Unit 1 Flashcards
Pharmacology
the study of the interactions of drugs (chemical substances) with biological systems
MEC = ?
Minimum Effective Concentration
Therapeutic window
difference in plasma concentration [Cp] between the desired and adverse response MEC
Pharmacodynamics
what the drug does to the body (mechanism of action)
-identifies drug target
Pharmacokinetics
what the body does to the drug
absorption, distribution, elimination
Bioavailability (F)
- how much drug reaches its target in the body
- Used for adjustment of dose when route is changed and when designing dosage regimens
F = AUC oral/AUC iv (%)
Time to peak (Tmax or Cmax)
how fast the drug reaches the target in the body
Volume of distribution (Vd)
what dose necessary to obtain desired plasma concentration
Absorption is the process of getting the drug from ______ into __________
site of administration (past membranes)
into the blood stream
Distribution is the process of getting the drug from ___________ to ________
bloodstream to intended target in tissues
Elimination
metabolism/excretion to eliminate drug activity after drug administration
Duration of action (aka ?)
aka half life
how long will the drug stay at its target and exert clinical effects
Factors that determine a drug’s ability to cross biological membranes (4)
1) Molecular size (small MW = better absorption)
2) Lipid solubility (more lipid soluble = cross membrane better)
3) Degree on ionization (more unionized = more lipid soluble = more absorption)
4) Concentration gradient
Mechanisms by which drugs can cross biological membranes (3)
Passive diffusion
Carrier mediated diffusion
Endocytosis
Passive diffusion of drugs can occur via… (2)
1) Aqueous diffusion/filtration of drug through aqueous channel (size dependent)
2) crossing lipid membranes via hydrophobic interactions
Carrier mediated diffusion of drugs can occur via… (2)
1) Facilitated diffusion driven by concentration gradient (no energy required)
2) Active transport - energy dependent, selective, saturable, unidirectional, for drugs which resemble endogenous compound
Enteral routes of drug administration occur via the ________ and include _______ and ________
GI tract
Oral and rectal administration
Oral drug administration bioavailability = ?
Depends on _______ , _________ and ___________
0-100%
Depends on:
1) survival in GI environment
2) ability to cross GI membrane
3) Efficiency of drug metabolism by gut wall or liver (first pass)
Oral drug administration rate of onset?
SLOW (15-30 minutes for immediate release)
Slower (hours) for enteric/sustained release
Most common drug absorption for oral administration is via ________, favoring ___________ drugs
passive diffusion
lipophilic, nonionized drugs
Rate of absorption of drug is higher in _______ than in ________
small intestine than in stomach
When your stomach is empty you have ________, which increases ________
increased GI motility
increases absorption
= drunk chicks
Enteric drug coat acts to…
protect stomach from irritation and protects drugs from low stomach pH
Controlled-release prep pros and cons
pros: fewer administrations, increased compliance, overnight therapy, elimination of peaks/troughs
cons: greater inter-patient variability in cytoplasmic concentration, and formulation could fail giving patient entire dose (dose dumping)
Rectal drug administration bioavailability?
variable, but generally greater than oral because first pass metabolism is less for rectal compared to oral
Rate of onset for rectal drug administration
not rapid
IV drug administration bioavailability and rate of onset?
F = 100%
MOST RAPID onset (along with gas inhalation)
sec to min onset
Sublingual/Buccal drug administration bioavailability and rate of onset?
F is generally high
Rate of onset = within minutes 5-10 min
Intramuscular (IM) drug administration bioavailability and rate of onset?
F = approaches 100%
Rate of onset: 5-10 min for aqueous solution, but slower for depot form
Subcutaneous drug administration bioavailability and rate of onset?
F = approaches 100%
Rate of onset: 5-10 min for aqueous solution, but slower for depot form
Inhalation (gaseous) drug administration bioavailability and rate of onset?
F = about 100%
Rate of onset: MOST RAPID (with IV),
Inhalation (suspension) drug administration bioavailability?
F = variable
Transdermal (systemic) drug administration rate of onset?
slow (hours)
Sublingual/Buccal administration bypasses _________ and is best for ________ and _______ drugs
hepatic first pass metabolism
best for lipid soluble, potent (
IV drug administration
- Most direct route, bypass all absorption barriers
- Accurate and fast drug delivery, used for drugs with narrow therapeutic window
- Most hazardous route b/c easy to reach irreversible toxic levels quickly, duration= t1/2 dependent
- Higher chance of infection
IM drug administration is used instead of subQ if __________
drug is too irritating for subQ
Cons of IM drug administration
- pain, tissue necrosis, microbial contamination
- absorption can be erratic/incomplete when solubility is limited
- absorption/onset effected by blood flow/muscle activity at site of injection
Cons of subcutaneous drug administration
volume of dose is limiting
only for non-irritating drugs
Gas inhalation is used for…
rapid onset of SYSTEMIC drug effects, rapid rate of absorption due to high SA and blood flow in pulmonary tissue
Suspension inhalation is used for…
local topical effects, applied at site of action in lung (reduces systemic effects)
Transdermal drug administration
- Prolonged drug levels, extended duration of action (24h, 3d, 7d)
- 1st pass metabolism is avoided
- Drug must be potent (dose ˂2 mg)
- Must permeate skin w/o irritation
Topical/Dermal drug administration
Localized application via skin/mucous membrane (vaginal, nasal, eye) for tx of local conditions
- Minimal systemic absorption
- In children potential for 3-fold greater system availability that in adult (body SA: weight is greater)
Highest bioavailability of substances if…
largely hydrophobic, yet soluble in aqueous in solutions
How handsome is Taylor on a scale from 1-10?
He exceeds the scale, trick question*
*High yield on USMLE Step I
Which form of weak acids/bases are more readily absorbed?
Unionized
Acids are trapped in _____
basic solutions
Bases are trapped in
acidic solutions
Which form of acid and base predominates if pH
protonated
Which form of acid and base predominates if pH>pKa
deprotonated
_____ of urine can trap aspirin (weak acid) in overdose situations
alkalinization
Greater potential to concentrate _____ drugs in more acidic breast milk
Basic
Factors that influence drug distribution (3)
i. Anatomic barriers (molecular size, lipid solubility, degree of ionization, concentration gradient)
ii. pH of compartment (important for weak acid/weak base drugs)
iii. Protein binding
Relationship between tight junctions and drug distribution
Tight junctions between cells: limit movement of some drugs, requires passage through lipid membrane
Tight junctions are present in (4)
GI mucosa, Blood Brain Barrier (BBB), placenta, renal tubules
How does drug binding to plasma proteins effect drug distribution? (4)
i. Reduces concentration of active free drug
- Limits fetal exposure to drugs – pregnant women given drugs highly protein bound
ii. Hinders metabolic degradation and reduces excretion
- Decreases elimination rate and INCREASES half-life
- Acts as circulating drug reservoir prolongs drug action
iii. Decreases volume of distribution (most of drug in plasma)
iv. Decrease ability to enter CNS through BBB
Drug binding to plasma proteins can be of clinical significance if: (4)
displaced drug has narrow therapeutic index, displacing drug is started in high doses, Vd of displaced drug is small, or if response to drug occurs more rapidly than redistribution
Describe protein binding/ displacement drug-drug interactions
i. Displacement of 1st drug from protein binding site by 2nd drug results in increased levels of unbound 1st drug, but levels of total drug are unchanged because administration is unchanged
Bolus toxicity
slow distribution out of plasma compartment can lead to toxicity for drugs given IV
Formula for Vd using: amount of drug in body (Ab) and concentration of drug in plasma (Cp)
Vd = amount of drug in body (Ab) / concentration of drug in plasma (Cp)
Volume of distribution
size of compartment necessary to account for total drug in body if present at SAME concentration in body as in plasma (Cp)
Vd will vary between patients depending on: (3)
i. Body size – units of L/kg – calculated based on weight
ii. Composition (fat vs. lean)
iii. Changes in protein binding
Calculate loading dose (LD) using Cp and Vd
*LD = Cp (desired) x Vd
Calculate Cp using dose and Vd
Cp = D (mg) /Vd (L/kg)
What would happen if the body relied solely on renal excretion to eliminate drugs without drug metabolism?
If only terminated by renal excretion, duration of action would be prolonged
Primary site of drug metabolism
Liver
% of drugs metabolized by the lungs
30%
% of drugs metabolized by the kidneys
8
% of drugs metabolized by intestines
6
% of drugs metabolized by skin
1
% of drugs metabolized by placenta
5
CYP450 enzymes are located where?
membrane bound enzymes of the SER
During metabolism of drugs, lipid soluble compounds are converted to
more H20-soluble (more polar) compounds that are more readily excreted
Phase I reactions (3)
- Oxidation—CYP450 dependent or P450 independent (most common)
- Reduction (azo, nitro, carbonyl reductions)
- Hydrolysis
Phase II reactions (4)
Conjugations:
- Glucuronidation
- N-acetylation
- Glutathione conjugation
- Sulfate conjugation
Phase I enzymes involved
- CYP450 (includes NADPH, flavoprotein NADPH-cytochrome P450 reductase, and O2) or non-CYP450
- Reductase
- Esterases or amidases
Phase II enzymes involved
- Transferases (ie: glucuronyl transferases, N-acetyltransferases)
Genetic polymorphisms Phase I?
Yes
Genetic polymorphisms phase II?
Yes (less)
Test to detect polymorphisms for phase I metabolism
Amplichip test detects polymorphisms in CYP2D6 / 2C19 (metabolize antidepressants, antipsychotics, opioid analgesics)
Age related changes in activity: phase 1
yes (decreases with age in 1/3 of patients)
Age related changes in activity: Phase II
Yes (especially UGT)
Inhibitory/Inducibility: phase I
yes
Inhibitory/inducibility: phase II
Yes (less)
Ease of saturability: phase I
minimal
Ease of satuability: phase II
Substantial
Limited supply of endogenous unit provided by coenzyme more easily saturable
Characteristics of CYP450 (4)
- Substrate must be lipid-soluble (drugs, endogenous substances, etc. serve as substrates)
- Inducibile and inhibitable (by drugs)
- Postnatal development variable (neonates have 50-75% adult levels, BUT some drugs metabolized faster)
- Many different isozymes
CYP3A4
- does most phase 1 metabolism
- in gastric mucosa, NOT in large intestine
Most drugs that are weak acids contain what functional group?
Carboxylic acid
Most drugs that are weak bases contain what functional group?
Amino
CYP2D6
converts codeine to morphine
an “Inducer” is a compound that causes ____________.
______ is the most common inducer
a qualitative (or quantitative) increase in activity
CYP450
Mechanism of induction mainly due to __________ BUT also causes ________. The result is that induction has a ________ onset
increased synthesis of enzyme protein
decreased turnover
slow onset (48-72 hours)
Therapeutic consequences of induction (3)
1) maximal effect seen in 7-10 days
2) causes pharmacokinetic tolerance (induction of drugs own metabolism)
3) Induction by one agent may increase clearance of another drug (drug-drug interactions)
Oral contraceptives and Rifampin
Rifampin is an inducer that increases the clearance of oral contraceptives
Inhibition of metabolism is…
Are phase I or phase II enzymes more prone to inhibition?
decrease clearance of drug by inhibiting drug metabolizing activity
Phase I
4 mechanisms of metabolic inhibition
1) inhibit enzyme synthesis
2) competitive inhibitor (substrate competing for enzyme)
3) Allosteric inhibitor (not a substrate)
4) Inhibition due to formation of a metabolite that destroys the enzyme (suicide) or forms a tight complex stopping activity
Lipitor and erythromycin
Erythromycin is an inhibitor of Lipitor clearance
Inducer or inhibitor?
Phenobarbital [1A2, 2C9, 2C19, 3A4]
Inducer
Inducer or inhibitor?
Phenytoin [2C9, 2C19, 3A4]
Inducer
Inducer or inhibitor?
Carbamazepine [2C9, 2C19, 3A4]
Inducer
Inducer or inhibitor?
Rifampin [1A2, 2C9, 2C18, 3A4]
Inducer
Inducer or inhibitor?
Ethanol [2E1]
Inducer
Inducer or inhibitor?
St. John’s Wort [3A4]
Inducer
Inducer or inhibitor?
Tobacco smoke (not nicotine) [1A2]
Inducer
Inducer or inhibitor?
Cimetidine [2D6, 3A4, 1A2]
Inhibitor
Inducer or inhibitor?
Erythromycin / Clarithromycin [3A4]
Inhibitor
Inducer or inhibitor?
Azole antifungals [3A4]
Inhibitor
Inducer or inhibitor?
Fluoxetine (other SSRIs) [2D6,3A4]
Inhibitor
Inducer or inhibitor?
Grapefruit juice [3A4]
Inhibitor
Inducer or inhibitor?
HIV protease inhibitors [3A4]
Inhibitor
Inducer or inhibitor?
Omeprazole [2C19]
Inhibitor
P-Glycoproteins
Transporters that act primarily to move drugs OUT of the cell (varies based on location)
- GI = decrease oral absorption of drugs
- Liver-Kidney = enhance biliary and renal excretion of drugs
- Blood-brain barrier = limits distribution of drugs to the brain
Excretion is ________
______ are the most important organ for excretion, especially for _______ and ________ compounds.
-loss of chemically UNCHANGED drug from the body
- Kidneys
- water-soluble and non-volatile compounds
Filtration in the kidneys
1) all drugs smaller than albumin (MW 69000) will be filtered
2) Only free drug is filtered
Renal excretion is affected by renal ________ and ________
blood flow and function
Active tubular secretion transports drugs from _____ –> ________ and occurs with drugs that are _________. This mechanisms is ________ and rate is NOT affected by ________
blood –> urine
strong acids and bases
saturatable, NOT affected by protein binding
________ is a poorly developed process in neonates resulting in prolonged half life of some drugs
active tubular secretion
Tubular reabsorption
i. Lipid-soluble, uncharged drugs can cross membrane → cleared at rate of urine formation (1ml/min)
movement based on concentration gradient
dependent on urine pH
ii. Primary function of drug metabolism → produce more water-soluble metabolite that is less likely to be reabsorbed.
iii. Active reabsorption: important for endogenous compounds (glucose, aa’s), most drugs REDUCE this active transport.
Urine pH can be acidified by ________ or _______ and alkalinized by ________
NH4Cl or ascorbic acid
NaHCO3
Enterohepatic Recycling
reduces the elimination of drug and prolongs its half life and duration of action in the body (keeps drug in the body, but out of systemic circulation)
Process:
Drug metabolites in liver (usually conjugates that increase MW to ˃300) secreted into bile
→ stored in gallbladder
→ small intestine via bile duct
→ hydrolyzed by bacterial enzymes back to the parent drug (more lipid soluble)
→ reabsorption from intestine into liver
Therapeutic implications of Enterohepatic Recycling
i. Some drugs have a “reservoir” of re-circulating drug (morphine, ethinyl estradiol)
ii. Antibiotics can reduce gut bacterial flora and DECREASE enterohepatic recycling → DECREASE plasma drug levels = potential for drug-drug interaction (EX - estrogen)
Breast Milk and drugs
most drugs cross (unchanged) into breast milk at LOW levels, BUT infant plasma level usually substantially below therapeutic level
Breast milk is more ______ than plasma, so has a tendency to accumulate ________ compounds via ion trapping
acidic
basic
Clearance
the volume of plasma (Vd) which is completely cleared of drug in a given period of time by the processes of kidney excretion and drug metabolism (and some minor others)
Clearance equation and units
CL (mL/min) = Vd x Ke
Half life
units?
time required to eliminate ½ of the drug amount
hours or minutes
Half life is _______ of total amount of drug present (Cp)
independent
Half life is dependent on both _______ and ______
clearance (increase clearance, decrease half life)
Volume distribution (increase Vd, increase half life)
Time it takes a drug to be eliminated?
4-5 half lives
Time it takes for a drug to reach steady state when administered continuously?
4-5 half lives
Degree of fluctuation between doses (equation)
= 2^x, where x=# of t1/2 in dosage interval
Virtually all drugs are eliminated via _______ kinetics when they are within __________.
first order
therapeutic doses
First order kinetics: ______ is proportional to ________.
rate of elimination (mg/hr)
plasma concentration (Cp) (mg/L)
Hepatic metabolism and renal excretion both use _________ kinetics
first order
In first order kinetics, if the concentration of drug is doubled then the rate of elimination is…
doubled
As drug is eliminated from the body, its concentration is __________, therefore, rate of elimination _________
constantly changing
also changes constantly
When plotted graphically, Cp vs. Time, the slope of this line represents _________
the rate of elimination (decreases as Cp decreases when drug is eliminated)
When plotted graphically, ln(Cp) vs time, the slope of the line represents _________
Ke (Rate constant of elimination)
Elimination rate constant (Ke)
- fraction of drug leaving body per unit time via all elimination processes.
- CONSTANT
Maintenance dose equation
CL = (Maintenance Dose / tau) / Cp
Disstribution phase
initial curvlinear portion of graph - represents drug equilibrating between blood and tissue
Half life equation
t 1/2 = 0.693 / ke
Vd equation
Vd = Dose / Cp o (initial plasma concentration)
Dose a bioavailability:
If oral F = 50% then to give the drug by IV you must…
times dose by 1/2
Phase I drug metabolism does what?
inserts or unmasks functional group (OH, NH2, SH) on drug that renders molecule more water-soluble.
→Molecule can then undergo conjugation in Phase II rxn.
Phase II drug metabolism does what?
endogenous substrate combines with pre-existing or metabolically inserted functional group on the drug forming a highly polar (water soluble) conjugate that is excreted via the urine.
There are lab tests that can determine a person’s Warfarin metabolizing abilities by testing the activity of the warfarin metabolizing enzyme _______. Warfarin targets __________ enzyme.
CYP2C9
VKORC1 (Vitamin K reductase)
First order elimination involves the elimination of a constant ________ of drug per unit time, where as zero-order elimination involves the limitation of a constant _______ of drug per unit time.
fraction (percent) - involves half lives
amount - does NOT involve half lives
Zero-order elimination is most commonly observed for drugs that ___________.
saturate metabolic pathways when given in therapeutic doses (or drugs given at toxic doses)
Hepatic clearance varies with…(3)
Low vs. high extraction drug?
1) Blood flow to liver
2) protein-drug binding
3) intrinsic hepatic metabolism (inducers and inhibitors)
- low extraction drug (metabolism not efficient) changes do NOT significantly influence clearance
- high extraction drug (metabolism efficient), changes will have a major influence on clearance
Time to reach steady state plateau is related to _______ only and is independent of _______
drug half-life
drug dosage
What effect will increasing maintenance dose have on time to reach steady state?
Increasing maintenance dose WILL NOT reach steady state sooner, will only cause Cpss to be higher when reached
Effect of Loading Dose on steady state
Use Loading Dose to reach steady state faster
LD = Cp x Vd
Zero order kinetics is most often due to saturation of ________ metabolic processes while _______ saturation is unlikely
hepatic
renal saturation unlikely
Drug-Receptor Concept states that…
greater number of receptors occupied by drug = greater response provided
Receptor (in Drug-Receptor Concept)
- drug target, the sites of action in body that mediates pharmacologic effects of drugs
- Specificity of fit of drug to receptor (recognition) induces conformational change in receptor protein.
Consequences of Drug Receptor Theory (3)
1) Receptor mediates the actions of receptor agonists and antagonists
2) Receptors are responsible for selectivity of drug action
3) Theory allows determination of quantitative relation between dose or concentration of drug and its pharmacologic effects via use of dose-response curve
3 Assumptions used with dose-response curves
1) Interaction follows simple mass action relationships
2) Binding is reversible
3) Response is proportional to receptors [R] occupied by drug [D]
What shape is the dose-response curve?
Hyperbolic - confirms mathematical relationship between dose and response
e/Emax = [D]/ EC50 + [D]
Therapeutic consequences of Drug-Response Curves
1) First part of curve is linear: at low doses, response increases in direct proportion to dose
2) Curve levels off at high drug doses: limit to the increase in response that can be achieved by increasing the drug dose
Advantages of log-dose response curve (2)
1) Allows for wide range of doses to be plotted allowing easy comparison of different drugs
2) Dose-response relationship is nearly a straight line over range of therapeutic doses
Potency
EC50 - concentration/dose required to produce 50% drugs max effect
represented on X-AXIS of dose-response curve
Potency is dependent on __________ and _______
affinity (Kd) of receptors for binding drug
efficiency of drug-receptor complex to generate a response
Max Efficacy (Emax)
Represented on Y-AXIS of dose-response curve (upper limit)
- Indicates relationship between binding to receptor and ability to initiate a response
- Most important determinant of drugs clinical utility
- Efficacies of different drugs are compared even though they act at different receptors or targets
Partial Agonist
occupy same receptor as full agonist, but bring about less than maximum response even at full dosage levels. (less efficacious)
Full Agonist
occupy receptors and produce full or maximal response (produced by powerful agonists in tissue
Agonist
drug that activates its receptor upon binding and brings about the characteristic tissue response
-effects efficacy of drug, NOT potency
Antagonists
drug that inhibits the action of an agonist but has no effect in the absence of an agonist
- Effect of antagonist depends on level of “normal tone” mediated by agonist in the tissue
- An antagonist binds to the drug receptor, but is unable to bring about characteristic response
Receptor Antagonists (aka?)
Pharmacologic antagonists
bind SAME receptor as the agonist
Competitive reversible antagonist
- Binds reversibly to active site of receptor
- Blocks agonist from binding to receptor and maintains receptor in inactive conformation
- Competes with agonist for receptor binding = reduces apparent agonist affinity for receptor (decrease potency)
Emax unchanged, EC50 increased, Potency decreased
Non-competitive active site or allosteric antagonist
- Binds irreversibly (covalently) or pseudoirreversibly (very high affinity) to the active site of receptor
- Increasing concentration of agonist can NOT overcome antagonism - functional receptors “removed” from system
Emax reduced, no change on x axis (EC50), no change in potency
May see a shift to the right (decrease in apparent potency) if spare receptors available.
Non-Receptor Antagonists include _____ and _______
physiological and chemical antagonists
Physiological antagonists
activates or blocks a different receptor that mediates a physiologic response that is opposite to agonist
EX) Histamine –> biolgoical response
Epinephrine –> counteracts biological histamine response
Chemical antagonists
does not involve receptor binding, antagonist acts to render agonist unable to interact with its receptor via modification or sequestration of agonist
Adverse Drug Reactions
Response to a drug that is not desired, potentially harmful
-occurs at USUAL therapeutic doses
Toxic reactions
occur at doses outside therapeutic range
Graded dose-response curve
ED50 = ? (in this graph)
Individual subject, increasing the dose and measuring graded response for each dose
→ allows determination of the max effect of drug (Emax)
ED50 (50% max response in an individual)
Population dose-response curve
ED50 = ? (in this graph)
characterize pharmacologic responses that are all-or-nothing events (not graded) in a population of subjects (not an individual)
ED50 = dose that initiates the response in 50% of the test population.
Therapeutic index
compares midpoint in population
TI = LD50/ED50
higher TI = safer drug
LD50
lethal dose that causes death in 50% of subjects
TD50
dose that produces an undesirable side effect in 50% of subjects
Standard Safety Margin
looks at the extremes in the population
SSM= [(LD1/ED99)-1] x 100
(ED99=response in 99% and LD1=toxic dose in 1%)
More conservative measure that TI, more reliable if pt response to therapy to specific drug varies, takes into account the extremes, SSM can be negative.
Pharmacokinetic drug-drug interactions: when 2nd drug changes ________ of 1st drug
Plasma levels
Pharmacodynamic drug-drug interactions includes ________ or _______ and does NOT change _____________
pharmacologic enhancement/antagonism OR physiologic enhancement/antagonism
NO changes in plasma concentration
Methods to prevent/decrease absorption (4)
1) Gastric lavage
2) Activated charcoal
3) Osmotic cathartics
4) Emesis
Gastric Lavage
washing of stomach contents with saline
- Most rapid and complete method of emptying stomach
- Problem is you only remove about 30% of most oral poisons with lavage + emesis
Activated charcoal
- binds drug in gut to limit absorption
- Will also bind ipecac
- Effective without prior gastric emptying
Osmotic Cathartics
3 drugs used
empty bowel contents (laxative)
1) Magnesium citrate or sulfate
2) Sodium sulfate
3) Polyethylene glycol (Golyetyl)
Emesis
2 drugs used
empties stomach contents rapidly
1) Syrup of Ipecac
2) Apomorphine
Two drugs used to inhibit toxication
Ethanol (competitive inhibitor)
Fomepizole (specific inhibitor)
Ethanol and Fomepizole act to…
inhibit alcohol dehydrogenase thus suppressing the production of toxic metabolites
-used to treat metanol and ethylene glycol toxicity
Methanol and Ethylene Glycol toxication results due to…
conversion to toxic species by alcohol dehydrogenase
Methanol –> formic acid, formaldehyde
Ethylene glycol –> oxacilic acid
Pharmacokinetic interventions available for treatment of drug overdoses/poisoning (5)
1) Prevent/Decrease Absorption
2) Inhibition of toxication
3) Enhancement of metabolism
4) Increase elimination of toxin
5) Antagonism of toxin action at target
Acetaminophen normal metabolism
Most eliminated by phase II conjugation reaction (80-90%)
BUT phase I (CP2E1) enzymes (10%) converted to a hepatotoxic metabolite (detoxified by phase II conjugation)
Metabolism of acetaminophen at toxic doses (> 10-20 g) (4 effects)
1) Saturate phase II metabolic pathways
2) Increased formation of phase I hepatotoxic metabolite
3) Depletion of glutathione stores for detoxification
4) Increased likelihood of hepatocellular injury
Treatment of acetaminophen toxic dose (3)
gastric lavage
supportive therapy
N-acetylcysteine
N-Acetylcysteine
Enhances toxic metabolite metabolism
precursor for glutathione synthesis
Acts as nucleophile to inactivate electrophilic hepatotoxic metabolite produced via acetaminophen metabolism
________ is the phase I enzyme that converts 10% of acetaminophen to a hepatotoxic metabolite
CP2E1
Acetaminophen and ethanol interaction (3)
3 strikes!
Ethanol induces CP2E1
Depletes glutothione
Is hepatotoxic on its own
Hemodialysis
blood pumped through filter
- Most effective for toxins with small Vd (large Vd = poorly removed b/c out of plasma) and low protein binding capacity
- Effective for: methanol-ethylene glycol, salicylates, theophylline, Li+, ethanol
Hemoperfusion
blood pumped through adsorbent column
For high molecular weight toxins with poor water solubility
Forced diuresis can be accomplished with ________ or _________
normal saline (fluids)
Flurosemide (high efficacy diuretics)
Toxicokinetics
Toxic dose of drug may alter “normal” pharmacokinetics
study of absorption, distribution and elimination of toxic parent compounds and metabolic products that aids in prediction of amount of toxin that reaches site of injury and resulting damage.
Which types of drug studies involve testing drug efficacy?
Phase II and III
Which types of drug studies involve testing drug safety?
Phase I, II, and III
What is required for determining equivalence of generic drugs with their counterparts?
Pharmaceutical Equivalence and Bio-equivalence
Therapeutic equivalence is assumed if bio-equivalence is met
3 criteria by which depressant and stimulant drugs and other drugs with abuse potential are classified
1) medical usefulness
2) abuse potential
3) physiological/physical dependence risk
before meals
ac
twice a day
bid
at bedtime
hs
after meals
pc
when needed
prn
every morning
qam
immedietly
stat
3 times a day
tid
by mouth, orally
po
per rectum, rectally
pr
subcutaneous
sc-sq
vaginally
vag
where are drugs required to go THROUGH cells as apposed to between cells?
1) absorption of drug from small intestine
2) Diffusion of drug from blood to CSF
3) Absorption of drug from the kidneys
Idiosynchratic reaction
occur elsewhere from the drug target in normal therapeutic doses
- rare and unpredictable
- EX) hepatotoxicity, allergic reactions
Side effect
drug reaches target in the wrong system
- dose dependent, predictable
- EX) drowsiness with antihistamines
Extension effect
drug acts on target system but and exceeds therapeutic doses
-dose dependent predictable
EX) bleeding/bruising with warfarin
