Additional Exam 1 Information Flashcards
Clinically relevant inducers
- Phenobarbital
- Phenytoin
- Carbamazepine
- Rifampin
- Ethanol*
- St. John’s Wort*
- Tobacco smoke (NOT nicotine)*
*don’t need RX
PK toxicokinetic strategies for poisoning
- Absorption: prevent or decrease absorption of toxin :(decrease rate in)
- inhibition of toxication (Prevent conversion to toxic species)
- Metabolism: enhance metabolism (detoxication)
- Elimination: increase elimination of toxin (increase rate out)
what is an ANDA (abbreviated new drug application) used for?
submitted for generic drugs allowing the manufacturer to bypass the expensive and time-consuming clinical trials for an already approved drug.
-only BIOEQUIVALENCE standards must be met
what patient info is required on a prescrption
name and address
*age and weight are not legal requirements but helpful in monitoring prescribed dose, esp. in peds
how do local anesthetics get metabolized?
hydrolysis by amides
Factors involved in GI absorption interactions
- disintegrating time
- dissolution rate
- gastric emptying
- absorptive SA
- intestinal transient time
- pH of lumen fluid
describe Schedule I drugs
High abuse potential, no currently accepted medical use, NOT prescribed
Information NOT required in dietary supplement lable
-Identification of active principle – not known for many
herbs
-Pharmacokinetic/F data
-Potential interactions with Rx and OTC drugs
What drugs do not have half lives?
drugs eliminated by zero order kinetics
-bc elimination rate is independent of the amount of drug in the body
pharmacodynamic interventions for poisoning include ___.
examples discussed include
antidotes
ex. acetaminophen–> N-acetylcysteine
methanol/ethylene gylcol–> Ethanol, fomepizole (Antizol)
Post 1994,___ must provide “reasonable”
evidence that the dietary supplement product is safe for human use
-do not have to provide the FDA with evidence that the
product is ___ and ____
-HOWEVER, burden of proof on ____ to show product is
not ___ before use restricted or removed from market
manufacturers
safe and effective
FDA
not safe
What CYP isozyme results in:
Codeine intoxication
CYP2D6 (UM)
- due to rapid metabolism to morphine
- metabolism is activiating
What Schedule of drugs are these?
-Opioids*: Morphine, codeine, OXYCODONE, hydromorphone, HYDROCODONE
- Stimulants: Methamphetamine, amphetamine, cocaine, methylphenidate
- Depressants*: BARBITURATES (pentobarbital, secobarbital)
Schedule II
How can absorption mechanisms be altered by D-D interactinons?
- decreased motility = decreased absorption = decreased Cp (**no change in F)
- change in pH or formation of insoluble complex= decreased absorption = decreased Cp (**F is changed bc it leads to physiochemical inactivation)
ex. Tetracycline + antacid milk= decreased absorption= decreased Cp= unresolved infection
*increasing rate of absorption in LESS clinically important
how can you reduce absorption of a drug given by IV that resulted in poisoning?
- activated charcoal
- back-diffusion of drug from blood w/ ion-trapping in stomach (reduces elimination half-life)
- best to given 10:1 ratio to toxin
-best to also give osmotic cathartics (ie. sorbitol 70%) to prevent “briquet” formation
how can you manipulates a drugs affinity for a specific receptor? Give an example.
change its shape, size or electrical charge
ex. Dobutamine will interact w/ B1-adrenergic receptor on the heart, but no effect on acetylcholine or adenosine receptors at therapeutic levels
- Dobutamine is an agonist of NE
Examples of drugs whose metabolism of active drug results in MORE ACTIVE compound
Codeine–> morphine
hydrocodone–> hydromorphone
how can you assess the Benefit-risk ratio for doses of drugs with a quantal dose-response curve?
- Therapeutic Index: compares MIDPOINTS in the population (ED50 and LD50)
- Standard Safety Margin: compares EXTREMES in the population (ED99 and LD1)
____ largely determines the dose necessary to administer to the pateint
potency (expressed in dosage units for a particular therapeutic end point ex. 20mg of lisinopril will lower BC by 10-15mg)
what is the difference between a graded dose-response curve and a quantal dose-response curve?
Graded: graded response from a number of increasing doses in an INDIVIDUAL (used to determine Emax)
Quantal: all or nothing response to a single dose— in a POPULATION (NOT used to determine Emax)
how can you reduce absorption in poisoning
- emesis (Ipecac)
- gastric lavage
- activated charcoal
- Osmotic catharitcs
generic drugs and brand drugs have the same:
- active ingredient
- same dosage, intended use, therapeutic effects, side effects, route of administration, risks, safety, and efficacy as the original drug
- mean bioavailability variation is less than 4%
*pharmacological effects are EXACTLY the same
how can drug-drug interactions affect metabolism
**most clinically important
- inducers= increased metabolism= decreased Cp= subtherapeutic levels
- inhibitors= decreased metabolism= increased Cp= toxic levels
*most interactions occur via effects on CYP450 system
tx of acetaminophen toxicity
- activated charcoal and gastric lavage (best w/in 4 hrs)
- supportive care
- N-acetylcysteine: best w/in 12-36 hrs of ingestion (ENCHANCE DETOXIFICATION)
What Schedule of drugs are these?
Opioids: buprenorphine, diphenoxylate-antidiarrheal, codeine-antitussive (in low amounts)
Schedule V
considerations for classification of a drug in OTC include:
- condition is self-diagnosable and self-treatable
- whats the products toxicity? habit forming? high dose safety profile?
- do benefits of OTC outweigh risks
- methods of use preclude OTC availability
- directions for safe use- understood by ordinary person
what does ED50 mean for a QUANTAL dose-response curve vs a GRADED dose-response curve
Quantal: ED50= dose that initiates therapeutic effect in 50% of test population
Graded: ED50= dose that produces 50% of the maximal response possible for an individual test subject
most drugs display what order kinetics?
1st order kinetics
-Rate of elimination is proportional to the concentration of the drug in the plasma
describe the relationship between drug potency and EC50
higher potency = lower EC50 and vise versa
Draw the Phase I and Phase II comparison chart
- reference notes
- categories include: Rxn type, enzymes, genetic polymorphism, induce-inhibit, dev. patterns, age changes, saturability
Contraindications of Emetic agents
- pt is comatose/stuporous (lack of gag reflex–> risk of aspiration)
- ingestion of corrosive poisons (strong acids or alkalis)
- ingestion of CNS stimulant such as strychnine (risk of seizure)
- ingestion of petroleum distillate (risk of pneumonitis)
- Pregnancy category C (weight risk vs benefit)
When can clinical trials in humans be performed and how long do they take and how much does it typically cost
- After IND approval
- takes 2-10 yrs
- Costs $100-200 million
what 2 drug categories is it advised to use one formulation (brand or generic) consistently?
- *1. Narrow TI: Levothyroxine and anti-epileptic drugs
2. Non-linear (zero order) pharmacokinetics (ex. phenytoin)
5-10% of Caucasians have what CYP isoform?
20% of Asains have have CYP isoform?
C: CYP2D6- PM
A: CYP2C19- PM
What is Class X drugs for pregnancy?
examples?
- Contraindicated in pregnancy
- Risks involved in the use of the drug in a pregnant women clearly outweigh any potential benefits
examples: statins (HMG CoA reductase inhibitor), accutane (isotretinoin)
hepatic metabolism and renal excretion exhibit what order kinetics?
1st order kinetics
how does protein-binding and displacement w/ drug-drug interactions effect distribution?
When is this of clinical consequence?
displacement of 1st drug from protein by 2nd drug= increased levels of unbound first drug
Of clinical consequence when:
- first drug has narrow TI
- Vd of 1st drug is small
- 2nd drug is started in high doses
- Drug response is more rapid than drug distribution
Describe Schedule III drugs
Accepted medical use, MODERATE abuse potential and dependence liability
parameters for absorption
- F
2. rate (estimated by Tmax and Cmax)
what mechanisms can lead to decreased Cp leading to sub-therapeutic levels
- increased drug elimination (most common)
- decreased drug absorption
What is Class C drugs for pregnancy?
examples?
- Risk cannot be ruled out
- Potential benefits may warrant use of drug in pregnant woman despite potential risks
examples: pseudoephedrine, antidepressants, emetic agents
what phase II enzyme is inducible?
glucuronyl transferases – but not to the extent of CYP450
*induced by N-acetylcysteine
Describe Schedule II drugs
Accepted medical use, HIGH abuse potential with severe dependence liability
What is Class B drugs for pregnancy?
examples?
- No evidence of risk in humans
examples: opioids (D near term) ondanstetron, acetaminophen, thiazide diuretics
Describe Phase III testing in human trails
Phase III: Full scale Clinical trail: Does it work, double blind?
- 3 yrs
- 1000-6000 pts (similar to those anticipated for ultimate drug use)
- Efficacy measured against established therapy
- Monitor for ADR from chronic use
- Sometimes omitted for drugs used in serious, life-threatening illnesses (AIDs, CA)–> drugs w/ greatest potential benefit may obtain an accelerated or conditional approval that then requires more definitive clinical trials to be conducted after initial approval
- Positive results may result in approval of NDA, which is then submitted to FDA
how does a therapeutic index number relate to the saftyness of a drug.
-Most drugs in clinical use have a therapeutic index of
higher TI value= safer the drug
-Greater than 10-20
what type of drugs are typically considered to have a “narrow therapeutic index”
drugs with less than a 2-4 fold difference in therapeutic vs toxic Cp levels
Potency depends on:
- affinity that receptor has for that drug
2. efficiency of receptor to generate a response (intrinsic)
when can spare receptors be found?
- duration of effector is greater than that of the DR interaction
- the actual number of receptors exceeds the number of available effector molecules (R increase sensitivity to the agonist as the likelihood of DR interaction increases in proportion to the number of receptors available)
information required on dietary supplement label
- Name of product - if herb, name of plant-plant part used
- Net quantity of contents
- Manufacturer information
- Directions for use
*need to include for medical FOODS too
what phase II enzyme helps with the metabolism of acetaminophen?
glutathione-s-transferase (GST)
**glutathione conjugation is extremely important in the detoxification of carcinogens, pollutants and toxic metabolites
What Phase I oxidation reactions are CYP450 dependent?
- aromatic hydroxylation
- aliphatic hydroxylation
- epoxidation
- Oxidative dealkylation
- deamination
- desulfuration
- dechlorination)
what is the most frequent pathway of drug metabolism
oxidation (phase I)
When does zero order kinetics occur? Give examples of drugs this is seen with
Occurs due to saturation of hepatic metabolic enzyme systems by drug administration (unlikely w/ renal excretion processes)
ex. ASA, phenytoin, ethanol and with toxic doses for many hepatically eliminated drugs
what does the federal government control in regards to drug regulation?
-controls WHAT drugs may be prescribed or sold directly OTC via FDA
The clinical effectiveness of the drug depends on the drug’s _____
maximal efficacy
*more important to prescribers than potency
What is the schedule for these types of codeine?
- Codeine combined w/ non-opioids
- codeine-antitussive
- Codeine
- Hydrocodone
- Oxycodone +/ non-opioid
- Codeine combined w/ non-opioids= schedule III
- codeine-antitussive= schedule V
- Codeine- schedule II
- Hydrocodone- schedule II
- Oxycodone +/ non-opioid= schedule II
- opiod analgesic drugs (fentanyl, morphine, codeine,, Oxycodone +/ non-opioid, hydrocodone +/- non-opioid, methadone) = schedule II
Types of osmotic cathartics and when you would use them
- Sorbitol 70%- recommended– use w/ charcoal
- Magnesium citrate or sulfate: avoid in renal disease or poisonings w/ nephrotoxic agents
- sodium sulfate: avoid in CHF or HTN (systemic Na absorption –> fluid overload/edema)
- Polyethylene Glycol: use for poisonings w/ sustained-released drugs, metal ions, drug packets
what are extension effects? Give examples
- arise from an extension of therapeutic effects
- dose-related
- predictable
ex. insulin lowers BG causing hypoglycemia
heparin tx clots causing bleeding
What does changes in hepatic blood flow affect hepatic clearance?
only when the drug has a high extraction rate (metabolism is very efficient)
what drugs tend to accumulate in breast milk?
basic compounds (opioid analgesics) by ion trapping bc breast milk is more acidic than plasma (pH 6.5 vs 7.4)
Convert metric to avoidrupois/ apotheracry/household: VOLUME 0.05ml= 5ml= 15ml= 29.56-30 ml= 946 ml= 473ml= 3785ml (3.785L)=
0.05ml= 1 drop 5ml= 1 teaspoon 15ml= 1 tablespoon 29.56-30 ml= 1 fluid oz 946 ml=1 quart 473ml= 1 pint 3785ml (3.785L)= 1 gallon
why are generic drugs cheaper?
- bc manufacturers have not had the expense of developing and marketing a new drug and there is no patent to prevent other companies from making and selling the drug so competition also drives the price down
- not cheaper bc they are inferior
what is the most rapid and complete method of emptying the stomach
gastric lavage (washing of stomach contents w/ saline and removal via nasogastric tube)
chart orders consists of
- name and strenght of med
- dose
- route and freq.
- date
- signature of prescriber
*duration of therapy or number of doses NOT always indicated– order continues until DC’ed by prescriber or terminated per hospital policy
What CYP isozyme results in:
increased antipsychotic drug toxicity
CYP2D6 (PM)
*metabolism is detoxifying
what are idiosyncratic reactions? Give example
- Genetically determined abnormal response to a drug
- unpredictable
ex. prolonged muscle paralysis due to impaired metabolism
what is the difference between a drug and a dietary supplement
Drug- therapeutic agent (Rx or OTC) intended to DIAGNOSE, TREAT, CURE, or PREVENT a disease— has been tested to demonstrate safety and efficacy in studies
Dietary supplement- intended to SUPPLEMENT diet and contains a VITAMIN, MINERAL, AMINO ACID, or HERB/BOTANICAL– sold to public w/o prior evidence of safety and efficacy
give an example of a indirect pharmacodynamic effect drug-drug interaction
pharmacologic effects of one drug indirectly affects another’s drug action
ex. diuretic (hypokalemia) + digoxin –> enhanced digoxin toxicity
What are the 4 main categories of drugs and what are they primarily distinguished by
- prescription drugs
- controlled substances
- OTC drugs
- dietary supplements
Distinguished by:
- were they evaluated for efficacy and safety prior to use in patient
- availability by RX only or direct purchase OTC
- potential for abuse (physiologic or psychologic dependence)
Most common mechanism for drug passage across biological membrane
Lipid passive diffusion
*drug must be lipophilic
How can you manipulate passive reabsorption in the kidneys?
change pH
Acidify w/ NH4Cl / ascorbic acid
Alkalinize w/ NaHCO3
what Phase I oxidation reactions are CYP450 independent?
- Amine oxidases
2. Dehydrogenations (alcohol and aldehyde)
Dietary Supplements and herbal medications are NOT inherently safer bc they are natural. They should only be used for:
- tx of mild, self limiting conditions
- Pt can self-diagnose condition
- Pt. can self-assess when persistence of condition requires physician visit
ex. diarrhea
what is a drug allergy? Example
- adverse response of immunologic origin
- unpredictable
- severity is does INDEPENDENT
ex. Penicillin-induced anaphylactic shock
What is the purpose of phase I reactions
-usually inserts of unmasks a functional group on the drug (-OH, -SH, -NH2) that renders the molecule more water soluble and the molecule can then undergo conjugation in a phase II rxn
what CYP enzyme helps w/ detoxification of acetaminophen
CYP2E1
What Schedule of drugs are these?
- Opioids: Codeine combined with non-opioids*
- Anabolic Steroids: Testosterone and esters, synthetic androgens
- Cannabinoids: Dronabinol
Schedule III drugs
how can drug-drug interactions effect excretion?
- change GFR (ex. aminoglycosides)
- change tubular secretion (ex. PCN)
- change tubular reabsorption via changing urine pH (ex. amphetamine, ASA)
parameters for distribution
Vd
What is the most important organ for excretion?
kidneys
*esp. for water-soluble and non-volatile compounds
___ will have NO effect in the absence of the agonist for that receptor
Antagonist
*the extent of the effect of an antagonist will depend of the level of “normal tone” mediated by the agonist in that tissue
What CYP isozyme results in:
non-response to antidepressants
CYP2D6 (UM)
*metabolism is detoxifying
Convert metric to avoidrupois/ apotheracry/household: WEIGHT 1 grain= 1 oz= 2.2 pounds= 1 pound=
1 grain= 60-65mg
1 oz= 28.35-30 grams
2.2 pounds= 1 kg or 1000 grams
1 pound= 16 oz or 454 grams
treatment of methanol and/or ethylene glycol toxicity
- inhibit rate limiting enzyme (alcohol-DH) w/ ethanol (a competitive inhibitor) or fomepizole to inhibit production to toxic metabolite (INHIBIT TOXICATION)
- hemodialysis
- Correction of metabolic acidosis w/ sodium bicarb
Factors influencing Drug Membrane passage
- Molecular size
- lipid solubility
- Degree of ionization
- Concentration gradient
what do these abbreviations mean? (used in freq. or timing) *qd= *qid= hs= stat= bid= *qod= ac= prn= tid= qam= pc=
qd=every day qid= 4x a day hs= at bedtime stat= immediatel bid= 2x a day qod= every other day ac= before meals prn= as needed tid= 3x day qam= every morning pc= after meals
Describe Schedule V drugs
- Accepted medical use, abuse potential EVEN LESS than drugs in schedule IV
- Can be obtained without prescription (OTC) in some states (with restrictions)
*Treated like schedule III-IV in Colorado
what claims require FDA evaluation and authorization prior to its use?
*Health claims— effect substance has on reducing
risk of or preventing a disease
ex. Ca may reduce the risk of osteoporosis
Structure/function claims DO NOT
what are example of drugs with narrow TI that need to be closely monitored for drug-drug interactions
warfarin
insulin- antidiabetic agents
FDA requires that manufacturers of generic drugs demonstrate their formulation is ______ to brand name formulation, which entails __
bioequvialent
- bioequivalent if:
1. Rate and F of the active drug is absorbed and becomes available at the site of action is similar to brand name
2. if 90% CI of the mean AUC and mean Cmax of generic product is within 80-125% of the brand product
what method of absorption prevention is best if poison was ingested w/in 60 min.
gastic lavage
what does the state government control in regards to drug regulation?
- controls WHO can prescribe drugs through licensing process
* exception is federal DEA regulates controlled substance prescribing
pharmaceutical equivalent formulations that are bioequivalent means what?
-The rate and extent to which the active ingredient is absorbed from a drug FORMULATION and becomes available at the site of action
most schedules of drugs have the same risk of developing physiologic and psychologic dependence EXCEPT for
Schedule III
Physiologic= MODERATE Psychologic= HIGH
how can you change tubular reabsorption?
change urine pH
- increase urine pH=
- decreased tubular reabsorption for WA= decreased Cp (ex. ASA)
- increased tubular reabsorption for WB= increased Cp (ex. amphetamine) - decrease urine pH=
- increased tubular reabsorption for WA= increased Cp
- decreased tubular reabsorption for WB= decreased Cp
Time to reach steady state plateau AND time to eliminate all drug is related to what?
Half life of a drug only
-INDEPENDENT OF DRUG DOSE
what are pharmaceutical equivalents
drug products containing the same:
- active ingredient in same dosage formulation (capsule, tablet, solution, etc.)
- that have the same route of administration, and
- are identical in strength or concentration
Prescription Construction components
- Choice of drug/product
- Date*
- Identity of the prescriber*
- Patient information*
- The symbol Rx (latin for recipe-“take thou”
- Drug, strength, quantity/formulation*
- Directions to patient, aka dosage regimen or signa/”sig”
- Chart order in hospitals or similar type inpatient settings- Consists of name/strength/dose/route/frequency of admin/date/signature
- Refill information
- Childproof container
- Signature, DEA number
*indicates required by law
what are medical foods?
And what are examples of diseases that can be MANAGED by a medical food?
- a foof which is formulated to be consumed or administered ENERTALLY under the supervision of a physician and is intended for a SPECIFIC dietary management of a disease or condition
ex. inborn errors of metabolism can be managed by a medical food - diseases resulting from essential nutrient deficiencies ARE NOT (ex. sucvy, pellagra)
how can drug-drug interactions affect distribution?
- protein-binding and displacement of 1 drug by other
- drug effects blood flow, which can effect clearance
ex. drug decreases CO= decreased hepatic flow= decreased hepatic clearance= increased Cp
Effects of drug binding to protein
- reduces concentration of active, free drug
- reduces metabolic degradation and reduce rate of excretion (which leads to decreased elimination rate and increased half life–> prolong drug action)
- Decrease volume of distribution (by enhancing apparent solubility in blood)
- Decrease ability to enter CNS across BBB
Describe Phase II testing in human trails
Phase II: Clinical Investigation: Does it work in patients?
- 2 yrs
- 200-300 selected patients (ideally w/o other conditions)
- compare to placebo or existing treatment
- safety and efficacy evaluated: final dosing and regimen adjusted, may detect broader range of toxicities
*usually done at Universities or Gov. medical centers under IRB suppervision
What is Class A drugs for pregnancy?
examples?
Controlled studies showed NO risk in 1st trimester
-Possibility of fetal harm appears remote
ex. potassium chloride
what is the difference between physical and psychological dependence?
physiologic–stop abruptly and if you experience W/D sx
Psychologic – craving, w/o medical complications
What CYP isozyme results in:
Insufficient analgesia w/ codeine
CYP2D6 (PM)
- due to failure to metabolize to active metabolite morphine
- metabolism is activating
what type of antagonist can be overcome by increasing [agonist]
competitive antagonist
- shifts curve to the right
- Emax unchanged, potency decreased, EC50 increased
what patients are at higher risk for drug-drug interactions
- elderly
- in high risk clinical situations: dependent on drug treatment, acute illness, unstable disease
- renal/hepatic disease
- have multiple prescribing physicians
what is a structure/function claim?
- describes the role of substance intended to maintain the structure or function of the body
- Do not require preapproval by FDA
- CANNOT mention SPECIFIC disease
ex. Ca may help maintain bone health
what is the schedule for:
- Barbiturates
- Tramadol
- Benzodiazepines
- Marijuana
- Barbiturates= 2
- Tramadol= 4
- Benzodiazepines= 4
- Marijuana= 1
How can you reduce fluctuations between doses?
-You want tau (dosing interval) MUCH SHORTER than t1/2
- If tau is less than or equal to t1/2= fluctuate less than 50%** (most drugs do this)
- if tau is much larger than t1/2= fluctuation is maximal
- if tau is much shorter than t1/2= little fluctuation
FDA has ___ regulatory control over sale and distribution of dietary supplements
minimal
The single most important determinant of poisoning is ___
provision of good SUPPORTIVE CARE (ie. vitals and fluids)
**essential until the toxin is eliminated
Convert metric to avoidrupois/ apotheracry/household: VOLUME 1 drop= 1 tsp= 1 Tbsp= 1 fluid oz= 1 quart= 1 pint= 1 gallon=
1 drop= 0.05 ml 1 tsp= 5ml 1 Tbsp= 15ml 1 fluid oz= 29.56-30ml 1 quart= 946ml 1 pint= 473ml 1 gallon= 3785ml (3.785L)
How can we increase elimination?
- increase conjugation
- increase H2O solubility
- increase ionization via conjugation
Describe Phase IV in new drug evaluation
Post-marketing Surveillance
- manufacturers required to submit reports to FDA of any ADR
- Studies often continue after approval (on mortality/morbidity/safety)
- Study groups omitted in phase I and II due to increased risk (preg, kids, elderly, multiple diseases)
- FDA can REVOKE approval or restricted drug use if unpredictable ADR become apparent
What does chelation w/ heavy metals do to help with drug poisoning?
- chelating agents complex w/ free metal ions in body fluids reducing their concentration and thereby promoting the dissociation of metals from functional intracellular macromolecules
- increases renal elimination and inactivates the metal toxin
what does the FDA regulate (fed. gov)
- Evaluation process for new drugs (safety and efficacy) and removal of unsafe dietary supplements (BUT only AFTER their availability to public)
- equivalency of brand vs generic
- placement of drugs into RX or OTC catergories (DEA reg. controlled substances)
when Identifying prescriber on a prescription, you must include
name
address
license classification (professional degree)
phone number
*usually preprinted
Reminder phrases for Rx directions include: \_\_ for internal use \_\_ for ointment/lotion \_\_ for eye, ear, and nose meds \_\_ for suppository \_\_ for inhalers
take- for internal use apply- for ointment/lotion place/instill- for eye, ear, and nose meds insert- for suppository inhale- for inhalers
describe the progression of methanol and ethylene glycol toxicity
Methanol–> FORMIC ACID–> metabolic acidosis w/in 4-12 hrs–> retinal damage and blindness–> stop breathing–> death
Ethylene glycol–> OXALIC ACID –> deposition of calcium oxalate crystals –> acidosis and acute renal failure
**minimal toxicity until they undergo metabolism
what Schedule of drugs are these?
Opioids: Heroin and other synthetic opioids Hallucinogens: LSD, MDMA, peyote, mescaline, psilocybin, phencyclidine (PCP) Marijuana Methaqualone
Schedule I
What is Class D drugs for pregnancy?
examples?
- Positive evidence of human fetal risk BUT potential benefits may outweigh the potential risks if needed in a life-threatening situation or a serious disease
examples: Oral anticoagulants, ACE inhibitors/AT1 antagonists, diazepam-lorazepam, alprazolam, paroxetine
what type of drug metabolism reaction is most utilized in pro-drugs?
esterases (hydrolysis) - phase I
Describe Schedule IV drugs
Accepted medical use, LOW potential for abuse leading to limited dependence
what method of absorption prevention is best if poison was ingested more than 60 min. or if toxin is in enteric coated tablets, or if toxin is hydrocarbon
osmotic cathartic
Controlled substances are divided into 5 schedules based upon potential for:
- medical usefulness
- abuse potential
- degree to which they may lead to physical/psychological dependence if they are abused
(Schedule I= highest for abuse, Schedule V= lowest/limited)
what is good at prediciting which drugs will be removed by dialysis/ exchange transfusion
drugs w/ low Vd (less thank 1L/kg)
what is the toxic dose of acetaminophen
- Single dose greater than 10-20g
- more than 4g/day
Describe what efficacy is
Emax
-Shows the LIMIT of the DR response at Emax
describe the pre-clinical testing phase of a new drug
- animal studies for 5-8 yrs
- evaluate: pharmacology, metabolism, and toxicity (and chronic toxicity)
- Attempt to determine safe dosage for human use (highly predictive, but not totally reliable)
- then submit IND application. NDA filed for specific indication/use
what are side effects? Give examples
Reactions that are unrelated to the therapeutic goal
- same DR interaction for TE but at different organ/system
ex. B-adrenergic R. lowers BP on heart but causes bronchospasm at lung - unrelated pharmacodynamically to therapeutic response
ex. Minoxidil (an antihypertensive) causes hypertrichosis
- dose-dependent
- predictable
what are pharmaceutical alternatives
Drug products that have
SAME therapeutic moiety, BUT
-different salts, esters, or complex of that moiety, OR are different dosages forms
ex. capsules vs tablets or 200mg vs 250mg
Convert metric to avoidrupois/ apotheracry/household: WEIGHT 60-65mg = 1 gram= 28.35-30 grams= 454 grams= 1000 grams (or 1 kg)=
60-65mg = 1 grain
1 gram= 15.43 gains
28.35-30 grams= 1 oz (437.5 grains)
454 grams= 1 pound (16 oz)
1000 grams (or 1 kg)= 2.2 pounds
what do these abbreviations mean? (used for routes) *ad= *od= IA= IVPB= sc, sq= *as, al= *os, ol= IM= po= vag= *au= *ou= IV= pr=
*ad= right ear
*od= right eye
IA= intra-arterial
IVPB= IV piggyback
sc, sq= subcutaneous
*as, al= left ear
*os, ol= left eye
IM= intramuscular
po= by mouth, orally
vag= vaginally
*au= both ears
*ou= both eyes
IV= intravenous
pr= per rectum, rectally
how can toxic doses affect absorption
large amount of ingested drug may slow tablet dissolution, alter GI emptying, or injure GI tract–> alter absorption rate–> delay peak effect
Examples of drugs whose metabolism of inactive compound results in active compound (designed to)
omeprazole–> a sulfenamide
enalapril–> enalaprilat
valacyclovir–> acyclovir
If the FDA approves the NDA, it will allow sales as Rx or OTC w/ stringent controls on __, __ and ___
labeling
packaging insert
advertising
*FDA regulates what indication for drug use the manufacturer can place in the package insert and what claims the manufacturer can make in advertising BUT CANNOT regulate how a drug is actually prescribed by physician (off-label use)
how does N-acetylcysteine help tx acetaminophen toxicity
- precursor for tluthation synthesis, which helps detox. Ac*
- acts as a neutrophile to inactivate the electrophilic Ac*
Describe different mechanisms of transduction signal amplification
- ligand-ion gated- Fastest– change in membrane potenital
- G-Coupled Receptors (fast)– produce effector/ 2nd messenger (cAMP, cGMP, IP3)
- Hormone R. or Kinase linked R.- (slow)– change in gene transcription
Clinically relevant Inhibitors
- Cimetidine*
- Erythromyocin/ Clarithromycin
- Ketoconazole/ Azole antifungals
- Fluoxetine (and other SSRIs)
- Grapefruit juice*
- HIV protease inhibitors
- Omprazole*
*don’t need RX
how is acetaminophen toxicity eliminated
5-10% in phase I via CYP2E1–> produces Ac* when phase II becomes saturated
70-80% in phase II w/ glucuronic acid or sulfate (glucuronidation and sulfate conjugation)
Ac* is DETOXIFIEDby GSH-transferase
how might toxic doses affect half life?
prolong half life due to saturation of the elimination mechanisms
what type of reactions can produce toxic intermediates?
Nitro reductions (phase I)
what are ways to circumvent or prevent drug-drug interactions in patients
- Document all meds the patient is on
- minimize number of prescription drugs
- use alternative non-interacting drug
- modify dosing schedule (to compensate for anticipated interaction)
- be vigilant w/ patients on drugs with narrow TI or in high risk clinical situation (acute illness, depended on drug tx, have unstable disease)
when is hemo/peritoneal dialysis and hemoperfusion good choices for enhancing elimination to help tx poisoning?
hemo/peritoneal dialysis:
- toxins w/ small Vd
- low protein-binding capacity
- assists in correction of fluid and electrolyte imbalance
hemoperfusion:
- toxins w/ high MW
- poor water solubility
- Might CAUSE bleeding and electrolyte disturbance
Are immediate-release products equivalent to extended-release products of the same active ingredient?
NO!
what mechanisms can lead to increased Cp leading to toxicity
- reduced elimination (most common)
- protein bound displacement
-Product FORMULATION are tested for ____ NOT __
bioequivalence NOT the drug’s bioavailabilty
Rx directions for a patient should include
amount of drug taken, time freq, route of adminstration, duration of therapy
What is the purpose of phase II reactions
-Endogenous substrate combines w/ pre-exisiting or metabolically inserted functional group (via phase I) on a the drug forming a highly polar (water soluble) conjugate that is readily excreted via the URINE
what prescriptions CANNOT be called in
controlled substances
what 3 sections did the FDA add to recognize shortcomings of pregnancy and breastfeeding in current prescription drug labeling
- Fetal risk summary- known effects of fetus and risk
- Clinical Considerations-effects of use of the drug and RISK OF THE DISEASE to the mother and fetus
- Data- details regarding use of drugs in humans and animal studies
What CYP isozyme results in:
Decreased efficacy of PPIs for peptic ulcer disease
CYP2C19 (PM)
*metabolism is activating
what is the relationship between receptors occupied by drug (DR) and response?
RD is proportional to response
(as depicted by dose-response curve)
RD can reach a max so therefore response levels off too (Emax= all receptors are occupied by drug)
what is the primary organ of drug metabolism
liver
How can you reach a steady state concentration sooner?
By giving a loading dose
-increasing MD will only set your [SS] higher
what is Ipecac and how does it work?
- an emesis (empties stomach contents rapidly) to REDUCE absorption in poisoning
- works w/in 15-30 min., may repeat 1x in 20 min.
- Mechanism: LOCAL irritation and CNS stimulation of chemoreceptor zone (CTZ)
*effective orally, must be given BEFORE charcoal
Predisposing factors for hepatocellular damage from acetaminophen toxicity
- increased CYP2E1 activity
- decreased hepatic glutathione content
*both occur w/ excessive alcohol consumption
how can an INHALED drug be manipulated for systemic vs local use?
volatile gas= systemic
aerosol particles = local
Describe Phase I testing in human trails
Phase I: Clinical pharmacology: Is it safe, PKs?
- 1-10 yrs
- select 20-100 normal healthy volunteers (males 18-45y/o)
- Toxicity and metabolism studies (look at half-life, absorption, elimination)
- Determine if animal/human response differs significanly
when will low incidence drug effects be missed and why?
in Phase I-III
To detect a 2-fold increase in incidence to effect (drug vs non-drug) if:
1 in 100 incidence need 1,800 pts
1 in 1000 incidence need 18,000 pts
1 in 10,000 incidence need 180,000 pts
**practitioners must play active role in reporting ADR
What Schedule of drugs are these?
-Opioids: Pentazocine, Butorphanol
-Stimulants: Phentermine, Sibutramine
-Depressants:
Benzodiazepines* (alprazolam, diazepam, triazolam, lorazepam, midazolam)
Zolpidem, zaleplon
Chloral hydrate
Meprobamate
-Tramadol*
Schedule IV drugs
Protein binding and displacement drug-drug interactions is only of clinical consequence when:
- displaced drug has narrow therapeutic index
- displacing drug is started in high doses
- displaced drug has low Vd
- Response to drug occurs more rapidly than redistribution
bioequivalent products are assumed to be _____
therapeutic equivalents (same dosage regimen provides same efficacy and safety)
*requires expensive, time-consuming human trials so not usually determined and NOT required by FDA
How can you enhance elimination to help tx poisoning
- extracorporeal removal (hemo-/peritoneal dialysis and hemoperfusion)
- enhance metabolism via induction, inhibition or enhancing detox.
- Enhance renal excretion (forced diuresis or block passive tubular reabsorption in kidney via changing urine pH)
- Chelation of heavy metals
Examples of drugs whose metabolism of active drug results in a toxic metabolite
Acetaminophen–> N-acetyl-benzoquinoneimine (hepatotoxic, Ac*)
Controlled Drugs Current Requirements for Prescribing
- a DEA number (physician registers with DEA)
2. Schedule I drugs may NOT be prescribed
3. All schedule II-III-IV drugs require a prescription (in
Colorado II-III-IV and V)
4. Schedule II must be in ink in prescriber’s handwriting- cannot be telephoned to pharmacist - cannot be
refilled *cannot fill for more than 90 days - Schedule III and IV (plus V in Colorado) may be
telephoned to pharmacist- may be refilled up to 5
times in 6 months (if so noted on prescription)
when is standard safety margin used over therapeutic index?
- more reliable if the patient response to the therapeutic and/or toxic effects of a specific drug varies widely
- more conservative measure than TI and takes into account the EXTREMES of a population, rather than midoints
types of pharmacodynamic drug-drug interactions
- Antagonistic effects: occur when 2 drugs w/ opposite pharmacological effects given together
- Synergistic or additive TE: when drugs w/ similar therapeutic effects given together (ex. BB + diuretic= enhaced BP lowering)
- Synergistic or additive side effects: similar to above, but involves SE (ex. ethanol and Benzo= increased CNS sedation)
- Indirect pharmacodynamic effect: pharmacologic effects of one drug indirectly affects another’s drug action
is inhibition or induction faster?
inhibition
*w/in hrs while induction requires 48-72 hrs
are herbal medications required to show proof of safety, efficacy, purity, and quality control?
purity and quality control: Yes- as of 2011
*do not have to show safety or efficacy– burden of proof w/ FDA to show unsafe
