exam 1 Flashcards
Transfer of drug from site of administration to systemic circulation
Absorption
Transfer of drug from systemic circulation
Distribution
Enzymatic alteration of a drug
Metabolism
Removal of a drug from the body
Excretion
metabolism + excretion
Elimination
Action of the drug on the body
The reason you take the drug
Pharmacodynamics
Action of the body on the drug
Fate of the drug in the body
“ADME”
Pharmacokinetics
The more _____________ the drug, the easier it is to cross the cell membrane
lipophilic
Hydrophilic
heads
lipophilic:
tails
The extent of drug absorption
bioavailability (F)
what is the primary area of absorption
duodenum
(dissolution + disintegration = stomach)
reflects loss of drug due to hepatic (and intestinal) metabolism on the way to the systemic circulation
first pass effect
what type of drug form diffuses across membrane
NON-ionized (lipid soluble)
where does the majority of metabolism occur
plasma or central compartment (where the kidneys and the liver reside)
true or false
IV (both infusion and single dose/bolus) are always 100% or 1
true
what are the 3 steps of distribution
1st disintegration: drug leaves the capsule; optional step (e.g., suspensions)
2nd dissolution: drug molecules dissolve in gastric fluid
3rd absorption
_____________ = metabolism + excretion
elimination
The more ____________ the drug, the easier it is to cross the barrier
lipophilic
the heads of the membrane are _______________
Hydrophilic
the tails of the membrane are ________________
Lipophilic
______hill Transport = Passive
DOWN
What is an example of passive diffusion
facilitated diffusion
particles that are transported by facilitated diffusion (passively) are (4):
o Small (monomers)
o Polar (water-soluble/hydrophilic)
o Charged ions (e.g., glucose, Ca, Cl, Na, K)
o Transport proteins (e.g., membrane transporters)
2 types of facilitated diffusion
pores/channels
carrier proteins
___hill Transport = Active
UP
factors that influence the GI tract
- GI motility
- Gastric emptying
- Intestinal motility
- Perfusion of the GI tract
- Presence of other drugs
- Presence or absence of food
second opportunity to be absorbed
enterohepatic recycling
which form is most easily absorbed
un-ionized form
Primary site for drug:
disintegration + dissolution
stomach
Primary site for oral drug:
absorption
duodenum
binding to tissue/protein components
ADsorption
water-soluble, high protein binding
small/low Vd
lipid-soluble, low protein binding
large/high Vd
> ____% protein bound = highly protein bound
this IS clinically relevant for protein binding issues
> 90%
what 3 things create DIFFICULT transport
tight junctions
astrocytes
pericytes
what 2 things create EASY transport
lipophilic/un-ionized
small molecular weight
If an efflux transporter is exposed to a drug inhibitor (preventing the efflux pump from working properly), it will ___________ the likelihood of absorption
ENHANCE
EFFLUX transporter example
ATP-Binding Cassette (ABC) Transporters
INFLUX transporter example
Solute Carrier Transporters (SCT)
Factors Impacting Drug Binding for HIGHLY Bound (>90%) Plasma Proteins
- Protein concentration
- Protein size (Da, kDa)
- Number of protein binding sites; bound (CB)
- Association binding constant
o Measure of the tightness of the binding (whether the drug can detach from a protein easily) - Concentration of unbound drug (Cu) or free drug (Cf)
hydrostatic balance; keeps the blood volume intact
medium MW
large concentration
albumin
medium MW
VARIABLE concentration (goes up in times of stress; non-detectable in healthy people)
a1-acid glycoprotein (AAG)
protein carrier of fat
large MW
small concentration
lipoprotein
Factors that Decrease Albumin Concentrations
decreased protein synthesis
liver dx
Factors that Decrease Albumin Concentrations
excess elimination of protein
kidney dx
Factors that Decrease Albumin Concentrations
increased protein catabolism
trauma, surgery
Factors that Decrease Albumin Concentrations
decreased protein synthesis and increased protein catabolism
malnutrition
Factors that Decrease Albumin Concentrations
distribution of albumin into extravascular space
burns
Metabolism =
Biotransformation
* Enzymatic (usually) or non-enzymatic
what 3 things impact the liver metabolism
blood flow
enzyme activity
protein binding
the liver makes the drug more ______________, _____________ the polarity (so that the kidneys can eliminate it)
HYDROphilic
INCREASED polarity
so that it can be eliminated
- Drugs are transported into hepatocytes by
o 1) Passive diffusion
o 2) Carrier-mediated transport
4 Major Consequence of Drug Biotransformation/Metabolism
- Increase in water solubility
- Increase in rate of elimination
- Termination of biologic activity
- Bioactivation (desired or undesired)
Something that is not pharmacologically activated until the body does something to activate it
Normally metabolized to their active form, and then can be metabolized further
prodrug/desired drug
codeine
Instead of being inactive, it is __________, and could be transformed into an active metabolite, same effect, or different effect from a drug
active drug
demerol (normeperidine)
superfamily of monooxygenases
Heme-containing enzymes, catalyze the oxidation of organic substances
CYP450
phase 1
of hepatic metabolism
o Conjugation reactions
o Glucuronide
phase 2
of hepatic metabolism
P-Glycoprotein (P-gp) or ABC-B1
ABC transporters
efflux
Proposed to predict the kinetics of drugs such as
digoxin,
cyclosporine
and fexofenadine
P-Glycoprotein (P-gp) or ABC-B1
transporters: influx
SLC transporters (solute carrier)
Located on both the basolateral/blood/plasma side and the apical/lumen/organ side
SLC (influx) + ABC (efflux)
plasma/blood
side
basolateral
lumen/organ
side
apical
most important factor for excretion
nephron
transporters actively making the drug more concentrated in the urine
secretion
(example: abx)
drug gets placed back into the plasma/blood from the urine; GIVE EXAMPLE
reabsorption
lithium is example
If clearance of a drug is LESS than < 120 ml/min, then we know the drug is filtered + net ___________________
reabsorption
If clearance of a drug is MORE than > 120 ml/min, then we know the drug is filtered + net ______________
secretion
taken back up through the portal vein into the liver
enterohepatic recycling
Excretes drug by emptying into the duodenum
bile
_______________ ____________ is why some drugs have a long half-life
enterohepatic recycling
Primary drug of
biliary extraction (intact or as metabolites)
diazepam
Primary drug of
enterohepatic circulation:
morphine
Determinants in the Selection of Drug Route
- Type of desired effect
- Physiochemical properties
- Rapidity of effect
- Quality of effect
- Condition of patient
Pharmacokinetic Parameters:
Assessment of ________________
Bioavailability
Max concentration
Cmax
Time to max concentration
Tmax
the % of the drug available to systemic circulation
fraction absorbed from gut
The rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action
Bioavailability (F)
rate + extent of drug exposure in the body
Area Under the Curve (AUC)
RATE of ELIMINATION, per unit of time
K
hr-1, min-1, sec-1
Rate of elimination, per unit of time (K)
o Linear vs. non-linear (____________-________)
Michaelis-Menten
VOLUME of drug eliminated per unit of time
clearance (Cl)
ml/hr, L/min
only ml or L!
hour, min, seconds
t 1/2 life
5 x t1/2 =
steady state
ml or L only
Vd
The comparison of bioavailability of different formulations, drug products, doses, or batches of the SAME drug product
Example: tablet vs solution
bioequivalence
example of drug with narrow therapeutic index/range
phenytoin
most drugs have a _______ therapeutic index
WIDE
peak (tied to _________) and a trough (tied to _________)
efficacy
toxicity
AUC:MIC
AUC: minimum inhibitory concentration (MIC) needed to kill off bacteria
amount= changes
fraction= constant
first order
most common route of elimination
follows natural log
K= h-1, sec-1, min-1
first order
amount=constant
fraction=changes
example: ethanol/beer
zero order
least common
K0 = amount/time (mg/h, g/h, mcg/min)
“Saturation Kinetics”
zero order
1st: First-order elimination
at low amounts
2nd: Zero-order elimination at high amounts/saturation
Mixed order (Michaelis-Menten)
example of mixed order
phenytoin
2 phases:
1st: Alpha=distribution phase
2nd: Beta=elimination phase
TWO-compartment model
Hydrophilic
Bound drug
Example: digoxin
(not in the heart right away, takes time to equilibrate between plasma and heart tissue)
TWO-compartment model
Instantaneous
Lipophilic
Unbound drug
ONE-Compartment model
1st: central/plasma
2nd: rapidly goes into CNS
3rd: slowly goes into fat or adipose tissue (leading to drug accumulation and side effects)
Example: general anesthetics
THREE-compartment model
4 main hepatic enzymes
- CYP3A4
- CYP2C9
- CYP2C19
- CYP2D6
fraction not bound to protein
fu
innate ability of liver enzymes to metabolize (intrinsic clearance)
Cl int
well-stirred model
hepatic clearance
impacted by:
1) QH: liver blood flow
2) Clint: innate ability of liver enzymes to metabolize (intrinsic clearance)
3) fu: fraction NOT bound to protein
bioavailability provides evidence by understanding how much of a drug is metabolized*
first pass effect
Absolute: AUCPO x DoseIV/ AUCIV x DosePO
Basis for determining GFR in the clinical setting
This is because it is almost exclusively filtered by the kidneys
Creatinine Clearance (CrCl)
equation that utilizes serum creatinine for GFR estimation
Cockcroft and Gault Equation
fraction excreted unchanged in the urine
fe
Assumptions/True Statements:
Bioavailability (F) = 1 or 100% is available at time zero (0)
C0 (initial concentration), Tmax, Vd = 100% of drug delivery
Not effected by the “first pass effect”
IV bolus
One Compartment Model = ___________ Compartment
CENTRAL
primarily hydrophilic drugs
Assumptions/True Statements:
Vd is complete at time = 0 (Tmax)
Distribution equilibrium is instantaneous
IV BOLUS + ONE comparment model
mcg/ml, mg/L, etc
AUC
concentration at a given time
Ct
initial concentration at time=0
Co
RATE of elimination between Co and Ct
K
time between Co and Ct
T
Assumptions/True Statements:
Bioavailability (F) = 1 or 100%
You CANNOT assume that 100% of the drug is there at time = 0 (Co = 0)
Cmax, Tmax, Vd = 100% of drug delivery
Enters the body: zero order
Leaves the body: first order elimination
IV INFUSION
C0 (initial concentration), Tmax, Vd = 100% of drug delivery
Tmax = time 0
bolus
Cmax, Tmax, Vd = 100% of drug delivery
infusion
true or false
amount/concentration eliminated is HIGHER at the beginning in FIRST order
true
takes into account ln, NOT evenly spaced on the Y axis
semi-log paper (first order)
The more the drug-to-enzyme interactions, the ____________ the binding
stronger
The degree to which a drug acts on a given site relative to other sites
selectivity
The dose range of a drug that provides safe and effective therapy with minimal adverse effects
therapeutic window
Binds to a receptor and turns it “on”; causing activation of signaling cascades within the cell
agonist
Binds to a receptor and turns it “on”; LESS EFFICACY than full agonists
PARTIAL agonist
Binds to a receptor and does not activate it
antagonist
Most drugs bind to ____ type of receptor
This can result in “non-discriminatory” negative effects
> 1
example: antipsychotics and antidepressants
receptors are STILL THERE, by constantly stimulating it, you keep the G-proteins from interacting with the receptor (the drug binds and no response occurs)
desensitization
Over time, the receptor is physically REMOVED from the membrane, it is not there anymore
down-regulation
true or false
down-regulation occurs with AGONISTS
true
tolerance develops
albuterol, insulin
When a constant stimulus (agonist) is applied to a receptor, the cell’s response will diminish over time
tolerance
RAPID development of tolerance
To achieve the same response: must increase the dose
tachyphylaxis
at the drug/receptor level:
the observed response is not the %, but rather the ___________
number/amount
1,000 receptors at 50% is > 10 receptors at 50%
Over time, more receptors appear on the membrane
Antagonists: constant blockade of a receptor
Sensitivity occurs if meds abruptly stopped
up-regulation
“BUS”
fastest “receptor”
LIGAND-gated ion channels (milliseconds)
example of ion channels
o Examples: nicotinic; Ach
o Drug: Lidocaine, NMBs, Lorazepam
2nd fastest “receptor”
G-protein coupled receptors (GPCRs)
example of G-protein coupled receptors (GPCRs)
o Examples: muscarinic; Ach
o Drug: epi, opioids
6 main types of “receptors”
- 1) Ion channels
- 2) G-protein coupled receptors (GPCRs)
- 3) Transmembrane receptors
- 4) Intracellular receptors
- 5) Extracellular enzymes
- 6) Cell surface adhesion receptors
Shift the dose-response curve to the ______ (more SENSITIVE)
LEFT
lorazepam + GABA
Receptor activated ion channel
example
Muscarinic M2 in the nodal cardiac tissue w/ vagal nerve stimulation; the channel is being altered by a receptor
VOLTAGE Gated
Some drugs bind to the:
Inactivated state (propafenone)
Activated state
Local anesthetics
Neuromuscular, nicotinic
LIGAND GATED ion channels
comprised of abY subunits
heterotrimeric
Alpha a subunit gives up ______, takes on GTP
GDP
GTP is activated
How can closely related GPCRs cause completely OPPOSING cellular responses
TYPE of ALPHA subunit; G PROTEIN types are different
How can UNrelated GPCRs cause a similar cellular response
similar G-protein pathways
What are the 2 steps for drug-receptor binding
1) binding = receptor occupancy
2) activating = tissue response
Numerator=_____________=K off
dissociation
Denominator=______________= K on
association
Kd
the lower the value, the _________ the affinity of the drug
higher
Reflects the ligand concentration at which 50% (half) of all available receptors will be BOUND with ligand
Kd
only _________ can cause a tissue response/activate a receptor
agonists
lower affinity = _________ shift
lower=RIGHT (you need a HIGHER concentration to achieve the % bound)
higher affinity = _________ shift
higher=LEFT
receptor occupancy, % bound
Kd
Bmax
tissue response, % effect
EC50
Emax
effective concentration for 50% (half) of max EFFECT
EC50
the response/effect elicited by a drug
efficacy
efficacy is determined by 2 things
Related to the NUMBER of ligand-receptor complexes formed
Related to the EFFICIENCY in which the ligand-receptor complex can produce a response
How is efficacy assessed from the dose-response graph
How high the Emax plateaus
- Antagonist= 0 efficacy
- Partial agonist= halfway
- Full agonist= all the way at the top (100%)
INVERSELY related to drug concentration required to produce a defined effect or response
potency
Potency is a comparable thing
morphine and fentanyl have the same _________, but different potency
efficacy
HIGHER EC50=*
requires MORE to obtain the same effect
“weaker drug”
surmountable antagonist
Reversible/Surmountable/Competitive
full agonist + reversible antagonist
would cause a ___________ shift
RIGHTward shift (would require additional agonists to achieve the same response)
full agonist + IRreversible antagonist
would cause a ___________ shift
DOWNward shift
because you would have less max attainable effect
example of physiologic antagonists
counteracts each other
glucagon and insulin
example of chemical antagonists
interacts directly with the drug
protamine and heparin
example of a
Partial Agonist + Full Agonist
Abilify
Schizophrenia drug (D2 partial agonist)
Partial Agonist + Full Agonist
EXCESS dopamine
DOWNward shift
Partial Agonist + Full Agonist
DEFICIENT dopamine
UPward shift
- Considered the safety factor of a drug
- The relationship between the amount of drug that causes a specific adverse effect and the amount that causes the desired effect
Therapeutic Index/Range
You want the toxic dose to be __________ than the dose that causes the desired effect*
higher
this causes a wide TR
examples of mismatch between:
Drug Level and Drug Effect
(3)
Irreversible/pseudo-irreversible binding to a receptor
Clotting factors (half-lives of 2-3 days)
Exceptionally high therapeutic index (“very safe” drugs with high doses)
examples of
irreversible/pseudo-irreversible binding to a receptor
- Omeprazole, Plavix, Exelon
Half-life and duration do NOT match up
true or false
Even beta1 selective drugs (like metoprolol) still have some effect on beta2 receptors (CAUTION with asthma)
true
- Once activated, they initiate a phosphorylation cascade
- Similar to G-protein coupled receptor, but uses a different second messenger
- Changes gene transcription, takes hours
- Example: insulin receptor
Kinase Linked Receptors
often in anesthesia; can use lower doses to achieve the same effect
synergistic
1+1=3
usually the drugs act on the same site
additive
effect of one drug with known effect is increased by a 2nd drug that does not have that effect
o Levodopa + carbidopa
potentiation
4 types of CNS depressants that work on GABA
Benzos (versed)
Barbiturates (phenobarbital)
Ethanol
most IV + volatile anesthetics
positive allosteric modulators
increase the (2)
FREQUENCY of the chloride channel opening
or
DURATION of chloride channel opening
Opioids + inhaled anesthetics
Majority effect: ____________
analgesia
Opioids + benzos
effect: ____________
Sedation
is sweating common with PNS symptoms
yes
anti-muscarinics should be cautioned with ____________
elderly
6 examples of anti-muscarinics
Benztropine: treats Parkinson’s
Prochlorperazine: anti-emetic
Diphenhydramine: blocks histamine + muscarinic, motion sickness
Atropine: dries secretions, bradycardia
Glycopyrrolate: dries secretions, bradycardia
Scopolamine: motion sickness, N/V
o Hyperkalemia can cause (6)
Bradycardia
Heart block
Muscle weakness
Flaccid paralysis
Metabolic acidosis
Death
DILATE the AFferent arteriole
(Increase blood flow into glomerulus)
prostagladins
CONSTRICT the EFferent arteriole
(Decreases outflow from glomerulus)
ATII
NSAIDS inhibit _________________
prostaglandins
ACEi/ARBs decrease production of ______
ATII
think “A&A”
long-acting; opioid treatment therapy
naltrexone
With naltrexone levels decreased (at the end of dosing interval), the body has upregulated the opioid receptors, leading to an ________________ response to opioids
exaggerated response!
INCREASE in transporters or metabolizing enzymes
induction
INHIBITION of transporters or metabolizing enzymes
inhibition
with a drug that INHIBITS P-gp activity, ________ digoxin will stay in the body
MORE will stay
with a drug that INDUCES P-gp activity, ________ digoxin will stay in the body
LESS will stay
what are the 4 INDUCERS for CYP3A4*
Carbamazepine
Rifampin
Phenobarbital
Phenytoin
“CRPP”
what are the 8 INHIBITORS for CYP3A4:
macrolide abx (clarithromycin)
verapamil
diltiazem
grapefruit juice
HIV protease inhibitors (ritonavir)
cyclosporines
amiodarone
azoles (antifungals)
“My sons, Vera and Dilt are grapeful to navigate their cycles amid the Azoles.”
with INHIBITORS, it will lead to toxicity, except with ____-_______
pro-drugs
opposite effect (fewer active metabolites are occurring due to inhibition of metabolism; so, there is LESS therapeutic effect; example: codeine)
major types of inhibitors
1) Reversible: temporary
2) Irreversible: permanent
Example: clarithromycin
Which type of drug is more absorbed
non-ionized
Chelation is a type of ____________
absorption
examples of di-valent and tri-valent cations
minerals
Calcium, Iron, Zinc, Magnesium, Aluminum
(Antacids, dietary/vitamin supplements, dairy products)
they DECREASE absorption of some drugs when taken together
when taking minerals, wait at least 2-4 hours for these 3 types of drugs
- TetraCYCLINES (doxycycline, minocycline)
- Quinolones (levofloxacin, moxifloxacin)
- Osteoporosis drugs
INHIBITION leads to
toxicity (except with prodrugs)
INDUCTION leads to
decreased drug effects
Any drug that is ____ protein bound can be passively filtered
NOT protein bound = passive
true or false
URINE filtration is passive and does NOT use transporters
true
it is passive
ligand gated*
how long?
milliseconds
g-protein*
how long?
seconds
kinase-linked*
how long?
hours
nuclear*
how long?
hours
alterations in DNA inherited from a parent and are found in the DNA of virtually all cells
hereditary/germline
alterations in DNA that develop throughout a person’s life
acquired/somatic
examples of pharmacoDYNAMICS
drug-receptor,
agonists/antagonists
therapuetic effect vs toxic effects
downregulation vs upregulation
the reason you take the drug
examples of pharmacoKINETICS
ADME
first pass effect
Vd
Cmax, tmax, bioavailability
human genome started
year
1990
sequencing center
year
2001
finished version of human genome sequence completed
year
2003
laboratory (one illumina sequencer)
year
2017
rare, single gene, several mutations, large phenotypic effect
o Example: down syndrome
mendelian/simple
2 different versions/alleles
polymorphic
DNA variants for which we know the location in the genome and can easily determine a person’s genotype
marker loci
- Tailoring medical prevention and treatment therapies to the characteristics of each patient, improving their quality of life and health outcome
o “The right medicine to the right person at the right dosage at the right time”
precision medicine
Example of Pharmacogenomics (gene)
CYP2D6: codeine
true or false
IV infusion is F=1
true
anything IV, whether infusion or bolus
