Exam 1 (Lectures 5, 6, & 7) Flashcards
what is pharmacodynamics
study of drug effects on the body
what meds do to our body and how they do it
pharmacologic effect
occurs due to change in the function of the cell/organism
drugs do not elicit new functions
true
they produce the same action as body’s own chemicals
block the normal action of body’s own chemicals
what do drugs do
drugs do not elicit new functions
they produce the same action as body’s own chemicals
block the normal action of body’s own chemicals
what brings about a drug action?
ligands (extracellular molecules like antibody, hormones, NT or drugs, that binds to receptor) bind to receptor at cellular level
what are receptors
specialized target molecule that binds to a drug & mediates its pharmacological action
once a drug binds to receptor, response can result from the binding action
biological response
formation of drug-receptor complex
where are receptors found
present either - on the outside of the membrane, inside of the membrane, spanning both sides of cell membrane
receptor sites on a single cell can
metabolize or regulate enzymes, proteins or glycoproteins associated with cell transport mechanisms, structural and functional parts of the membrane, & nucleic acids
what is a free receptor
unoccupied receptors
what is an occupied receptor
reversibly bound to a drug receptor
explain what happens when enough receptors are bound
when enough are bound (occupied by a substance) the combined effect of the filled receptors is strong enough to cause the max response that that cell can produce
when this happens in many cells, the effect is apparent in the organ and/or the PT
drugs react by
Covalent, ionic, hydrogen, hydrophobic, or Van der Waals bonding to produce a definable pharmacological response
which bonding in drugs are the most common
hydrogen & ionic are the most common
what determines how strong a drug sticks to a receptor and how it attaches to it
drugs chemical structure determines how strong a drug sticks to a receptor and how it attaches to it
When a drug binds to its receptor, it starts a series of steps that lead to either
a positive effect or an unwanted side effect.
If you increase the amount of the drug (ligand) or the number of receptors, the effect of the drug can also increase.
true
what is the lock in the model
enzyme (receptor)
what is the key in the model
substrate (drug molecule/ligand)
what is the lock and key method
only the correct key (drug) fits into the key hole (active site) of the lock (receptor)
believed that body has natural ligand (key) for every receptor
what is the induced fit model
not all reactions are explained by lock and key theory
this model assumes the substrate (drug molecule) plays a role in determining the final shape of the receptor
receptor is partially flexible)
what does the induced fit model explain
certain compounds can bind to the receptor but doesn’t cause a reaction because the receptor is distorted too much
other molecules are too small to cause a reaction
only the proper substrate is able to fit into the active part of the receptor in order for it to work correctly and produce the desired effect
differences between the lock and key model & induced-fit model
Lock and Key Model:
Concept: In this model, the receptor and the molecule (often called the ligand) have specific shapes that fit together perfectly, like a key fitting into a lock. The receptor’s shape is fixed, and only a molecule with the exact matching shape can bind to it.
Analogy: Imagine a lock (the receptor) that only a specific key (the ligand) can open.
Induced Fit Model:
Concept: In this model, the receptor is more flexible. When the molecule approaches, the receptor adjusts its shape slightly to better fit the molecule. This change helps the binding to be more effective.
Analogy: Imagine a glove (the receptor) that changes shape slightly to fit the hand (the ligand) as you put it on.
Key Difference:
The Lock and Key Model suggests that both the receptor and the molecule have fixed shapes that fit together perfectly from the start.
The Induced Fit Model suggests that the receptor can change its shape to accommodate the molecule, making the binding process more adaptable.
what are G proteins
involved in transmitting signals from variety of stimuli outside the cell to its interior important processes
funtion: activates production of second messengers (signaling molecules) that convey input provided by the first messenger to cytoplasmic effectors
bind to guanine nucleotides GDP (guanine-dinucleotide proteins) and GTP (guanine-trinucleotide proteins
g proteins
family of proteins that act as molecular switches inside cells
g proteins
most abundant class of cell receptors in the body
g proteins
describe the production of second messengers when activated by g proteins
When a first messenger (like a hormone or neurotransmitter) binds to a receptor, it triggers the production of second messengers inside the cell. These second messengers then carry the signal from the first messenger to other parts of the cell (cytoplasmic effectors) to create the desired response.
activity is regulated by factors that control their ability to bind and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP)
larger group of g protein enzymes
GTPases
what are transmembrane ion channels
cellular functions require passage of ions and other molecules across the membrane and specialized transmembrane channels (ion channels) regulate this process
what is the function of the transmembrane ion channels
The function of ion channels is diverse, including fundamental roles in regulating the flow of ions across cell membranes, maintaining the cell’s electrical charge, controlling cell signaling, enabling muscle contractions, and supporting nerve impulse transmission
what is cell signaling
process by which cells communicate with each other and respond to their environment. This communication occurs through a series of molecular events that involve signaling molecules, receptors, etc.
all organisms have signal systems that warn presence of pathogens that leads to a protective response
true
where do signals come from for the cell
signals come from light, heat, chemicals (NTs), water, odors, touch and/or sound
cells can receive and interpret signals from their environment and from other cells like signals for cell division, differentiation, and apoptosis
what are cell responses to a signal
ion channels open or close
intracellular second messenger is formed
gene expression of cell is altered
initiation or alterations in cell growth and differentiation
how does a cell respond to a drug
cell function or structure change is the cell’s response to the drug
cell response can be the same, greater or less than the normal endogenous response
what happens to get a cell to change function or structure
ligand attaches to a spot on a receptor protein causing the receptor to change shape which is passed down along the inside of the cell membrane causing changes in how that cell functions or is structured
what is confirmational change in a cel
when a receptor is actived or blocked the cell changes shape and affects how it works or looks
what causes cell signaling to occur
agonist attaches to receptor
causing g protein activation
which causes second messenger
which causes cell signaling activation
what are cognate receptors
two biomolecules that typically interact
pharmacological properties of drugs are based on
the effects they have on the state of their cognate receptors (two biomolecules that typically interact)
what is an agonist
drug that after receptor binding results in active conformation
ligands that activate receptors
the _______ the bond bw drug & receptor the more likely it will have the intended effect
stronger
drugs with a weak attraction to a specific receptor attaches to it more readily than others
false
strong
examples of agonists
all NT that are at their respective sites - acetylcholine (ACh - excitatory)), Gamma-amino butryic acid (GABA - inhibitory), glutamate (excitatory), histamine, norepinephrine (NE), Seratonin 5 hydroxytryptamine (5-HT)
excitatory agonists
acetylcholine & glutamate at their respective sites
although all NT are agonists at their respective receptor sites there are drugs that are agonists & antagonists to NT actions
true
examples of drugs that are agonists & antagonists to NT actions
seratonin produced in the brain & stomach
triptans - drug that mimics seratonin effects = agonists at 5-HT1 receptor site which is mainstay of migraine treatment
serotonin antagonist drugs can block the release - used to prevent/relieve nausea and vomiting from chemotherapy and after surgery from effects of anesthesia
what is an antagonist
drug that favors inactive conformation after receptor binding
inhibit action of natural agonists at receptor sites
you can have an antagonist effect without an agonist
false
without an agonists there is no effect of an antagonist
inhibit actions
antagonists
activates receptors
agonists
examples of antagonists
Beta-receptor antagonists or beta-blockers are drugs that affect heart rate and blood pressure by blocking the effect of norepinephrine (a natural agonist) at its respective binding site on beta receptors
Med used to treat vertigo or Meniere’s
ACh receptor antagonist scopolamine (Transderm scop patch) and meclizine (antivert)
Histamine receptor antagonist or “antihistamine,” diphenhydramine (Benadryl)
some drugs like promethazine (Phenergan -1st generation histamine H1 antagonist) can block multiple neurotransmitters
It exhibits an anticholinergic, antihistamine, and antidopaminergic properties all in one product
what can be targets of drug action
enzymes & proteins
examples of enzymes & proteins can be targets of drug action
ibuprofen, the non-steroidal anti-inflammatory drug (NSAID) inhibits the enzyme cyclooxygenase
Cyclooxygenase is needed to create the inflammatory prostaglandins that can form secondary to muscle injury
Another drug that inhibits prostaglandin formation is acetylsalicylic acid (Aspirin), one of the first NSAIDs discovered and brought to market
true
what are the antagonist classifications
antagonist
non receptor agonists or receptor agonists
non receptor - chemical & physiological
receptor - active site bonding & allosteric binding
active - reversible (competitive) or irreversible (noncompetitive active)
allosteric - reversible & irreversible (noncompetitive allosteric)
Antagonists can be categorized based on whether they bind to a site on the receptor for agonist (receptor antagonists) or interrupt agonist–receptor signaling by other means (nonreceptor antagonists).
true
Receptor antagonists can bind either to the
active receptor sites (prevents binding of an agonist to the receptor) and allosteric (not active) (prevents conformational change required for receptor activation
are receptor antagonists reversible
yes
Agonist (active) site receptor antagonists prevent the agonist from binding to the receptor. If the antagonist competes with the ligand for agonist site binding, it is termed a competitive antagonist; high concentrations of agonist are able to overcome competitive antagonism
allosteric sites
(not active) prevents the conformational change required for receptor activation
a receptor antagonist can bind to
active site or allosteric site
what does an active receptor site do
prevents binding of an agonist to the receptor
what does an allosteric site do
prevents confirmational change required for receptor activation
Receptor antagonists can be
reversible or irreversible
reversible receptor antagonists
bind to a receptor site reversibly
irreversible receptor antagonists
binding of a receptor site is irreversible
Both agonist and antagonist compete for the same receptor sites
If an antagonist binds first, it prevents the agonist from producing its effect
true
what types of binding can occur with antagonists
competitive or non competitive
what is a competitive antagonist
Bind reversibly to the same active site on the receptor as the agonist. Their presence competes with the agonist for binding. - remains in inactive form
binding is reversible -administering additional agonist displaces the antagonist from the receptor, allowing the agonist to produce its effectf
what is a non-competitive antagonist
can bind to either the active or the allosteric (non-active) receptor site
Noncompetitive antagonist bind irreversibly often through covalent bonding
They cannot be displaced even with high agonist concentration
what is the therapeutic window
range of doses (concentrations) of a drug that elicit a therapeutic response without unacceptable adverse effects (toxicity)
what happens when a drug has a small window
plasma drug levels monitored closely to keep effective dosage without becoming toxic
what is therapeutic index (TI)
TW quantified by TI, aka therapeutic ratio
TI = TD50 ÷ ED50
what is TD 50
Drug dose that causes a toxic response in 50% of the population
what is ED50
Drug dose that is therapeutically effective in 50% of the population
What is a large TI
large (wide) TW
what is a small TI
small (narrow) TW
what is a dose-response relationshi[
Pharmacodynamics of a drug can be quantified by the relationship between the dose (concentration) of a drug and the organism’s (patient’s) response
two types of dose response relationships
graded & quantal
When a drug exerts an effect on a biologic system, the effect can be quantified according to the dose (how much) of the drug is given compared against the intensity (magnitude) of the effect
true
what is the graded dose response
describes the effect of various drug doses on an individual
what are the two parameters of graded dose response
potency of a drug (EC50) & efficacy (EC max) of a drug
what is EC50
potency
what is ECmax
efficacy
what is the potency of a rug
concentration which the drug elicits 50% of its maximal response
potency = affinity of a drug to its receptor
what is the efficacy of a drug
maximal response produced by a drug
efficacy = related to receptor occupancy by drug molecules
give an example of potency and efficacy
Demerol and Morphine are similar in efficacy
Both results in all receptors being occupied by the drug
they differ in potency
If 100 mg of Demerol is required to relieve severe pain
Then 10 mg of morphine is required to relieve the same severe pain
what is quantal dose response
describes effect of various drug doses on a population
describes concentrations of a drug that produce a given effect in a population
reponses = present/not present
what is the goal of quantal dose response
generalize the result to a population rather than examine graded effects of drug doses on an individual
Population responses that can be examined using quantal-dose response relationship include
Effectiveness (therapeutic effect)
Toxicity (toxic effects)
Lethality (lethal dose)
The doses that produce these responses in 50% (median) of the population, are known respectively as
median effective dose ED50
median toxic dose TD50
median lethal dose LD50
study of drug effects on the body
pharmacodynamics
can only bring about a pharmacological effect on the cells if it can attach to specific receptors that are either on the cell membrane or in the cell
drugs/ligands
Drugs can either cause
The same action as a natural ligand on cell receptors – agonists or
Stop the effect of a natural ligand on cell receptors - antagonists
The same action as a natural ligand on cell receptors
agonists
Stop the effect of a natural ligand on cell receptors
antagonists
adding more agonists will break the cell receptor–drug binding
competitive antagonists
will not break the cell receptor-drug binding even if more of the drug is added
noncompetative antagonists
Poisons act in this manner where the cell receptor–drug binding is generally irreversible
noncompetitive antagonists
what is the therapeutic window/index
range of doses that will elicit a therapeutic response without toxicity
Drug dose determines whether a drug will be
Effective for 50% of the population (ED50)
Toxic for 50% of the population (TD50)
Lethal for 50% of the population (LD50)
related to affinity of a drug to its receptor
Potency (EC50 )
______ the potency, ______ amounts of the drug needed to cause action
Higher
less
refers to the maximal response produced by a drug and is related to receptor occupancy by drug molecules
Efficacy (ECmax)
measures population response to drugs
quantal dose response
measures individual responses to drugs
graded-dose response
what is pharmacokinetics
study of how drugs are acted upon by phsiological functions
what the body does with the drug
overview of pharmacokinetics
drug enters body circulates through it, changed by the body and then leaves it
Pharmacological therapy will fail in clinical trials when
drug cannot reach the target organ(s)
concentrations are not sufficient enough to cause an effect
what makes a drug successful
Characteristics in the body that protect from foreign bodies & toxins also limit modern drugs to combat pathoogical processes within a PT
successful drugs have to cross the physiological barriers in the body that are in place to limit access to foreign substances (viruses, bacterial and environmental toxins)
4 steps of drug movement
absorption
distribution
metabolism (biotransformation)
excretion (elimination)
what affects free drug that reaches the target receptor site
ADME
only a fraction that successfully binds to the target site will exert its effect
true
metabolism of the drug produces
active and inactive metabolites (drug products after metabolism)
exert an effect on either the drug target receptor or other receptors
active drug product
prerequisite for establishing optimal plasma drug levels for therapeutic drug actions
absorption
what happens in drug absorption
can occur by a number of mechanisms designed to either exploit or breach the body’s physiologic barriers
different drug routes affect how it is absorbed
first pass metabolism
Physiological barriers to drug movementf
cell membrane
BBB
BLB
BPB
factors affecting the rate of drug movement across the membrane
solubility of the drug
route of administration
what is solubility of a drug
the ability of it to dissolve in a solvent (liquid - water, bodily fluids like blood or stomach acid)
drugs in solutions more rapidly absorb than insoluble ones
closer to the site of administration is to a blood vessel the faster a drug can be absorbed
true
what molecules pass the cell membrane easily
nonpolar molecule (steroids)
what are not passed easily through the membrane
most drugs & polar molecules - larger
A polar (water soluble) molecule has a partial
+ve charge in one part of the molecule and complementary –ve charge in another part
factors affecting drug’s passing ability across
lipid solubility
degree of ionization (charge)
molecular size
drug shape
describe lipid solubility & membrane
more lipid soluble drug = easier crossing because they are water hating
what drug molecules can generally pass through easily
hydrophobic
can charge molecules cross the membrane?
charged molecules cannot cross (mus use pores/channels), Hydrophobic drug molecules can generally pass through easily
what size can pass through the membrane
smaller = easier & larger = harder
what drug shape can pass through the membrane
shape shifters can go through easier (induced-fit model)
well insulated from foreign substances
CNS (also the testes and cochlea
what is the BBB
selective barrier, separates circulating blood from brain extracellular fluid in the CNS
made by capillary endothelial cells connected by tight junctions & astrocytes (CNS supporting cells)
allows passing of water, some gases, lipid soluble substances by passive diffusion
allos selective transport of molecules like glucose amino acids crucial to neural function
can prevent entry of potential neurotoxins by way of an active transport (requires energy) mechanism
BBB and prevention of drugs
prevents diffusion of most drugs from systemic to cerebral circulation
drugs designed for CNS are hydrophobic to easily pass biological membrane or use existing facilitative/active transport systems
Such drugs can be administered through intrathecal infusion (injected directly into the CSF)
The intrathecal route is useful for single or limited doses and to treat meningitis or CNS cancers
true
is intrathecal route practical for drugs that need to be taken on a more regular/daily basis
no
what is the BLB
homeostatic mechanism protecting IE
how can drugs affect BLB
Small molecular weight molecules can enter the perilymph in a dose and time dependent manner
Several ototoxic drugs and bacteria can cross the BLB and enter the perilymph
The rate of elimination from perilymph is much slower than that from serum
Disruption of BLB can disrupt
ion transport system of the lateral cochlear wall, lead to disturbances of inner ear homeostasis, resulting in functional disruption of the auditory system
what is the BPB
serves as a barrier between maternal and fetal circulation and protects the fetus from harmful agents
what molecules can pass the BPB
antigens & antibodies cross both ways
small molecules can cross the placenta barrier
examples of small molecules that can pass the placenta barrier
Many viruses, including cytomegalovirus (CMV), rubella (German measles), varicella-zoster (chicken pox), measles, HIV (AIDS), Zika, and poliovirus can cross the placenta
all of these viruses can potentially cause congenital deafness/HL
what doesn’t cross BPB
Bacteria & other protozoa usually don’t cross
but treponema palladium (syphilis) and toxoplasma gondii (toxoplasmosis) that can cause congenital hearing loss
is BPB a strong barrier for drugs
no
most can cross easily with non-ionized & lipid-soluble drugs crossing the easiest
what allow or prevent drug movement in the body
physiological barriers
what are the drug administration routes
enteral
topical
parenteral
what is the enteral route
drug given directly into the gastrointestinal tract; non-enteral routes do not go through first-pass metabolism by the liver
oral & rectal administrion
simplest route
benefits of enteral route
easy self administration, portable, less likely for systemic infections unlike parenteral route
disadvantages of enteral route
exposes drug to harsh environments
lipid soluble drugs pass through GI tract the easiest
food in stomach can alter absorption rate
pH of stomach and drug can interfere with absorption
other drugs in stomach can cause drug interaction (in oral route)
drugs pass through first-pass metabolism in liver
what is the first pass metabolism
only impact oral drugs & happens in the liver
pass from GI tract to portal veins to enter liver before the systemic circulation
protects from the effect of ingested toxins - detoxified in the liver
drugs enduring this need the right dosage to make sure the effective concentration happens on the target organs due to some inactivation in the liver
process of first pass metabolism
When a drug is taken orally, it is absorbed through the lining of the stomach or intestines into the portal vein, which carries blood from the GI tract to the liver.
Liver Metabolism: Upon reaching the liver, enzymes, particularly those from the cytochrome P450 family, metabolize the drug. During this process, a portion of the drug may be inactivated or converted into metabolites, some of which might be active, while others are not.
Reduced Bioavailability: After passing through the liver, only a fraction of the original dose may reach the systemic circulation. This phenomenon reduces the bioavailability of the drug—the proportion of the drug that reaches the bloodstream in its active form.
describe the topical route
drug applied to the surface of the body
transdermal - skin patches or ointments
otic - ear drops
nasal - nose drops
ophthalmic - eye drops
describe the parenteral route
drug given in other routes than above
drug bypasses GI tract & its barriers
usually injectable drugs using syringes & needles
advantages of parenteral
availability (IV drug is immediate in circulation, IM/SC has slower entry but faster than enteral), fast onset of drug action (IV - 15 to 30 ms; IM/SC - 3 to 5 mins) & if bioavailability is 100% the drug reaching system is the same for all routes parenteral & non-IV parental routes take longer for drug to reach peak values in circulation, useful route for drugs not absorbed by gut or too irritating (chemotherapeutic drugs), IV delivery is more controlled, one injection lasts for days/months, IV route delivers continuous meds (saline, pain meds, antibiotics etc.), & useful when PT unable to take med through GI (unconscious/coma, ER, before/after surgery)
disadvantages of parenteral route
higher addiction risk due to rapid onset action, not all PTs can administer injections (belonephobia - fear of needles & injections), risk of hepatitis, HIV, etc w/ shared needles, most dangerous route (bypasses all natural defenses including BBB if given intrathecally, exposing PT to death due to adverse rxns or health problems like HIV, hepatitis, abscess, infections), fatal air bubbles, strict sterile environment, costs more (requires trained/skilled personnel)
examples of perenteral route administration
inhalation, intradermal, intravenous, intrarterial, intramuscular, intraosseous, sublingual (enters venous circulation), intrathecal (injected into the spinal canal/subarachnoid space), & intraperitoneal (injected into the peritoneum),
what is bioavailability
subcategory of absorption; a fraction of administered drug that reaches systemic circulation
how much of the drug you took and how much of it is available
bioavailability equation
Bioavailability = Quantity of drug reaching systemic circulation ÷ Quantity of drug administered
bioavailability of IV drugs
IV drugs injected into the systemic circulation = generally 1 (max) bioavailability
bioavailability of oral drugs
oral drugs = <1 bioavailability
what is bioavailability dependent on
route of administration, the chemical form of drug & PT factors (GI enzymes, pH and hepatic metabolism
why is bioavailability important in generic drugs
these drugs have the same molecular structure but concentration and route of administration may differ
FDA mandates generic has to have _____% of the bioavailability of the parent compound
90
how are oil soluble drugs administered
subcutaneous or IM
drugs able to dissolve in water-based solutions at pH levels found in the body can be administered
orally
what is drug distribution
after absorption of the drug from the site of administration, its distributed to site of action primarily by circulatory system (blood plasma) and minor from the lymphatic system
after absorption from the site of administration, drug utilizes the body’s distribution system (blood & lymphatic vessels) to reach the target in appropriate concentrations
therapeutic drug levels are determine from the concentration of it in the plasma
measuring in the target organ is hard to measure
correlates well with drug effect on the target site
what has the most blood flow
liver & kidneys
what affects drug concentration in the plasma
drug distribution in various tissues and compartments and blood flow variability bw different organs
Drug occurs in two forms in the blood
bound to plasma proteins (common is albumin)
free or unbound drug (uncoupled from the protein) - active part of the drug
waht is the active part of the drug
free (unbound) drug
what is the car analogy
you sittin in the car, car going on the highway
you are the drug, car is the protein, highway is the blood
once the car and you go to the destination you decouple from the car (cannot bring car into the classroom)
if you didnt want to get out of the car, you wouldnt get
one that leaves the car (protein) unbound = bring about the change
one that stays in the car (protein) bound = no action brought about
10 molecules are now unbound so now they do the same thing and as they do their thing 10 more get unbound
not all of them get unbound
how much of free drug is available based on
chemicals in body and chemicals in the drug
What is Protein Binding?
When a drug enters your bloodstream, some of it attaches to proteins like albumin, which are floating in your blood. This is called “protein binding.” Think of it as a drug hitching a ride on a protein.
What Happens When a Drug Binds to Proteins?
If a drug is bound to a protein, it stays in the blood and cannot move into other parts of the body (like tissues or organs) to do its job. The drug is essentially “stuck” in the bloodstream.
What About Drugs That Don’t Bind Much to Proteins?
Drugs that don’t bind strongly to these proteins (like Drug A) can easily leave the bloodstream and spread into different parts of the body. This allows them to quickly reach their target and start working. However, they also get eliminated from the body faster because they are free to move to organs that clear drugs out of your system (like the liver or kidneys).
Examples: Acetaminophen (Tylenol) and nicotine.
Drugs That Bind Strongly to Proteins:
Some drugs (like Drug B) bind very strongly to proteins in the blood. Because they are mostly bound, only a small portion of the drug is free to move out of the bloodstream and into the tissues where it needs to work. This means that to get enough of the drug into the tissues, you need a higher total amount of the drug in your blood.
Examples: Naproxen (a pain reliever) and warfarin (a blood thinner).
Easily moves into tissues, works quickly, and is cleared out fast. You don’t need much of it in your blood.
low protein binding drug a
Stays mostly in the blood, needs a higher amount to get enough of it into tissues, and is cleared out more slowly.
high protein binding
drug b
what is drug metabolism
process which biochemical reactions alter within the body
aka drug biotransformation
breaks down the drug to be excreted from the body
reactions convert lipid-soluble drugs to water soluble metabolites so the drugs can more easily be excreted by the kidneys
true
_____ contains greatest quantity and diversity of metabolic enzymes
liver
majority of drug metabolism happens in the
liver
other drug metabolism happens in
kidneys, lungs, nerves, skin, plasma & GI tract
biotransformation reactions are classified as
Oxidation/Reduction or Phase I
Conjugation/Hydrolysis or Phase II reactions
what is phase I
modifies chemical structure of a drug through oxidation reduction & liver has enzymes to facilitate these rxns
what is the most common pathway in the liver
Cytochrome P450 system or CYP enzymes
primary machine for metabolizing drug
cyp enzymes
how much in your liver determine how fast drug breaks down & is removed
true
cyp enzymes
more CYP =
faster drug metabolism
less CYP =
slower drug metabolism
mediates oxidative reactions
Cytochrome P450 system or CYP enzymes
the specific set of CYP enzymes a person has in their livers affects
how fast they can break down and process drugs - amount CYP
these enzymes are involved in metabolizing about 75% of all drugs used today
Cytochrome P450 system or CYP enzymes
If cytochrome P450 liver enzymes (CYP enzymes) are induced, it
if you increase the enzyme you increase metabolism (faster break down) so the drug leaves the body faster - inverse effects = induced (increasing the rate of metabolism would decrease the action of the drug
If cytochrome P450 liver enzymes are inhibited, it
if there is less of the enzyme there is decreased metabolism (less breakdown) so the drug stays in the body faster = inhibited (decreasing the rate of metabolism would increase the action of the drug
what is a prodrug
Some drugs are administered in an inactive prodrug form so that they can be metabolically altered in the liver to the activated form
drug that doesn’t become active until going through metabolic phase I used to not lose as much of the drug in the liver
prodrug helps to
facilitate oral bioavailability
decrease GI toxicity
prolong elimination of ½ life of a drug
Differences bw Phase I Metabolism & First-Pass Metabolism
first phase of metabolism in the liver
after drug has exerted its effect and gone to receptor organs and now it is taken out of the body here and happens for all types of route of administer
what is first pass metabolism?
happens in the liver but happens with oral meds and it detoxifies it and happens before it goes into the bloodstream
before the drug goes to the receptor organs and only happens for the oral route
location is the same but function and ____ are different
what is phase II
Conjugation/Hydrolysis
these reactions hydrolyze or conjugate a drug to a larger polar molecule by adding other molecular groups such as glutathione, sulfate, and acetate
This reaction inactivates the drug or enhances the drug solubility and excretion rate into urine or bile
what is conjugation
forming a compound by joining two or more chemical compounds
what is hydrolysis
reaction involving breaking of a bond in a molecule using water
effect of Phase I & II on a drug are dependent on presence of
other drugs taken at the same time
some drug classes, like barbiturates, are powerful _____ of enzymes mediating Phase I reactions
inducers
what do barbiturates do to metabolic process
barbiturates speed up metabolic process & decrease action of drugs being taken simultaneously - drug leaves the body faster
what does erythromycin do to enzymes in metabolic process
can inhibit these enzymes
slow down the metabolic process and increase action of drugs being taken simultaneously - drug stays in the body longer
what is polypharmacology
taking several drugs together
drug to drug interactions are important for setting appropriate drug dosage and monitoring adverse effects
true
Outcomes of Phase I & II reactions; the liver can
convert active drug to inactive - most common outcome; inactive drug formed from the parent drug
convert inactive drug form (prodrug) to active - inactive parent drug is converted to active drug after metabolism
convert active drug to active - active parent drug is converted to a second active drug
what is the function of phase I and II biotransformation
to enhance the hydrophilic nature of a hydrophobic drug so it can excrete out of the body easily
what is drug excretion
movement of a drug and or its metabolites out of the body
how is a drug primariliy excreted?
primarily through renal excretion (urine) & biliary excretion (feces
minor through respiratory (breath – i.e., alcohol, useful for Breathalyzer), and dermal routes (sweat) & smaller through breast milk during lactation
renal flow comprises ~_____% of total systemic blood flow
25
what happens if a drug is still fat soluble when it reaches the kidney
it will be reabsorbed by the kidneys and placed back into the bloodstream
what happens if kidney function is affected
excretion of the drug will take longer and can increase drug toxicity
waht kidney conditions affect its function
Age (kidney function declines with age)
Drug toxicity
Altered kidney function from disease such as
diabetes (impaired renal blood supply)
hypertension
renal diseases - polycystic kidneys & glomerulonephritis from any case
cancers
After being metabolized, the drug is excreted out of the body
Primarily through
the kidneys (urine), liver (bile), and gut (feces)
waht is drug clearance?
rate of elimination of drug from body relative to the concentration of the drug in the plasma
rate at which drug would need to be cleared from the plasma to account for the change sought by the drug in the body
what is drug clearance equation
Clearance = Metabolism + Excretion ÷ Drug(plasma)
Metabolism and excretion are expressed as rates (amount ÷ time)
what are clearance mechanisms
metabolism and excretion
Although metabolism and excretion (collectively called clearance mechanisms) are different physiologic processes, the endpoint is equivalent
Reduction in circulating levels of an active drug
Clearance(total) = Clearance(renal) + Clearance(hepatic) + Clearance(other)
what are drug elimination kinetics
zero order and first order elimination kinetics
Elimination of a constant quantity per time unit of the drug quantity present in the organism
zero order elimination kinetics
Elimination of a constant fraction per time unit of the drug quantity present in the organism
first order elimination kinetics
what drugs are eliminated through zero order
Salicylates, ethanol, and cisplatin
what drugs are eliminated through first order
The elimination is proportional to the drug concentration
95% of drugs are eliminated in this fashion
what is a drug half life
time required for the serum drug concentration to decrease by 50% (T½)
quickly removed from the body; short duration of action
short half life
slowly removed from the body; long duration of action
long half life
drug is cleared (removed) from body in ~ ______ half-lives
four to five
Renal failure ______ excretion rates and _______ the half-life of drugs
decreases
increases
Knowledge of half-life allows the estimation for frequency of dosing of the drug required to maintain the therapeutic range of the drug in plasma
true
most drugs are eliminated by zero-order kinetics
false
first order
all factors affecting the volume of distribution and clearance of a drug also affect
half life of a drug
formula used to calculate the elimination half-life of a drug based on the volume of distribution and clearance of the drug
t1/2 = 0.693 x Vd ÷ Clearance
which one bypasses all barriers? what is the risk?
intrathecal - directly into the CSF and bypassess because of this.
risk: blow past the barriers, acts immediately, if anything goes wrong (allergy etc.) there isn’t much time to react
what is wrong with zero order kinetics?
ex: 100 mg in body, but for this drug, body removes 20 mg but if there is 200 mg it sti8ll only removes 20 mg
what is the issue with this? becomes toxic
what is zero order kinetics
amount of drug present, body will eliminate a constant amount no matter how much is in the body
what is first order kinetics
if the level in body goes up (higher medication), the amount leaving the body also goes up
adaptive
constant
zero order
proportional
first order
how much time the drug will be in the body
half life
half life is constant for most drugs
true
how do we measure a drug concentration
measure drug amount in the body by concentraton of the drug in the plasma because it is the easiest way to do it
long half life
slowly removed from the body
short half life
doesn’t stay in the body long
what is steady state
amount you want in the bloodstream to brig about the best change you want from the drug
it takes about four to five half-lives for a drug to build up to a steady state (level amount) in the body
true
if drug is in body longer, half life increases, which increases concentration
true
what is t1/2
elimination half life
what is Vd
volume of distribution
what is .693
approximation of inverse of 2
what is the formula to calculate elimination half life of a drug
t1/2 = 0.693 x Vd ÷ Clearance
what is redistribution of drugs
movement of drugs from specific site of action to nonspecific sites of action
redistribution to a nonspecific sites will terminate the drug’s action
true
what are examples of redistribution
An “induction” agent is administered to induce sleep before anesthesia for surgery
After a few minutes, the action is terminated
Because the drug has been redistributed from the CNS via the plasma to skeletal muscle (action terminated) to fat depots in the body (no action)
A highly absorbed drug generally requires
lower dose than a poorly absorbed drug
A highly distributed drug requires
higher drug doses
The elimination rate of a drug influences
its half-life and, therefore, determines the frequency of drug doses to maintain therapeutic levels
liver and kidney function (involved in cleaerance) affect
½ life and drug dosage
The therapeutic dosing of a drug seeks to maintain
trough (lowest) plasma concentration above minimally effective levels
peak (highest) plasma concentration below toxic levels
range of dosage
the most you can give to get the effect or the least amount you can give to bring about the therapeutic change wanted
what is steady state accumulation
At a regular dosing frequency, the drug does not accumulate, and a steady state (equilibrium) is reached
Steady-state occurs because the elimination process is concentration dependent
The higher the drug concentration, the _____ is the amount eliminated per unit time
greater
After several doses, the plasma drug concentration will have climbed to a level at which
the amounts eliminated and taken in per unit of time become equal – steady state is reached
It takes about four to five half-lives of a drug to build up to a steady state level in the body
true
what is a loading dose
Higher initial or loading dose of drugs administered to compensate for drug distribution in the tissues from plasma
what is a maintenance dose
Once steady state is reached, subsequent drug doses must replace only what is lost through metabolism and excretion
Most drug elimination follows first-order kinetics meaning
Elimination increases as drug concentration in plasma increases
what happens when the body metabolism is saturated at therapeutic or slightly above therapeutic values
elimination may change from first-order to zero-order kinetics
elimination rate then doesn’t increase with increasing concentration
Continuous drug administration in such cases, can result in rapid drug accumulation with drug concentrations reaching toxic values
