Unit 1 Flashcards
Federal government roles (3)
- Safety & Efficacy of new drugs; removal of unsafe dietary supplements
- Equivalency generic and brand
- Place drugs in categories Rx and OTC and schedules
State government roles
Controls who may prescribe drugs via medical/dental board. Controlled substance needs DEA (Drug enforcement admin of department of justice)
Local Government Role
Pass laws that concern drug use in their jurisdiction
Phase 1 clinical trial (Goals, approximate timing, number of volunteers)
<100 healthy males 18-45 yrs
~ 1year
Goals: Determine if it is safe and toxicity/metabolism studies, if animal/human response differ
Phase 2 clinical trial (Goals, approximate timing, number of volunteers)
200-300 patient pools
2 years
Goals: Does it work in patients, safety and efficacy, final dosing, regimen adjust. Detect broader range of toxicity
Phase III clinical trial (Goals, approximate timing, number of volunteers)
1000-6000 patients
~3 years
Goal: Does it work double blind; efficacy, adverse reaction with chronic use
Can be skipped for high need drugs (accelerated/conditional approval)
ANDA Abbreviated new drug application
Generic drugs can bypass clinical trials, just needs to prove bioequivalency
Phase 4 clinical trial (Goals, approximate timing, number of volunteers)
Report adverse effect post marketing surveillance data on mortality/morbidity Other groups - women/older/children Low incidence drug effects missed in phase I-III seen here
Dietary Supplements Define
Taken by mouth. Vitamins/minerals/amino acids/botanical-herbs.
Herbal: Majority of molecular entity pharmaacologic activity not known
Dietary supplement regulation and differ from drugs
Prior to 1994 - assumed safe
No need to prove safe/effective - need reasonable evidence produce is safe.
Sold first, and remove from market if harmful vs proven first, then allowed to sell
Pharmaceutical Equivalence
Same: active ingredient, dosage formulation, rout of adminstration, identical in strength/concentration. “formulation”
Pharmaceutical alternatives
Same therapeutic moiety - differ in salts, ester, complex or dosages/strengths
Bioequivalence
Extent of absorption (bioavailability) and Rate of absorption same for active ingredient. “Formulation –> drug molecules –> Cp –> target”
Therapeutic equivalents
Admin to same individual in same dosage regimen –> same efficacy and safety. Assumed bioequivalent = therapeutically equivalent. “therapeutic effects”
1 gram = ? grains
15.43
1 kg = ? pounds
2.2
1 ounce = ? grains = ? grams
437.5 grains; 28.35 grams
1 drop = ? mL
0.05
1 tsp = ? mL?
5
1 tbsp = ? mL
15
1 fl oz = ? mL
29.56 or “30”
1 quart = ? mL
946
1 pint = ? mL
473
1 gallon = ? L
3.785
HS
at bed time
Stat
immediately
Bid
twice daily
Ac
before meals
Prn
As needed
Tid
three times daily
Qam
every morning
Pc
after meal
IA
intra-arterial
IVPB
IV piggy back
Sc/Sq
subcutaneous
IM
intramuscular
Po
by mouth
Vag
vaginally
Iv
intravenous
Pr
per rectum/rectally
how are drugs scheduled?
Medical use; abuse potential; physiological dependence; psychological dependence
Schedule 1 drugs
No medical use
High abuse potential
High dependence
- Dr cannot prescribe
Schedule 2 drugs
Yes medical use
High abuse
High dependence
- Dr prescribe in ink - cannot phone/fax
Schedule 3 drugs
Yes medical use
Moderate abuse
Mod/high dependence (phys/psych)
- Dr prescribe
Schedule 4 drugs
Yes medical
Low abuse
Low dependence
- Dr prescribe
Schedule 5 drugs
Yes medical
limited abuse
lowest dependence
- Some states do not require prescription but CO does
Legal components of written prescription in CO
Date, ID of prescriber (name, address, license, phone), PT info (name, address), Drug + strength, signature, DEA number
5 parts of dosage regimen
Drug, DOse, Rout, Frequency, Duration
Loading Dose vs Maintenance Dose (purpose and equation)
LD higher to reach desired Cp faster; MD to keep at Cpss
Cp = LD/Vd
MD/T = CL x CPss (T = dosing interval)
Bioavailability F (Definition + Equation)
Extend of absorption of drug from non-intravenous site - used to convert dosage
F = AUC route/AUC IV
Rate of absorption is determined by which 2 factors?
Tmax and Cmax
DIstribution Vd
Drug from plasma to site of action target - extent of drug movement ( dilution factor)
Equation for clearence depends on…
CL = Vd x Ke (elimination rate constant and half life)
Use also to determined interval between dosages to maintain Cpss (MD/T = CL x Cpss)
List routes of administration
Oral, IV, inhalation, Rectal, Sublingual, Intramuscular, Subcutaneous, Transdermal patch, Dermal
Absorption depends on which 4 drug factor
- molecular size - affected by drug -protein binding
- Lipid solubility - O/W
- Degree of ionization - Affected by tissue pH - affects lipid solubility
- Concentration gradient - at site of admin.
Methods to cross lipid bilayers
- Passive diffusion via aqueous channels - water soluble drugs, limit by size
- Passive diffusion via hydrophobic binding - membrane lipids
- Facilitated diffusion - Membrane carrier molecules
- Active transport
Routs of admin fast –> Slow (Oral, IV, Intramuscular, subcutaneous)
IV = Inhalation > intramuscular > subcutaneous > oral
Which routes have high bioavailability
IV, Inhalation, Subligual, Intramuscular, subcutaneous (Transdermal patch)
Routes with low bioavailability
Oral, rectal (varies)
Note: Dermal is NOT systemic
High/low Vd meaning?
Drugs spread to ECF/tissues and longer to eliminate
Drug remains in plasma - quickly eliminated
pH > pKa drug trapping
high pH = basic form dominates - traps acids because WA are ionied, WB is non ion
HH equation
pH = pKa + log A/HA; 10^(pH-pKa) = A/HA
Drug - protein binding effects
Reduce free drug concentration
INcrease half life/prolong drug action - hinders metabolic degradation
reduce excretion
Decrease Vd and ability to enter CNS
Drug Drug interaction concerning if
displaced drug = narrow therapeutic index
displaced drug = starts in high dose
Displaced drug’s Vd = small
Response rate > distribution rate
Special anatomic consideration for distribution (where and why)
GI mucosa, blood brain barrier, placenta, renal tubules - tight junctions so drug must move through cells - lipid soluble
(fenestration in post cap venules - through openings)
Total concentration of drug is _____ on side where ionization is greater
greater
Acidic drugs are trapped in more ____ solutions
basic
Drug metabolism, where, how, and goals
In liver via oxidation (or reduction/hydrolysis)
Smooth ER - catalyze transformation
Detox –> makes inactive (sometimes makes more active, activate, or toxic)
Phase 1 goals:
Make drug more polar/water soluble
Phase 1 process
Inserting/unmasking function group (OH, NH2, SH)
Oxidation, reduction, hydrolysis
Phase 2 goal/process
Conjugation/ endogenous substrate + functional group –> highly polar conjugate –> readily excreted via urine
Metabolism to more active compound example
codeine –> morphine
Hydrocodone –> hydropmorphone
Metabolism inactive –> active example
Omeprazole –> a sulenamide
Enalapril -> analprilat
Valacyclovir –> acyclovir
Metabolism toxic metabolite example
Acetaminophen –> N acetyl benzoquinoneimine
Cytochrome P 450 dependent oxidation needs 3 parts:
Liver smooth ER - NADPH, Flavoprotein, O2
Therapeutic consequence induction:
effect takes 48-72 hours - max effect 7-10 days:
Increase clearance of other drugs = reduce therapeutic effect/increase toxic metabolite
Therapeutic consequence inhibition:
Hours
Effect on Cpss - depends on t1/2
Decrease clearance –> increase toxicity
Clinical Examples for inhibition
Cimetidine Erythromycin/Clarithromycin Ketoconazole/Azole antifungals Fluoxetine Grapefruit juice HIV protease inhibitors Omeprazole
Clinical Examples for inducers
Phenobarital Phenytoin Carbamazepine Rifampin Ethanol St. John's Wort Tobacco smoke
Phenobarbital is a _________
Inducer
Phenytoin is a _________
inducer
Carbamazepine is a _________
inducer
Rifampin is a _________
Inducer
Ethanol is a _________
inducer
St. John’s wort is a _________
inducer
Tobacco smoke is a ______
inducer
Cimetidine is a _________
inhibitor
Erythromycin/clarithromycin is a _________
inhibitor
Ketoconazole/azole antifungal is a _________
inhibitor
Fluoxetine is a _________
inhibitor
Grapefruit juice is a _________
Inhibitor
HIV protease inhibitor is a _________
inhibitor
Omeprazole is a _________
inhibitor
Glomerulous (filtration rate, t1/2, size limit)
120 mL/min
1-4 hours
mw 69000 (>albumin)
Glomerous filtration rate depends on ______ and ______
renal blood flow and renal function
Active secretion (rate, types, t1/2)
120-600 mL/min; stronger acids/base in proximal tubules, 1-2 hours
Tubular reabsorption depends on _____, _____, ____, and ____
concentration gradient, lipid solubility, size, non-ionized
Decrease Urine pH
trap base in urine, use NH4Cl
Increase urine pH
Trap acid in urine, use NaHCO3
Enterohepatic recirculation
Conjugates –> bile –> intestines –> bacterial flora enzyme hydrolyze to parent drug (lipid soluble ) –> reabsorption
MW>300
Reduce elimination + prolong half life
Factors affect drug passage from plasma to breast milk
Timing
milk is more acidic - basic drugs trapped
Lipid soluble –> increase milk concentration
High protein binding –> decrease milk concentration
Drugs affect milk production
1st order half life
0.693/k = t1/2
Ke definition
fraction of drug leaving body per unit time (via all elimination process)
1st order constant _____ of drug removed per time
fraction
0th order constant _____ of drug removed per time
amount
Drug Receptor concept
Specificy of fit between receptor and conformation –> generate response
Drug-response curve
linear at the beginning -> more drug ->more receptors occupied -> more response
Level off -> receptors are saturated, dose independent
Potency
Measured by amount of drug or concentration to reach 50% of max effect
High potency = high affinity, low Kd, low EC50
Efficacy
Ability to reach a response to the max biological response
Partial agonist
Low efficacy
Full agnoist
high efficacy
tau»_space;t1/2
fluctuation is max - drug effectively eliminated before next dose
tau <= t1/2
fluctate less than 50% - little fluctuation
pharmacologic antagonist
Binds to receptor –> no effect but blocks entrance of agoinst
Receptor antagonist can do _______ binding or ________ binding
Active site; Allosteric
Nonreceptor anatongist
(physiological antagonist) bind to different receptor or (Chemical antagonist) bind agonist molecule directly
Shift downwards
Noncompetitive active site antagonist
Binds irreversibly/pseudoirreversibly to active site - limits number of available receptor “removed”
Shift downwards
Noncompetitive allosteric site
Reversibly/irreversibly at an allosteric site - receptor unable to respond to agonist
Shift downwards
Competitive (reversible) antagonist
Shift graph to the right - competes for same active site as agonist - can be outcompeted with more agonist
Physiologic antagonist
activate/block a distinct receptor that mediates physiologic response opposite of agonist
Chemical Antagonist
inactivate agonist itself EDTA (chelating agent) to iron ions antacid base neutralize HCl Osmotic diuretic Protamine
Graded dose response curve
Histogram - frequency distribution of dose
Population drug response curve
Summation/cumulative frequency distribution
Therapeutic index
LD50/ED50 - higher is better
clinical 10-20
Standard safety margin SSM
(LD1/ED99 - 1)x100
Therapeutic window
arbitrary, Cp - ED99 and LD1
Pregnancy category A
No risk
KCl
Pregnancy category B
Risk unknown
Opioids, penicillins, erythromycin, ondansetron, acetaminophen, thiazide diuretic
Pregnancy category C
Risk possible; Benefit > Risk
Pseudoephedrine, antidepressants
Pregnancy category D
Positive Risk - Benefit > Risk - life threatening
Oral anticoagulants, ACE inhibitors/AT1 antagonist, diazepam-lorazepam, alprazolam paroxetine
Pregnancy category X
Risk > Benefits
HMG CoA reductase inhibitor
Pharmacokinetic drug/drug and drug/food interaction methods
Absorption, Distribution, Metabolism, Excretion
Prevent absorption methods
Emesis, Gastric Lavage, Chemical Absorption (activated charcoal), Osmotic cathartics (laxative)
Limitation for emesis
Lack of gag reflex, corrosive poison, CNS stimulant drug (Seizure), Petroleum distillate (pneumonitis), pregnancy category C
asa[p
Gastric lavage
within 30 min, washing stomach with saline/removal nasogastric tube
Activated carbon (how it works and how to use)
Effected without gastric emptying - binds drug in guts
10:1 ratio
Osmotic cathartics (when to use and which to avoid)
> 60 min
Sorbitol 70% - give with charcoal
Magnesium citrate/sulfate - not with renal disease
Sodium sulfate - avoid in congestive heart failure/hypertension
Polyethylene glycol - use with sustained release drugs/metal ions, drug packets
Inhibition of toxication
Fomepizole - blocks alcohol dehydrogenase
Ethanol –> aldehyde using alochol dehydrogenase - competitive reversible antagonist
Methanol –> formic acid; Ethylene glycol –> oxalic acid
Enhancement of detoxication process (metabolism)
Acetominophen overdose
give N-acetylcysteine - precursor for glutathione synthesis (needed to detox)
Enhancement of Elimination methods
Extracorporeal removal, enhanced metabolism, enhanced renal excretion, chelation of heavy metals
Extracorporeal removal
Remove toxin from blood
Hemodialysis
Hemoperfusion
Hemodialysis
blood through filter
- small Vd, low protein binding -
helps with fluid/electrolyte balance
Hemoperfusion
Blood pumped through column of adsorbent material
- high MW
- Poor water solubility
Risk: Bleeding - removing platelets + electrolyte disturbance
Enhanced renal excretion
Forced diuresis - fluid overload/protect kidney
Block reabsorption from kidney - pH/ion trapping in urine
Chelation of heavy metal
Chelating agent forms complex with free metal ions
ion forms coordinate covalent bonds with proteins –> enzyme inhibition/alteration of membrane structure
antidote for acetominophen
N-Acetylcysteine (Mucomyst)
Naloxone (Narcan) antidote for ______
Narcotics (opiates)
Flumazenil (Romazicon) antidote for ______
Benzodiazepines
Pralidoxime/atropine antidote for _____
Nerve gas/insecticide
Digoxin Fab antidote for _____
Digoxin
Protamine antidote for ____
Heparin
Vitamin K (Phytonadione) antidote for ________
Oral anticoagulants (warfarin)
antidote for Methanol/ethylene glycol
Ethanol, 4-methylpyrazole (antizol)
antidote for Iron Salts
Deferoxamine (Desferal)
antidote for Arsenic, gold, mercury
Dimeraprol (BAL)
antidote for for lead/mercury
Succimer (Chemet)
antidote for Copper, lead, gold, mercury
Penicillamine (Cuprimine)
antidote for cyanide
Hydroxcobalamin (Cyanokit)
antidote for Carbon monoxide
oxygen
Methylene blue antidote for ____
Nitrites/nitrates
Acidic medication (active tubular secretion)
Penicillin, salicylate, diuretics (Thiazides, acetozaolamide, thacrynic acid)
Basic medical (active tubular secretion)
Morphine, catecholamines, Histamine, hexamethonium, tolzoline