble a drug is?
the extent of ionization depends on pH of the solution, and an intrinsic property of the molecule (pKa).
what affects drug movement throughout the body?
the PH of body fluids
low or high pH is acidic or basic?
low pH associated with acidity
what is the order of low to high pH?
LOW TO HIGH:
1. stomach fluid
2. small intestine
3. blood
4. kidney urine
5. saliva
6. cerebrospinal fluid
what is pKa?
the pH at which that drug would be 50% ionized and 50% non-ionized.
which means at that volume, half of a given drug would be in it’s lipid soluble form and half would be in the water soluble form
what drugs ionize more readily in an alkaline environment?
weak acids
what drugs become less ionized in an alkaline environment?
weak bases
describe aspirin as an acid or a base
aspirin is a weak acid
it is absorbed very rapidly because it is lipid soluble and absorbs throught the GI tract which is an acidic environment
For any drug to get to CNS, it must pass through the..
circulatory system
biggest challenges for administration?
GI tract
First Pass Metabolism
what are the Routes Through Which Drugs Can Leave the Body?
Kidneys
Lung
Bile
Skin
Major Route of Drug Elimination?
Renal (urinary) excretion of drug metabolites produced by biodegradation of drug in liver
the key to a drug being psychoactive?
it is lipid soluble so it can get into the CNS
why do most drugs have to be metabolized before being excreted out the body?
Usually too lipid-soluble to be passively excreted in urine where only water soluble molecules can get into
Must be transformed into metabolites and a rapidly excreted form by hepatocytes (liver cells) on endoplasmic reticulum membranes.
once Metabolites are created in the liver, they are typically more?
More water soluble and less active (or inactive) than parent drug
what is the most important enzyme in the liver for drug metabolism?
Phase I reactions: P450 system
Cytochrome P450 enzymes
what do Cytochrome P450 enzymes?
Turn lipophilic fat-soluble drugs into more water-soluble, polar compounds
Which are then excreted out the liver, and reabsorb and conserve lipophilic compounds
what are polar compounds?
molecules having opposing charges; polar molecules are attracted to water
why do fat soluble molecules tend to build up in the body?
because they tend not to be excreted since they were not able to be converted into water soluble
the liver reabsorbed and conserves these lipid compounds
phase 1 vs phase 2 in the P450 system?
Phase 1: Primary chemical reactions catalyzed by P450 enzymes
-Oxidation: Losing (negative) electrons, causing the compound to have a net positive charge
-Reduction: Adding electrons by adding hydrogen atom
-Hydrolysis: Adding water and causing molecule to split into two polar molecules
Phase 2: Conjugation
-Combining drug with another molecule
-Occurs after Phase I when drug not sufficiently hydrophilic
most common form of conjugation is?
Glucuronidation (Glucuronic acid bound to drug; made from glucose)
*the path by which many psychoactive drugs are metabolized
in addition to their effect with psychoactive drugs, the Cytochrome P450 enzyme family can also…
detoxify chemically diverse substance groups
the Cytochrome P450 is not a single enzyme, but rather…
a family of enzymes
why do Genetic variations affect medication response?
people have different liver functioning depending on age and genetics
In general, genetic, environmental , cultural , and physiological factors are the most relevant.
what is Genetic DNA testing?
used to see?
identification of how person metabolized several drugs of different therapeutic classes
Toxic reactions (slow/overdose); response failures (too fast/the level is never reached for a sustained period)
Genetic DNA testing can detect…
slow, normal, or fast metabolizer for specific drug
negative consequences for not testing genetic DNA differences?
you end up with drug levels that are TOXIC (too high) or give no results (too slow from fast metabolizers)
Kidneys perform two major functions.. what are they?
- excretion
-of most metabolic products - metabolism
-Regulation of level of most body fluid substances (provided that these molecules are water-soluble)
What are the kidneys?
The kidneys are a pair of bean-shaped organs that lie at the rear of the abdominal cavity at the level of the lower ribs.
-located on either side of the spine in the back
explain Role of the Liver in Drug Metabolism?
- Reabsorbs drug (after it had been filtered through the kidneys into the bloodstream)
- Portion of drug cleared from blood, metabolized to by-products, and returned to bloodstream
- Metabolites carried in bloodstream to kidneys and excreted
(When the metabolite is filtered into the kidney, it cannot be reabsorbed and is therefore excreted in urine)
Why is knowledge about the relationship between the time course of drug action in the body and its pharmacological effects important?
(Drug Half Life)
- Predicting optimal dosages and dose intervals needed for therapeutic effect
- Maintaining therapeutic drug level for desired time period
- Determining time needed to eliminate drug
-allows us to know when to readminister to keep therapeutic level
what is the Drug Half-Life?
Time for the plasma level of drug to fall by 50 percent
(related to how long a drug remains in body)
Cited to describe duration of action of psychoactive drugs in the body
what does knowing the drug’s half life allow us to do?
Allows comparisons between drugs with similar actions but differing half-lives
what is the Measurement of half-life?
Mostly in hours; some measured in days
two important concepts in relation to the time of elimination of a drug?
examples?
- First-order elimination
-most common elimination pattern - Zero-order elimination
-ethyl alcohol
how many half lives does it require for a drug to basically be eliminated from the body?
what should we keep in mind when dosing?
6 half lives
estimating how many half lives it requires for the drug to be eliminated, where would it fall below or above therapeutic level
Although a different absolute amount of drug is metabolized within each half-life, what remains constant?
the time interval remains constant.
so even though the half lives of drugs are very different, it is STILL six half lives between administration and elimination
what is Steady-State?
Point of balance, at which the rate of drug administration approximates the rate of excretion
Steady-state concentration?
the level of drug achieved in the blood with repeated, regular-interval dosing
Time to reach steady-state concentration?
About six times drug’s elimination half-life; independent of actual drug dosage
To achieve steady-state concentration, you need….?
Steady regular-interval dosing (DOSING ROUTINE)
*Leads to predictable accumulation with steady-state concentration
*When dosing is frequent enough, it is prevents the dosage from falling too low
Clinically, these factors guide drug therapy when blood levels of the drug are monitored and correlated with therapeutic results.
Steady-State
Steady-state concentration
Time to reach steady-state concentration
Steady regular-interval dosing
Basic principle in therapeutic Drug Monitoring (TDM)?
Threshold plasma concentration of a drug is needed at the receptor site to initiate and maintain a pharmacological response
(if you are below threshold, then you don’t get the proper action)
Plasma concentrations of psychoactive drugs correlate well with tissue or receptor concentrations
(best way to estimate a drug is to measure this)
define Therapeutic Window.
Highlights the importance of the right amount of drug being maintained in the blood. Well-defined range of blood levels associated with the optimal clinical dosage
Drugs should be given in such a way that the blood concentration stays between a level that is too high and too low
TOO HIGH: effect will not be any better and there will be more undesirable side effects which may be too toxic
TOO LOW: it won’t have any beneficial effect
The relationship between the therapeutic effect and the drug dose is in the shape of an
inverted U.
That is, after the therapeutic effect reaches a plateau, an increase in dose does not produce further improvement, but may actually decrease the drug’s effectiveness.
what is Drug Tolerance ?
State of progressively decreasing responsiveness to the same dose of a drug.
Mechanisms involved in development of drug tolerance?
- Metabolic tolerance
-inducement of liver enzymes (p450) so that ability to break down drug becomes efficient, can cause cross tolerance - Pharmacodynamic tolerance (Cellular-adaptive tolerance)
-refers to changes in CNS
-upregulation or downregulation - Behavioral conditioning processes
-must learn to recognize cues of intoxication
-you learn to behaviourally compensate for the effects
what is Sensitization or reverse tolerance?
often occurs with?
Amplified or potentiated response to drug after repeated exposure
Often occurs with the rewarding effects of stimulants such as cocaine and MDMA
what is meant by Physical Dependence?
Drug taken to avoid withdrawal symptoms
leads to
Abstinence syndrome
Discontinuation syndrome
the degree to which drugs are able to pass into different layers of the body depends on
how lipid soluble the molecule is
