Principles of Pharm- Quiz 1 Flashcards
What is Pharmacokinetics?
What the body does to a drug
What 4 things determine the onset, intensity, and duration of action of a drug?
- Absorption
- Distribution
- Metabolism
- Elimination
What is the pKa value?
A method used to indicate the strength of an acid.
A lower pKa value indicates a STRONGER acid.
The LOWER value indicates the acid more FULLY DISSOCIATES in WATER.
Absorption
From the moment of administration, absorption allows entry of the drug [either
directly or indirectly] into the plasma
Distribution
Next, the drug
may reversibly
leave the
bloodstream
and distribute
into the
interstitial and
intracellular
fluids
Metabolism (drug)
3rdstep—
metabolism
cause the drug to
be biotransformed
through metabolism by the liver or other organs
Elimination
The drug and
its metabolites are then
eliminated from the body—and excreted via
the urine bile or feces
Enteral Routes of Administration
Pharmacological Implications
Oral
Buccal
Sublingual
-Most common, convenient and economical method
-Toxicities and/or overdose of oral drugs may be overcome with antidotes like activated charcoal
-low gastric pH inactivates some drugs
-Enteric-coated drugs
-Extended release drugs
Routes of Parenteral Administration
Pharmacological Implications
IV
IM
SQ
Intradermal
-Route is irreversible
-Provides the most control over the dose delivered
-Since this way introduces the drug directly into systemic circulation it is used for drugs poorly absorbed from the GI tract, patients unable to take PO meds, and when you need a rapid onset of action
Other routes of administration (Other than Enteral or parenteral)
-Oral Inhalation
-Nasal Inhalation
—Rapid delivery to large amounts of mucus membrane of lung
—Drugs that are gasses or aerosols
—Convenient with respiratory disorders as it is delivered directly to the location of action
-Intrathecal or Intraventricular
—Bypasses the BBB delivering drugs directly into the CSF and therefore the CNS
—Used if local or rapid effects are needed, or if needed drug is unable to cross BBB
-Topical
—Used when a local effect is needed
-Transdermal
—systemic effects when applied to skin
—absorption can VARY SIGNIFICANTLY
-Rectal
—Biotransformation of drug by liver is minimal (bypasses 1st pass), prevents GI destruction of drug.
—Useful if can’t take PO, vomiting
—Absorption is erratic and incomplete, many drugs irritate the rectal tissues
What is Absorption
-Transfer of a drug from the site of where it is
given into the bloodstream
-Rate of absorption depends on environment
where drug is absorbed, chemical
characteristics of the drug and route
What are the 4 mechanisms of Absorption from the GI tract?
- Passive Diffusion
- Facilitated Diffusion
- Active Transport
- Endocytosis/Exocytosis
What is 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
What is Facilitated Diffusion?
-Drug enters 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
What is 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
What is Endo/Exocytosis
-Used to transport drugs that are very large across cell membranes
-Endocytosis involves engulfing a drug by the membrane and transporting it into the cell by pinching off the drug filled vesicle
-Exocytosis is the opposite, cells secrete substances out of the cell through a similar process of vesicle formation
What factors influence absorption?
-pH
-Blood flow: intestines receive more blood flow than the stomach, so absorption of the intestines is preferred over the stomach
-Total surface area available: when a surface is rich in brush boarders containing microvilli the intestine has a surface areas 1000x than the stomach
-Contact time: if a drug moves through the GI tract quickly, it is NOT well absorbed. Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption
-Expression of P-glycoprotein
What kind of drugs pass more readily?
UNCHARGED
Why is drug pH a significant factor for absorption?
-Most drugs are either weak acids or weak bases
–acid drugs release a proton becoming
a charged form
–while bases are usually charged and when they lose a proton, they
become an uncharged base
—Drugs pass through membranes more readily
if it is UNCHARGED
How is pH related to pKa?
-Effective concentration of the permeable form of each drug at the absorption site is determined by the relative concentrations of the charged and uncharged forms
-Ratio between the 2 forms is determined by the pH at the site of
absorption and by the strength of the weak acid or weak base—which
is represented by the ionized constant pKa
-The lower the pKa of a drug, the more acidic it is
-The higher the pKa of a drug—the more basic it is
What is distribution equilibrium?
Distribution equilibrium occurs when the permeable form of a drug reaches an equal amount in all body water spaces
What is P-glycoprotein?
Where is it found?
What does it do?
-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 50mg of a drug is given PO, and 25mg is absorbed unchanged, then the bioavailability of the drug is 0.5 or 50%
-This is important for calculating dosages for non-intravenous routes
How is bioavailability determined?
-Compare plasma levels of a drug after a particular route of
administration with levels achieved by IV route
-Plotting concentrations of the drug vs. time, the area under the curve [AUC] can be measured
-Bioavailability is AUC of oral dose ÷AUC of IV dose multiplied by 100%
What factors influence bioavailability?
-First pass
-Solubility of the drug
-Chemical instability
-Nature of the drug
formulation
*IV drugs have a 100% bioavailability
**With oral agents-drugs undergo 1stpass metabolism, in addition, chemical and physical properties determine rate and extent to which the drug reaches the
systemic circulation
How does first pass work?
Why is this important to know?
-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
**—-This is 1stpass metabolism
-1stpass metabolism by the intestine or liver limits efficacy of many PO meds
-Drugs with high 1stpass metabolism must be given in doses sufficient to ensure that enough active drug reaches the desired site of action
How does solubility of a drug affect 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 stability affect 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 drug formulation affect 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?
What is pharmaceutical equivalence?
What is therapeutic equivalence?
-Drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood levels
-Drugs are therapeutically equivalent if they are pharmaceutically equivalent—with similar clinical and safety profiles
-Therapeutic Equivalence requires that drug products are bioequivalent and pharmaceutically equivalent
What is drug distribution?
-Process where a drug reversibly leaves the bloodstream and enters extracellular fluids and tissues
-For drugs given IV—absorption is not a factor, distribution begins immediately, where the drug leaves the circulation and enters the tissues
-Distribution depends 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 to different types of tissue affect distribution?
-Blood flow to brain, liver, and kidney is > than skeletal muscle
-Adipose tissue, skin and viscera have even lower rates of blood flow.
-High blood flow + high lipophilicity = rapid distribution to CNS
–slower distribution to skeletal muscle and adipose tissue
How does capillary permeability affect the movement of drugs into the CNS?
-Permeability determined by capillary structure and chemical nature of drug
-To get to the brain, drugs must pass thought the endothelial cells of the CNS capillaries or undergo active transport
-Lipid soluble drugs readily penetrate the CNS because they dissolve in the endothelial membrane
-Ionized or polar drugs usually fail to enter the CNS because they can’t get through the endothelial cells. This endothelium has no slits and are juxtaposed, having tight junctions that create the BBB.
What protein can serve as a drug reservoir?
Albumin
Why is it important to know that drugs can reversibly bind to plasma proteins?
-Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment
-Albumin is the major drug binding protein—it can serve as a drug reservoir
-As the concentration of free drug decreases, due to elimination, the bound drug dissociates from albumin
Why do we need to be aware of the potential for drugs to bind to plasma proteins and tissues?
-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 an prolong its actions or cause local drug toxicity
How do lipophilic drugs cross biologic membranes?
Dissolve in the lipid membrane and penetrate entire cell surface.
Move readily across most biologic membranes.
How do hydrophilic drugs move across a biologic membrane?
Hydrophilic drugs DO NOT readily penetrate cell membranes, must pass through SLIT JUNCTIONS
What is the 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
-It is calculated by dividing the dose that finally gets into the systemic circulation by the plasma concentration zero
-We compare distribution of a drug with the volumes of water compartments in the body
-Once a drug enters the body, it has the potential to distribute into one of 3 compartments—plasma, ECF, ICF
What does it mean if a drug has a LOW Vd?
What volume would it approximate?
If drug has high molecular weight [or extensively protein bound]—too large to pass through slit junctions of the capillaries, and thus is sort of “trapped” within the plasma [vascular] compartment
-It has a low Vd that approximates the plasma volume [or about 4L; Heparin is such a drug]
*Low Vd = High vascular concentration
***What does it mean if a drug has mid range Vd?
What volume does it approximate?
-If a drug has a low molecular weight but is hydrophilic, it can pass through endothelial slit junctions of the capillaries into the interstitial fluids
-Hydrophilic drugs can’t move across the lipid membranes of cells to enter into the ICF
-Thus, these drugs distribute into a volume that is the sum of the plasma volume + interstitial fluid, which together make up the ECF [14 L; Aminoglycosides are such drugs]
What does it mean if a drug has a high Vd?
What volume does it approximate?
If a drug has a low molecular weight and enough lipophilicity, it can move into the interstitium via the slit junctions and pass through the cell membranes into the ICF
-These agents have a highVd [42L; Ethanol is such a drug]
-A larger Vd indicates greater distribution into tissues; lower Vd suggests confinement to plasma
or ECF
What are the factors for HIGH Vd?
Why do we care?
-High Lipid soubility
-High Tissue binding
-Results in lower drug levels
What are the factors for LOW Vd?
Why do we care?
-High Water solubility
-High Protein Binding
-Results in Higher drug levels
What is the effect of Vd on 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
What are the three mechanisms for drug metabolism/ elimination?
Hepatic, Biliary or Urinary
What is the common measure of drug clearance?
Half life
What is first order or Linear kinetics?
-Constant fraction of the drug is metabolized per unit of time
-With each ½ life, the
concentration of the drug
decreases by 50%
-Always the same
What is zero order or non-linear kinetics?
-Enzyme saturation takes place by high free drug concentration
-Phenytoin is an example of non-linear kinetics
-Doubled dose does not mean that the drug level will be double at the same ~5 1/2life timeline, it could quadruple so be mindful to check levels and dose slowly.
-Use small dose increases for these medications (another example is warfarin)
-those eliminated from the body at a constant rate, regardless of their concentration in the bloodstream, meaning the same amount of drug is removed per unit time
What is Phase 1 metabolism?
Converts lipophilic drugs into more polar molecules
Phase I reactions usually involves
reduction, oxidation or hydrolysis
What happens in Phase 1 metabolism?
Why is it important?
-Phase I reactions most commonly involved in drug metabolism are catalyzed by cytochrome P450 [CYP]
system
- 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
-Individual drugs may
be a substrate for more
than 1 isoenzyme
What are the 4 most important groups of isoenzymes to prescribers?
CYP 3A4, CYP 3A5
CYP 2D6
CYP 2C8, CYP 2C9
CYP 1A2
Genetic variability in what two CYP450 enzymes are the most likely to cause ADEs?
CYP2D6- low ability to metabolize substrates, may have poor or no response to Codeine
CYP2C subfamily, poor metabolizers for drugs like Clopidogrel
What happens when a drug INDUCES CYP isoenzymes?
increased biotransformation of drugs can cause significant decrease in plasma levels of the drug.
LOW OR NO PHARMACOLOGIC EFFECT
What are the INDUCERS of the 2D9 isoenzyme?
Carbamazepine
Phenobarbital
Rifampin
What are the INDUCERS of the 3A4/3A5 isoenzymes (7)
- Carbamazepine
- Dexamethasone
- Phenobarbital
- Phenytoin
- Rifampin
- Griseofulvin
- St. John’s Wort
What are the natural isoenzyme INDUCERS?
- Tobacco / Marijuana smoke
- Chewing tobacco
- Alcohol
- Charcoal broiled food
- Cabbage, broccoli, brussels sprouts,
cauliflower - Oregano, chasteberry
Carbamazepine is a CYP INDUCER affecting what drug?
What is the outcome?
Cyclosporine
-Decreased immunosuppression
Cigarette smoke is a CYP INDUCER affecting what drug?
What is the outcome?
Theophylline
Asthma attack
Rifampin is a CYP INDUCER affecting what drug?
What is the outcome?
Oral contraceptives
Pregnancy
Alcohol is a CYP INDUCER affecting what drug?
What is the outcome?
Acetaminophen
Liver toxicity
St. John’s Wort is a CYP INDUCER affecting what drugS?
What is the outcome?
Warfarin
Digoxin
Theophylline
Protease Inhibitors
NNRTIs (non-nucleotide reverse transcriptase inhibitors- treats HIV)
MANY OTHERS
MANY MANY MANY EFFECTS
What happens when a drug INHIBITS CYP isoenzymes?
What are the most important ones?
Increased levels and significant ADEs or toxicity
Erythromycin, Ketoconazole, Ritonavir
What are the CYP isoenzyme INHIBITING drugs? (10)
Cimetidine
Estrogens
Macrolide Abx
Azole antifungals
Izoniazid (INH for TB)
Amiodarone
Sulfonamides
Ritonavir
Some SSRIs (Fluoxetine, paroxetine)
What are the natural CYP isoenzyme INHIBITORS? (9)
Grapefruit/juice
Licorice
Black Tea
Chamomile Tea
Milk thistle
Cloves
Ginger
Kava Kava
Acute alcohol ingestion
Cimetidine is a CYP INHIBITOR affecting what drug?
What is the outcome?
Warfarin
Hemorrhage
Erythromycin is a CYP INHIBITOR affecting what drug?
What is the outcome?
Glyburide- Hypoglycemia
Lovastatin- Myalgias (most statins but this one the most)
Ketoconazole is a CYP INHIBITOR affecting what drug?
What is the outcome?
Cyclosporine
INCREASED immunosuppression
Fluoxetine/Paroxetine is a CYP INHIBITOR affecting what drug?
What is the outcome?
Dextromethorphan
CNS depression
Grapefruit is a CYP INHIBITOR affecting what drug?
What is the outcome?
Fluvastatin (or any statin)
Increased GI side effects, increased myalgias
Phase 1 metabolism not involving the CYP system
Amine Oxidation (catecholamines, histamines)
Alcohol Dehydrogenation
Esterases (asa liver metabolism)
Hydrolysis
What are the Phase II metabolism pathways?
Conjugation rxns
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
Glucoronidation, sulfadation
What is the most important conjugation reaction?
Glucuronidation
Most common and most important
The highly polar drug conjugates are then excreted by the kidney or in the bile
Where does drug secretion mostly occur?
Proximal tubules using active transport systems, one for weak acids and one for weak bases
Competition between drugs for the carriers can occur within each of these transporter systems
Decreased clearance in the neonate
Preemies and neonates have an underdeveloped tubular secretion system and mechanism, therefore they can RETAIN certain drugs
Higher risk for toxicity
How does distal tubular resorption work?
-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
—–Create a gradient
What are the modalities of excretion?
Urine, intestines, bile, lungs and breast milk
-Drugs that are not absorbed after oral intake or drugs that are secreted directly into the intestines or bile are excreted in the feces
-Lungs primarily eliminate anesthetic gases
What is Total body clearance?
Who are the key players?
Total body [systemic] clearance is the sum of all clearances from drug metabolizing and drug eliminating organs
-Kidney is major organ of excretion
-Liver is also a major player—metabolizing and/or excreting drug into bile
What variables might extend a drug half life?
Diminished renal or hepatic blood flow
——Cardiogenic shock, heart failure, hemorrhage
Decreased ability to extract the drug from the plasma
—–Renal failure
Decreased metabolism
—–when a concomitant drug inhibits metabolism, cirrhosis
Be sure to DECREASE the dose or decrease dosing intervals
What might decrease a drug half life?
Increased hepatic blood flow
Decreased protein binding
Increased metabolism
These patients need higher doses or more frequent doses to achieve steady state
What is the steady state?
When the rate of drug elimination is equal to the rate of drug administration
-Attempt to maintain plasma and tissue levels relatively constant
How long does it take a drug to reach steady state?
4-5x 1/2 life
If an infusion is running 4-5 half lives it will reach steady state, after it’s stopped the plasma concentration of the drug washes out to zero in the same time needed to achieve steady state
What is the effect of dose frequency with PO medications?
- 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
How do you optimize the dose?
Goal—achieve and maintain concentrations within a
therapeutic response window while minimizing toxic and
ADEs
With careful titration, most drugs can achieve this
If therapeutic window of the drug is small—use caution
with the starting dose and monitor drug levels
Drugs given a maintenance therapy may need a loading
dose
What is the purpose of a loading dose?
Loading dose is given to achieve the desired plasma level
quickly—followed by a maintenance dose to maintain the SS
How do you calculate how much to give as a loading dose?
Calculate Loading Dose
Vd x desired SS plasma concentration ÷bioavailability
What are the disadvantages of a loading dose?
-Disadvantages—increase risk of drug toxicity and longer time for plasma concentration to fall if excess levels occur
