Principles of Pharmacology Flashcards
What is pharmacokinetics
what the body does to a drug
What determines pharmockinetics
absorption
distribution
metabolism
elimination
What is absorption
From the moment of administration,
absorption allows entry of the drug [either directly or indirectly] into the plasma
What is distribution
• Next, the drug may reversibly leave the
bloodstream and distribute into the
interstitial and intracellular fluids
What is metabolism
3rd step— metabolism cause the drug to
be biotransformed through metabolism by
the liver or other organs
What is elimination
The drug and its metabolites are then
eliminated from the body—and excreted via the urine bile or feces
Routes of administration
- enteral
- sublingual/buccal
- parenteral (IV, IM, subQ, and intradermal)
- oral inhalation/nasal preparations
- intratheacl/intraventricular
- topical
- transdermal
- rectal
Mechanisms of absorption in GI tract
- passive diffusion
- facilitated diffusion
- active transport
- endocyosis/exocytosis
Passive diffusion
Driving force for passive diffusion of a drug is the concentration gradient across a membrane—the drug moves from an area of high concentration to one of lower concentration
Does not involve a carrier, in not saturable and shows low structural specificity
Vast majority of drugs are absorbed by this
mechanism
Water-soluble drugs penetrate the cell membrane through aqueous channels [pores]
Lipid soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers
Facilitated diffusion
Drug enter the cell through. specialized transmembrane carrier proteins that facilitate the passage of large
molecules
Dose not require energy
Can be saturated
May be inhibited by compounds that compete for the carrier
Active Transport
Specific carrier proteins that span the membrane
Is energy dependent, driven by hydrolysis of ATP
Capable of moving drugs against a concentration gradient, from a region of low drug concentration to an area of higher concentration
Process is saturable
Selective and may be inhibited by other co-transported substances
Endocytosis/exocytosis
-Used to transport drugs that are very large
across cell membranes
-Endocytosis involved engulfing a drug by
the membrane and transporting it into the
cell by pinching off the drug-filled vesicle
-Exocytosis is the opposite—cells can
secrete substances out of the cell through a similar process of vesicle formation
Factors that influence absoprtion
- pH
- blood flow
- total surface area
- contact time
- expression of P-glycoprotein
Drugs that pass through a membrane more readily are
uncharged
What does pKa tell us
The pKa value is one method used to indicate the strength of an acid
pKa is the negative log of the acid dissociation constant or Ka value
A lower pKa value indicates a stronger acid. That is, the lower value indicates the acid more fully
dissociates in water.
What happens in distribution equilibrium
when the permeable form of a drug reaches an equal amount in all body water spaces
Why is absorption in the intestines better than the stomach
- receives more blood flow
2. has more surface area bc of microvilli
What is P-glycoprotein?
- P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules and drugs across cell membranes
- It is in liver, kidneys, placenta, intestines, brain capillaries
- Involved in transportation of drugs from tissues to blood. “it pumps” drugs out of cells
- In areas of high expression—P-glycoprotein reduces drug absorption
- P-glycoprotein is also associated with multidrug resistance
What is bioavailability
- Rate and extent to which a given drug reaches the systemic circulation
- If 50 mg of a drug is given orally and 25 mg is absorbed unchanged—the bioavailability is .5 or 50%
- Bioavailability is important for calculating dosages for nonintravenous routes
How is bioavailability determined?
Compare plasma levels of a drug after a particular route of administration with levels achieved by IV route
What influences bioavailability?
- IV administration is 100% availability bc it goes straight into your system
- Oral agents have to undergo 1st pass metabolism
- solubility of drug
- chemical instability
- natures of drug formulation
What happens in fist pass metabolism?
- Drug absorbed from GI tract—enters the portal circulation before entering systemic circulation
- If drug is rapidly metabolized in liver or gut wall during this passage, the amount of unchanged drug entering the systemic circulation is decreased
- 1st pass metabolism by the intestine or liver limits efficacy of many PO meds
How does solubility of the drug effect bioavailability?
- Very hydrophilic drugs are poorly absorbed
- Drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids and as such cannot get into the surface of the cells
- For a drug to be readily absorbed—it must be largely lipophilic, yet have some solubility in aqueous solution—this is one reason why many drugs are either weak acids are weak bases
How does chemical instability effect bioavailability?
Some drugs are unstable in pH of
gastric contents [PCN G]
Others are destroyed in the GU tract by
degradative enzymes [insulin]
How does the nature of the drug formulation effect bioavailability?
Drug absorption can be altered by factors unrelated to the chemistry of the drug—particle size, salt form, crystal polymorphism, enteric coatings, presence of binders and/or dispensing agents
What is bioequivalence?
Drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood levels
What is therapeutic equivalence?
requires that drug products are bioequivalent and pharmaceutically equivalent
What happens in drug distribution and how does it effect absorption
Process where a drug reversibly leaves the
bloodstream and enters extracellular fluids and tissues
What does distribution depend on?
CO, local blood flow, capillary permeability, tissue volume, degree of binding of the drug to plasma and tissue proteins and relative lipophilicity of the drug
How does blood flow influence absorption?
- Blood flow to brain, liver and kidney is > that to skeletal muscles
- Adipose tissue, skin and viscera have still lower rates of blood flow
- High blood flow + high lipophilicity = rapid distribution into the CNS
How does capillary permeability effect absorption?
- Determined by capillary structure and chemical nature of the drug
- To get into the brain, drugs must pass through endothelial cells of the CNS capillaries or undergo active transport
- Lipid soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane
- Ionized or polar drugs usually fail to enter the CNS because they can’t get through the endothelial cells—these cells have no slits and are juxtaposed—having tight junctions that create the “blood-brain barrier”
What is the major drug binding protein?
albumin
What happens as the concentration of a drug decreases due to elimination?
the bound drug dissociates from albumin
What do reversible binding plasma proteins do?
sequesters the drugs into a nondiffusable form and slows the transfer out of the vascular compartment
What does binding of drugs to plasma proteins and tissue do?
- Many drugs accumulate in tissues—causing higher concentration in tissues than in interstitial fluid and blood
- Drugs can accumulate because of binding to lipids, proteins or nucleic acids
- Tissue reservoirs can serve as a major source of the drug and prolong its actions or cause local drug toxicity
Name 10 highly protein bound drugs
- warfarin
- NSAIDs
- sulfonamides
- PCN
- valporic acid
- phenytoin
- nifedipine
- prazosin
- diazepam
- diphenhydramine
What is lipophplicity?
Lipophilic drugs readily move across most biologic membranes—and dissolve in the lipid membranes and penetrate the entire cell surface
Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions
What is volume of distribution (Vd)?
Fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma
Once a drug enters the body it has 3 potential places to distribute?
- plasma
- ECF-extracellular fluid
- ICF -intracellular fluid
What happens if a drug has a high molecular weight?
It becomes trapped in the plasma bc it is too large to pass through the slit junctions of the capillaries.
Facts about Vd
- if a drug has a low molecular weight and enough lipophilicty, it can move in the interstiitium via the slit junctions and pass through the cell membranes into the ICF
- a larger Vd indicates a greater distribution into tissues; lower Vd suggest confinement to plasma or ECF
Name a drug with a high Vd
ethanol
High Vd
- Caused by high lipid solubility
- Caused by high tissue binding
- Results in lower drug level
Low Vd
- Caused by high water solubility
- Caused by high protein binding
- Results in higher drug level
Effect of Vd on drug 1/2 life
- Because drug elimination depends upon the amount of drug delivered to the liver or kidney per unit of time—Vd can influence the ½ life of a drug
- If a drug has a large Vd, most of the drug is in the extraplasmic space and is unavailable to thee excretory organs
- An unusually large Vd indicates sequestration of the drug in some tissues or compartments
- Any factor that increases Vd can increase the ½ life and extend the duration of action of the drug
How is drug 1/2 life measured?
by metabolism
What happens if phase I metabolism?
-Converts lipophilic drugs into more polar
molecules
- Phase I reactions usually involves
reduction, oxidation or hydrolysis
What is CYP
- CYP important to metabolize endogenous compounds [steroids/lipids], biotransformation of exogenous substances [drugs, carcinogens, pollutants]
- CYP is a superfamily of heme-containing
isoenzymes found mainly in the liver and
GI tract
Name 4 isoenzymes responsible for most CYP catalyzed reactions
- CYP3A4, CYP3A5
- CYP2D6
- CYP 2C8, CYP2C9
- CYP1A2
Patients that have a mutation of CYP2D6, have poor response to_____
codeine
Patients with mutation of CYP2C, are poor metabolizers of ____
clopidogrel
What do CYP inducers do?
they induce CYP isoenzymes to metabolize drugs so there is less in the plasma making them have low or no pharmacologic effect
Name 3 drugs that are CYP2D9 inducers?
- phenobarbital
- rifampin
- carbamazepine
Name 7 inducers of CYP3A4 and CYP3A5
- carbamazepine
- dexamethasone
- phenobarbital
- phenytoin
- rifampin
- griseofulvin
- st. john’s wort
Name 7 natural CYP inducers
- tobacco/marijuana
- chewing tobacco
- alcohol
- charcoal broiled food
- cabbage, broccoli, brussel sprouts, cauliflower
- oregano, chasteberry
What happens if you (inducer) smoke and take theophylline?
asthma attack
What happens if you take (inducer) rifampin with OCPs?
pregnancy
What can CYP inhibitors do?
Inhibition [slows] of drug metabolism—and can lead to increased in drug levels and significant ADEs or toxicity
Name 3 important CYP inhibitors***
- erythromycin
- ketoconazole
- ritonavir
What are some nature inhibitors
- Grapefruit juice
- Licorice
- Black tea
- Chamomile tea
- Milk thistle
- Cloves
- Ginger
- Kava Kava
- Acute alcohol ingestion
What are some inhibiting drugs?
- Cimetidine
- Estrogens
- Macrolide antibiotics
- Azole antifungals
- Fluoroquinolones
- INH
- Amiodarone
- Sulfonamides
- Ritonavir
- Some SSRIs [fluoxetine; paroxetine]
What happens if you take erythromycin (inhibitor) with glyburide or lovasatin?
hypoglycemia
myalgias
What happens if you take (inhibitor) cimetidine with warfarin?
hemorrhage
What happens if phase II metabolism
- Conjugation reactions If the metabolite from phase I is sufficiently polar, it can be excreted by the kidneys
- But many phase I metabolites are still too lipophilic to be secreted
- Subsequent conjugation with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid or an
amino acid results in polar water soluble compounds
What is the most important reaction that happens in phase II metabolism in regards to conjugation?
Glucuronidation
What happens in elimination?
Drugs have to be polar enough to be eliminated by the kidney
Removal of drugs from the body occurs mostly by elimination in the kidney and into the urine
Those with renal compromise may be unable to excrete drugs and are at risk for drug accumulation and ADEs
Glomerular Filtration
Before elimination, several processes take
place—glomerular filtration, proximal tubular
secretion, distal tubular reabsorption
Lipid solubility and pH do not influence the
passage of drugs into the glomerular filtrate
Variations in GFR and protein binding of
drugs affect this process
What happens in proximal tubular secretion?
Secretion offers mostly in the proximal tubules by 2 energy requiring active transport systems—one
for weak acids and one for weak bases
Because premies and neonates have an incompletely developed tubular secretion system and mechanism, they can____
retain certain drugs in their blood
What happens in distal tubular reabsorption
- As a drug moves to the distal tubule, the concentration increases and exceeds that in the perivascular space—if the drug is uncharged, it may diffuse out of nephric lumen back into the systemic circulation
- Manipulating the urine pH to increase the fraction of ionized drug in the lumen can minimize the amount of back diffusion—and increase clearance of the unwanted drug
- Weak acids can be eliminated by alkalizing the urine
- Weak bases can be eliminated by acidifying the urine
Where can drugs be excreted?
intestines, bile, lungs, breast milk
What is total body clearance?
is the sum of all clearances from drug
metabolizing and drug eliminating organs
What 2 organs play an important part in excretion?
kidneys and liver
What can increase a drug’s 1/2 life?
Diminished renal or hepatic blood flow
[cardiogenic shock; HF; hemorrhage]
Decreased ability to extract drug from plasma
[renal failure]
Decreased metabolism[when a concomitant drug inhibits metabolism; hepatic cirrhosis]
If a person has an increased 1/2 life to a drug, what should you do
decrease the dosage of their medication or less frequent dosing intervals
What can decrease a 1/2 and what should you do?
increased hepatic blood flow, decreased protein binding, or increased metabolism
-these pts will need a higher dose of the medication
How many lives does it take for a drug to reach a steady state (SS)?
4- 5 1/2 lives
What is steady state concentration?
is reached when the rate of drug elimination is equal to the rate of drug administration—such that plasma and tissue levels remain relatively constant
What is the effect of dosing frequency?
- When drug is given at regular intervals, plasma concentration of drug oscillates around a mean
- Smaller doses at shorter intervals reduces amplitude of the fluctuations in drug concentration
- Dosing frequency does not change magnitude or rate of achieving SS
What kinds of drugs may need a loading dose?
drugs given for maintenance therapy
How do you calculate loading dose?
Vd x desired SS plasma concentration ÷ bioavailability
What is pKa?
The pKa value is one method used to indicate the strength of an acid
pKa is the negative log of the acid dissociation constant or Ka value
A lower pKa value indicates a stronger acid
The lower value indicates the acid more fully dissociates in water
What kinds of drugs can easily cross the blood brain barrier?
lipid soluble drugs
Which phase II metabolic reaction makes metabolites readily excreted by the urine?
glucuronidation
**Many phase I metabolites are too lipophilic to be retained in the kidney tubules; a subsequent phaseII conjugation reaction with an endogenous substrate, such a glucuronic acid, causes more water-soluble conjugates that excrete readily in the urine
Why would you alkalize urine (give bicarb) for a phenobarbital overdose?
- Usually, weak acid drugs, such as Phenobarbital, can be eliminated faster by alkalization of the urine
- Bicarbonate alkalizes urine and keeps
Phenobarbital ionized, thus decreasing its
reabsorption
What is pharmacodynamics?
what the drugs does to the body
A drug is consider an agonist if____
it binds to a site on a receptor and activated it to start a series of reactions
True or false all drugs exert effects by interacting with a receptor
FALSE
Receptor states
can be inactive (R) or active (R*)
What are antagonists?
drugs that bind to the receptor but
do not increase the amount of activity—instead, stabilizing the amount of inactive receptors
What are partial agonist?
shift the equilibrium from inactive to active—but the fraction of active receptors is LESS than that caused by an agonist
What are receptors
any biological molecule to which a drug binds and produces a response
Examples of receptors
Enzymes, nucleic acids, structural proteins
can act as receptors for drugs or endogenous agonists
Name 4 types of membrane bound protein receptors
- ligand-gated ion channels
- G Protein-couple receptors
- enzyme linked receptors
- intracellular receptors
What do hydrophilic ligands interact with
receptors that are found on the cell surface
How do hydrophobic ligands enter cells?
through lipid bilayers of the cell membrane to interact with receptors found inside the cells
What happens in Desensitization and Down Regulation of Receptors
Repeated or continuous administration of an agonist or an antagonist often leads to
changes in the response of the receptor
The receptor may become desensitized due to too much agonist stimulation—causing a diminished response—in dermatology we call this tachyphylaxis
Tachyphylaxis is from phosphorylation that
renders the receptor unresponsive to the
agonist
Receptors can be internalized in the cell—
making them unavailable for further agonist
interaction—this is down-regulation
Other receptors [especially those in ion
channels] require a finite time after
stimulation before they can become
activated again—during this recovery phase—unresponsive receptors are said to be
refractory
What happens with repeated exposure of a receptor to an antagonist
It results in upregulation of the receptors
Here, the receptor reserves are inserted into the
membrane, increasing the number of receptors
available—upregulation of the receptors makes
the cells MORE sensitive to agonists and/or
more resistant to effects of the antagonist
What happens in graded dose response relationships?
As the dose of a drug increases, its effect also gradually increases until all of the receptors are occupied [maximum effect]
Potency and efficacy can be determined by
graded dose-response curves
What happens in dose response relationships?
- Agonists mimic the action of the endogenous ligand for the receptor
- Amount of drug effects depends on receptor
sensitivity and drug concentration [which is
determined by dose, rate of absorption,
distribution, metabolism and elimination]
What is potency?
- measure of the amount of drug needed to produce an effect
2. concentration of drug producing 50% of max effect EC50 is used to determine potency
What is efficacy?
- Magnitude of response a drug causes when
it interacts with a receptor - Efficacy depends on number of drug receptor complexes formed and intrinsic
activity of the drug—its ability to activate
the receptor and cause a response - Maximum efficacy of a drug Emax assumes
that the drug occupies all receptors and no
increase in response is seen with higher
concentrations of the drug
Which is better potency or efficacy?
Efficacy is more clinically useful than is
potency—a drug with more efficacy is more
therapeutically helpful than one that is potent
What is Kd and what does it mean if it is high or low?
the equilibrium dissociation constant
for the drug from the receptor
- The higher the Kd the weaker the
interaction and the lower the affinity - The lower the Kd the stronger the
interaction and the higher the affinity
What is intrinsic activity?
Agonist binds to a receptor and produces a
biologic response based on concentration of the agonist, its affinity for the receptor and the fraction of the receptors that are occupied which means that Intrinsic activity further determines its ability to
fully or partially activate the receptors
What are full agonists?
If a drug binds to a receptor and produces a maximal biologic response that mimics the response of the endogenous ligand—it is a full agonist
Full agonists bind to the receptor, stabilize it in its active form and have intrinsic activity of 1
All full agonists for a receptor population should
produce the same Emax
What are partial angonists?
- Have intrinsic activities > zero, but < 1
- Even when all of the receptors are occupied,
partial agonists cannot produce the same Emax as a full agonist - Partial agonists can have an affinity that is
greater than, less than or equal to that of a full agonist
What do partial agonists have the ability to do?
A partial agonist may also act as a partial antagonist of a full agonist—as the number of receptors occupied by the partial
agonist increases, the number of receptors left for the full agonists to occupy decreases—and thus, Emax would decrease until it reaches the Emax of the partial agonist
Inverse agonist
Usually, unbound receptors are inactive an need interaction with an agonist to
become active
Some receptors can spontaneously convert from inactive to active form—in the
absence of an agonist
Inverse agonists stabilize the inactive receptor and cause the active receptor to
convert to an inactive state—this decreases the number of activated receptors to
below what is seen in the absence of drug
Inverse agonists have an intrinsic activity less than zero—reverse the activation
state of receptors and exert the opposite pharmacologic effect of agonists
Antagonist
Bind to a receptor with high affinity but have no intrinsic activity ⬇️ An antagonist have no effect on biologic function in the absence of an agonist—but it can decrease the effect of an agonist ⬇️ Antagonism takes place by blocking the drug’s ability to bind or activate the receptor
Competitive antagonist
- If the antagonist binds to the same site on
the receptor as the agonist in a reversible
manner—it is called “competitive” - Competitive antagonists interfere with an
agonist binding to its receptor and
maintains the receptor in its inactive state - Increasing the concentration of agonist
relative to antagonist can overcome this
inhibition
Irreversible Antagonists
Bind covalently to the active site of the
receptor, permanently reducing the number
of receptors available to the agonist
In contrast to competitive antagonists—
addition of more agonist does not overcome
the effect of irreversible antagonists
Name 2 noncompetitive antagonist
- irreversible antagonists
2. allosteric antagonists
Allosteric Antagonists
Binds to a site other than [allosteric] the
agonist-binding site and prevents activation
of the agonist
Foundation of new and novel ways to
antagonize / modulate the effect of drugs
What is functional antagonism?
Antagonist may act at a completely separate
receptor—initiating effects that are functionally opposite of those of the agonist
Ex: Epinephrine and histamine induced bronchoconstriction is classic example of this phenomenon. Histamine binds to H1 receptor causing bronchoconstriction Epi is an agonist of B2 adrenoceptors on bronchial smooth muscle—which causes the muscles to relax In medicine this is termed—physiologic antagonism
Dose response relationships
Important dose-response relationship is that between the dose of the drug and the proportion of a population that patients that respond to it—quantal responses
Quantal dose—response curves are useful to determine doses to which most of the population responds
ED50 is the drug dose that causes a therapeutic response in ½ of the population
What is the therapeutic index
- The ratio of the dose that produces toxicity in ½ of the population [TD50] to the dose that produces the clinically desired or effective response [ED50] in ½ of
the population - TI is the measure of the drug’s safety
- A larger value means a wide margin between doses that are effective and those that are toxic
Name 10 drugs with a low TI that is often used and require therapeutic drug monitoring
- Phenytoin / Carbamazepine /
- Valproic acid
- Warfarin
- Lithium
- Theophylline
- Digoxin
- Aminoglycosides
- evothyroxine
- Vancomycin
- Amphotericin B
**Isoproterenol produced maximal contraction of cardiac muscle in a manner much like Epinephrine. Which of the best describes Isoproterenol?
full agonist
**If 10 mg of Naproxen gives the same analgesic response as 100 mg of
Ibuprofen, which of the following is True?
Naproxen is more potent than is Ibuprofen
**If 10 mg of MSO4 produces a greater analgesic response than can be obtained
with Ibuprofen at any dose, which of the following statements is True?
MSO4 is a better drug to take for pain relief than is Ibuprofen
**Which of the following statements most accurately described a system having
spare receptors?
A single drug-receptor interaction results in many cellular response elements being
activated
An explanation of the existence of spare receptors is
that any 1 agonist-receptor binding event can lead to
the activation of many more cellular response
elements
Thus, only a small fraction of the total receptors
need to be bound to elicit a maximum cellular
response
The other choices do not accurately describe spare
receptor systems
