6. Dose-Reponse Relationships Flashcards
Objectives
• Following this lecture the student should be able to
– Explain differences between quantal and graded dose response curves
– Distinguish between drug potency and efficacy
– Identify agonists, antagonists and partial agonists from their dose response curves
– Calculate the therapeutic index of a drug
1. \_\_\_\_ - all-or-none; \_\_\_\_ is what we mainly deal with - more drug you give the bigger the response (beta blcoker, heart goes slower and slower, etc.) 2. \_\_\_\_ is a measure of strength, doesn't mean it's \_\_\_\_; \_\_\_\_ - talking about maximum effect a drug can have, if something is more efficacious then it might be \_\_\_\_ 3. Agonist - on/off/on/off; antagonist have higher \_\_\_\_ for receptor but don't readily dissociated; partial agonists are in between both (high affinity, but not as much as antagonist, but can partially activate the receptor; \_\_\_\_, so patients aren't craving opioid) 4. LD50/ED50 = \_\_\_\_; purely a measure of \_\_\_\_, doesn't tell you how well a drug works; the number is \_\_\_\_
quantal graded potency better efficacy better
affinity buprephenone TI safety unitless
Why are we interested in dose/response relationships?
Helps us clarify the proper dose of a given drug that produces the desired ____ without harmful side effects. To analyze the relationship between dose and effect we construct plots of the relationship.
Central Pharmacology DOGMA:
Show me a drug without side effects and you can’t show me a useful drug. So our real goal is to establish ____ doses while limiting ____.
therapetuic action
effective
side effects
Types of Dose-Response Curves
• ____ – with increasing dose see an increase in response. – Increase [ACH] > Increase force of ____ muscle contractions
– Increasing doses of oxycodone on pain relief (analgesia)
– Increasing doses of ____ on psychomotor impairment
• ____ – all or none dose response
– Percentage of rodents ____ at given dosages of phenobarbital
– Percentage of rodents “permanently asleep” (____) at given dosages of phenobarbital
– Effectiveness of an ____ agent
• Ach - receptor = \_\_\_\_ (skeletal muscle) • Never isolated a \_\_\_\_ for alcohol > binds somewehere near benzo's and opens up chloride channels, decreases excit AA release; multi mechanism CNS depressant • \_\_\_\_ - the safest barb - seizure disorders (anticonvulsant activity; a TI of 8) ○ TI only done on \_\_\_\_ (not done on humans)
graded
skeletal
alcohol
quantal
asleep
dead
oral contraceptive
nicotinic M cholinergic
receptor
phenobarbital
rates
Alcohol
* CNS depressent - certain sedatives at low doses - \_\_\_\_ - where you get a buzz, but you may take risks you normally wouldn't take, and say things you wou;nd't say > becomes important with sedating people * Low TI - resembles \_\_\_\_ more than it doesn benzo's
disinhibition
barbituates
COMPLICATED SLIDE LOOK AT ME!
* Substrate-enzyme complex gives you an effect * Drugs that maximally activate receptors, they also \_\_\_\_ readily (if they don’t readily, they're \_\_\_\_) * If bind half receptors - you get half maximal effect; on a lot of organs you have \_\_\_\_ receptors in case tissue gets damaged; effective concentration that gives you 50% max activity could be less than the \_\_\_\_ when 50% of receptors are bound * K3 > maximum effect > can be anywhere 0 to 1; 1 is an \_\_\_\_ an 0 is \_\_\_\_; and anywhere between it’s a partial agonist
dissociate antagonists spare Kd agonist antagonist
• Dose response plotted > ____
• In pharmacology, would rather deal withs traight line protions of curves, a way to make mathetmatically 70% of curve linear > ____ transform
○ Log10 - 1, Log100 - 2, and so on
* After log transform > \_\_\_\_ curve * 25-75% you get a realtively \_\_\_\_ portion * Early prtion of dose response curve > something may be going on at molecular level, but we don’t have \_\_\_\_ to measure it * Once it moves up > \_\_\_\_ dose; once you cant push the effect anymore > \_\_\_\_ dose (\_\_\_\_) * Go to 50% response point > EC50, and if dealing with system without spare receptors = \_\_\_\_
hyperbola sigmoidal linear technology threshold ceiling Emax Kd
Panel C
• X is more \_\_\_\_ than Y, but they both achieve same \_\_\_\_ ○ Go to 50%, so X is \_\_\_\_ more powerful (potent) (20 vs 80) • Z is less \_\_\_\_ than Y, and it cant reach the maximum effectiveness (less \_\_\_\_) • Curve on left > most potent; at 50% point that's how you figure out the potency
potent maximal effect 4X potent efficacious
Analgesic Dose/Response of Various Pain Relievers
• Oxy/percocet; codeine in tyelonol with the numbers • \_\_\_\_ and \_\_\_\_ are same in maximum effect; but oxycodone is more \_\_\_\_ • Oxy is \_\_\_\_ more poten than codeine ○ Hydrocodone is \_\_\_\_ more powerful than codeine • Low doses of this cause a lot of side effects • APAP > peaks at \_\_\_\_mg (peripheral acting analgesics have a \_\_\_\_ effect; if pain is severe enough you can't get up there) • Maximum dose of \_\_\_\_ and a little bit of \_\_\_\_ (combined with ibu or acetomen)
oxycodone codeine potent 12X 6X 1000 ceiling APAP opioids
Side Effect Profile
• Dosed when had pain and followed for four hours • Third column doesn't exist anymore (tylox) - cannot have more than \_\_\_\_ mg of acetomen • In opioid groups > \_\_\_\_ had side effects, up the oxy to \_\_\_\_mg and it gets worse ○ In two days > \_\_\_\_ in addition to nauseus ○ Heroin addicts don't cae if they get nauseus from it • Rescue drug here is ibuprofen, so if after hour you can bounce
325
21/45
10
constipated
The maximum daily dose for Tylenol was lowered on all acetaminophen-containing adult products from ____ mg
(8 Extra Strength Tylenol pills) to ____ mg (6 pills),
the manufacturer said today. The move is intended to reduce the risk of accidental acetaminophen overdoses that can lead to liver failure and death. Effective January 1, 2012.
In addition, as of Jan 1, 2014 all opioid combination drugs (i.e. acetaminophen plus hydrocodone or oxycodone will not be allowed to contain more than ____ mg
APAP per tablet!! ____ NO LONGER EXISTS AS WE KNOW IT!!!
4000
3000
325
vicodin
- All the vicodin preparation, all acetomineophen levels are now at ____
- The porblme now > most of efficacy comes aceto/aspirin/aleve > side effects for opiates; so now things don’t ____ as well anymore
- They’re now a ____ drug
300
work
schedule II
- ____ - #1 prescribed NSAID in the world
- Rapid release of diclofinac - ____
- You get a ____ response
- ____mg dose was approved > will side on caution (the FDA)
- Only availble by ____
- 1-2% of people will have elevations in ____ > liver inflammation > not OTC
diclofenac zipsor placebo 25 prescription liver enzymes
• Give overall impression of study drug based on how well it worked • Placebo - said it was bad ○ \_\_\_\_% said best pain reliever • Double blind • With \_\_\_\_ mg - 68% • \_\_\_\_ mg - 84% • \_\_\_\_ mg - 94% • \_\_\_\_ dose resopnse - enhanced dose response • Max dose is \_\_\_\_mg
6 25 50 100 graded 100
• fMRI > SPEC scan > measures cerebral blow fow
• Post surg dental pain > ____ (in the midbrain where amygdala is) > neuronal activity correlates with blood flow
• Given ____, pain calms down, and blood decreases, and both sides of thalamus almost normalize
○ Not common in acute pain, but it is common in ____ pain (back pain)
• Pharamacogenetics > 3/4 ____ expressed in patients prior to surgeyr that may tell us who the 80-85% are who will respond reeally well to ____ and ____ and don’t need opioid
thalamus chronic RNA ibuprofen tylenol
Oxycodone (Oxycontin®) is an ____ receptor ____. K3 = ____
* Binding site and activity site * \_\_\_\_, morphine, \_\_\_\_, fentanyl all are like this on the opioid receptor
opiate agonist 1 heroin codeine
