HTHSCI 2H03 Chapter Notes - Chapter 4: Pharmacology, Frequency Distribution, Adrenergic Receptor
18 Sep 2018
School
Department
Course
Professor
4.1$Pharmacodynamics
The$pharmaco$-medicine,$dynamics$-change
Refers$to$how$a$medicine$changes$the$body$
○
-
Frequency$distribution$curve$
Graphical$representation$of$the$number$of$individuals$who$respond$to$a$
drug$at$different$doses$
○
○
Few$individuals$respond$at$very$low$doses$(10$-20$mg)$
○
Dosage$increases$-more$individuals$respond$
○
Largest$amount$of$people$respond$at$50$mg$
Does$not$show$to$what$extent,$only$whether$a$measurable$response$
occurred.
§
For$example;$some$people$needed$only$20$mg$for$a$20$mmHg$
reduction$in$bp$whereas$others$needed$50$mg,$and$some$even$90$
mg
§
○
Median$effective$dose
The$dose$required$to$provide$a$specific$response$in$50%$of$a$group$
of$clients$
The$average$or$standard$dose$□
§
This$is$only$for$half$the$population$-many$will$need$more$or$less$
§
○
-
4.2$Therapeutic$Index$Describes$a$Drug's$Margin$of$Safety$
Therapeutic$Index
TD50$/$ED50$=$represents$the$margin$of$safety$of$a$drug$
-
Higher$index$=$safer$drug$
-
Median$Lethal$Dose
Will$be$lethal$in$50%$of$a$population$(group$of$animals)
-
Compared$to$ED50$to$determine$the$safety$of$a$drug
-
Therapeutic$Index$(TI)$
A$ratio$of$the$drug's$LD50$to$ED50
-
The$larger$ the$difference$between$the$two$doses,$the$greater$the$TI$
-
Example$A$-this$means$you$would$need$4x$the$average$dose$for$it$to$be$lethal$
-
Median$Toxicity$Dose$(TD50)$
LD50$cannot$be$determined$in$humans,$this$is$more$practical$ to$use$
-
TD50$is$the$dose$that$will$produce$toxicity$in$50%$of$population$
Must$be$recorded$from$animal$data$or$based$on$adverse$effects$in$clinical$
trials$
○
-
Margin$of$Safety$(MOS)
Calculated$as$the$amount$of$drug$that$is$lethal$to$1%$of$animals$(LD1)$divided$by$
the$amount$of$drug$providing$therapeutic$effect$in$99%$of$animals$(ED99)$
Higher$MOS,$safer$the$medication$
○
-
Only$accounts$for$lethality$of$the$drug$-not$the$non-lethal,$though$serious,$
adverse$effects$that$may$occur$at$lower$doses$
-
4.3$The$Graded$Dose-Response$Relationship$and$Therapeutic$Response
Dose-response$erelationship$-higher$dosage,$more$response$
-
Phase$1;$occurs$at$the$lowest$doses$-few$target$cells$affected$by$the$drug
-
Phase$2;$linear$relationship$between$dose$and$effect$
Double$dose,$double$response
○
-
Phase$3;$plateau,$increasing$dose$has$no$increased$effect$
Could$still$produce$adverse$effects$
○
Could$mean:$
All$receptors$for$drug$are$occupied
§
Drug$has$provided$100%$relief$(ex.$For$a$headache)$
§
○
-
4.4$Potency$and$Efficacy
Drugs$in$the$same$class$are$effective$at$different$doses;$
One$antibiotic$maybe$effective$at$a$dose$of$1$mg/kg
○
Another$is$most$effective$at$100$mg/kg
○
-
Two$ways$to$compare$medications$within$therapeutic$and$pharmacological$
classes;
Potency:)a$drug$that$is$more$potent$will$ produce$an$effect$at$a$lower$dose$
compared$to$another$drug$in$same$class
Drug$X$and$Drug$Y$both$reduce$BP$by$20$mmHg
If$drug$X$produces$this$at$10$mg$whereas$drug$Y$produces$this$
at$60$mg,$drug$X$is$more$potent$
□
§
○
Efficacy:)magnitude$of$maximum$response$that$can$be$produced$from$a$
particular$drug.$
○
○
-
What's$more$important$potency$or$efficacy?
Headache
Ibuprofen$(200$mg)$vs$ASA$(650$mg)
Ibuprofen$relieves$pain$at$a$lower$dose$(it$is$more$potent)$□
At$recommended$doses;$both$are$equally$effective$at$relieving$
headache$pain,$same$efficacy$
□
If$the$pain$isn't$going$away
Morphine$has$a$higher$efficacy$than$both$ibuprofen$and$
ASA$
®
Efficacy$is$always$more$important$than$potency
Example:$cancer$patient$will$be$more$concerned$
about$how$many$cancer$cells$are$killed$than$what$
the$dose$given$is$
◊
®
□
The$idea$that$higher$doses$produce$more$intense$adverse$
effects
Only$true$when$comparing$doses$of$the$same$drug$
®
Cannot$assume$that$a$drug$with$lower$dose$ex.$
Ibuprofen$will$provide$less$side$effects$than$ASA$
®
□
§
○
-
4.5$Cellular$Receptors$and$Drug$Action
Drugs$work$by$activating$or$inhibiting$cellular$receptors
-
Cell$signalling$is$a$part$of$a$complex$system$of$communication$that$enables$cells$
to$perceive$and$correctly$respond$to$their$environment$and$carry$out$basic$cell$
activity$
-
Cells$receive$information$via$receptors$
Receptor$is$a$molecule$to$which$medication$binds$to$initiate$effect
○
Some$are$outside,$others$are$inside$cell$
○
-
Molecules$that$activate$receptors$are$called$ligands$
Can$be$hormones,$neurotransmitters,$cytokines,$growth$factors$
○
-
The$information$cells$receive$achieved$through$signalling$pathways$
Activating$target$proteins$=$response$
○
-
These$receptors$do$not$exist$just$to$bind$to$drugs,$they$normally$bind$to$
hormones,$NT,$growth$factors$
-
How?
Drug$and$receptor$binds$similar$to$a$lock$and$key$model
Small$changes$in$structure$of$drug/receptor$can$weaken$or$eliminate$
binding
○
-
When$bound,$drugs$may$trigger$series$of second)messenger events
e.g.$conversion$ot$ATP$to$cyclic$AMP,$release$of$intracellular$ calcium,$or$
the$activation$of$specific$G$proteins$&$associated$enzymes
○
Not$all$receptors$are$bound$to$membrane,$some$are$intracellular$
molecules$(e.g.$DNA,$or$enzymes)
○
-
Agents$that$bind$intracellular$components$include$steroid$meds,$vitamins$&$
hormones
-
Receptor$subtypes$are$being$discovered$and$help$fine$tune$pharmacology
e.g.$alpha$and$beta$receptors
Makes$the$drug$action$more$specific$rather$than$affecting$all$
receptors$
§
There$are$even$more$subtypes$of$these$receptors$
§
○
-
Non-specific)cellular)responses: drugs$that$act$independently$of$cellular$
receptors$are$associated$w/$other$mechanisms
e.g.$changing$permeability$of$MBs,$depressing$MB$excitability,$ altering$
activity$of$cellular$ pumps
○
Example:$diuretics$
○
-
4.6$Type$of$Drug-Receptor$Interactions$
When$a$drug$binds$to$its$receptor,$it$may$produce$a$response$mimicking$the$
effect$of$the$endogenous$regulatory$molecule
e.g.$bethanechol$binds$to$acetylcholine$ receptors$and$produce$the$same$
actions$as$acetylcholine
○
-
A$drug$that$produces$the$same$response$as$the$endogenous$substance$is$called$
an agonist
Agonists$sometimes$produce$a$greater$maximum$response$than$the$
endogenous$chemical
○
-
Partial)agonist: describes$a$medication$that$produces$a$weaker$or$less$
efficacious$response$than$an$agonist
-
Antagonist: a$drug$that$will$occupy$a$receptor$and$prevent$the$endogenous$
chemical$from$acting
Antagonist$and$agonist$compete$for$receptors$
○
For$example,$the$drug$atropine$competes$with$acetylcholine$for$specific$
receptors$in$the$autonomic$nervous$system
If$the$dose$is$high$enough,$atropine$will$inhibit$the$effects$of$
acetylcholine$because$acetylcholine$cannot$bind$to$its$receptors
§
○
-
Agonists,$partial$agonists$&$antagonists$are$substances$that$compete$w/$drugs$
for$receptor$binding$and$can$cause$drug-drug$and$food-drug$interactions
-
Functional)antagonists inhibit$effects$of$an$agonist$not$by$competing$for$a$
receptor$but$by$changing$pharmacokinetic$factors
-
??
-
4.7$Pharmacology$of$the$Future
Pharmacology$will$likely$be$customized$to$match$the$genetic$makeup$of$each$
client
-
Pharmacogenetics: the$area$of$pharmacology$that$examines$the$role$of$genetic$
variation$in$drug$response
-
Chapter(4
Thursday,$September$ 13,$2018
5:09$PM
4.1$Pharmacodynamics
The$pharmaco$-medicine,$dynamics$-change
Refers$to$how$a$medicine$changes$the$body$
○
-
Frequency$distribution$curve$
Graphical$representation$of$the$number$of$individuals$who$respond$to$a$
drug$at$different$doses$
○
○
Few$individuals$respond$at$very$low$doses$(10$-20$mg)$
○
Dosage$increases$-more$individuals$respond$
○
Largest$amount$of$people$respond$at$50$mg$
Does$not$show$to$what$extent,$only$whether$a$measurable$response$
occurred.
§
For$example;$some$people$needed$only$20$mg$for$a$20$mmHg$
reduction$in$bp$whereas$others$needed$50$mg,$and$some$even$90$
mg
§
○
Median$effective$dose
The$dose$required$to$provide$a$specific$response$in$50%$of$a$group$
of$clients$
The$average$or$standard$dose$
□
§
This$is$only$for$half$the$population$-many$will$need$more$or$less$
§
○
-
4.2$Therapeutic$Index$Describes$a$Drug's$Margin$of$Safety$
Therapeutic$Index
TD50$/$ED50$=$represents$the$margin$of$safety$of$a$drug$
-
Higher$index$=$safer$drug$
-
Median$Lethal$Dose
Will$be$lethal$in$50%$of$a$population$(group$of$animals)
-
Compared$to$ED50$to$determine$the$safety$of$a$drug
-
Therapeutic$Index$(TI)$
A$ratio$of$the$drug's$LD50$to$ED50
-
The$larger$ the$difference$between$the$two$doses,$the$greater$the$TI$
-
Example$A$-this$means$you$would$need$4x$the$average$dose$for$it$to$be$lethal$
-
Median$Toxicity$Dose$(TD50)$
LD50$cannot$be$determined$in$humans,$this$is$more$practical$ to$use$
-
TD50$is$the$dose$that$will$produce$toxicity$in$50%$of$population$
Must$be$recorded$from$animal$data$or$based$on$adverse$effects$in$clinical$
trials$
○
-
Margin$of$Safety$(MOS)
Calculated$as$the$amount$of$drug$that$is$lethal$to$1%$of$animals$(LD1)$divided$by$
the$amount$of$drug$providing$therapeutic$effect$in$99%$of$animals$(ED99)$
Higher$MOS,$safer$the$medication$
○
-
Only$accounts$for$lethality$of$the$drug$-not$the$non-lethal,$though$serious,$
adverse$effects$that$may$occur$at$lower$doses$
-
4.3$The$Graded$Dose-Response$Relationship$and$Therapeutic$Response
Dose-response$erelationship$-higher$dosage,$more$response$
-
Phase$1;$occurs$at$the$lowest$doses$-few$target$cells$affected$by$the$drug
-
Phase$2;$linear$relationship$between$dose$and$effect$
Double$dose,$double$response
○
-
Phase$3;$plateau,$increasing$dose$has$no$increased$effect$
Could$still$produce$adverse$effects$
○
Could$mean:$
All$receptors$for$drug$are$occupied
§
Drug$has$provided$100%$relief$(ex.$For$a$headache)$
§
○
-
4.4$Potency$and$Efficacy
Drugs$in$the$same$class$are$effective$at$different$doses;$
One$antibiotic$maybe$effective$at$a$dose$of$1$mg/kg
○
Another$is$most$effective$at$100$mg/kg
○
-
Two$ways$to$compare$medications$within$therapeutic$and$pharmacological$
classes;
Potency:)a$drug$that$is$more$potent$will$ produce$an$effect$at$a$lower$dose$
compared$to$another$drug$in$same$class
Drug$X$and$Drug$Y$both$reduce$BP$by$20$mmHg
If$drug$X$produces$this$at$10$mg$whereas$drug$Y$produces$this$
at$60$mg,$drug$X$is$more$potent$
□
§
○
Efficacy:)magnitude$of$maximum$response$that$can$be$produced$from$a$
particular$drug.$
○
○
-
What's$more$important$potency$or$efficacy?
Headache
Ibuprofen$(200$mg)$vs$ASA$(650$mg)
Ibuprofen$relieves$pain$at$a$lower$dose$(it$is$more$potent)$□
At$recommended$doses;$both$are$equally$effective$at$relieving$
headache$pain,$same$efficacy$
□
If$the$pain$isn't$going$away
Morphine$has$a$higher$efficacy$than$both$ibuprofen$and$
ASA$
®
Efficacy$is$always$more$important$than$potency
Example:$cancer$patient$will$be$more$concerned$
about$how$many$cancer$cells$are$killed$than$what$
the$dose$given$is$
◊
®
□
The$idea$that$higher$doses$produce$more$intense$adverse$
effects
Only$true$when$comparing$doses$of$the$same$drug$
®
Cannot$assume$that$a$drug$with$lower$dose$ex.$
Ibuprofen$will$provide$less$side$effects$than$ASA$
®
□
§
○
-
4.5$Cellular$Receptors$and$Drug$Action
Drugs$work$by$activating$or$inhibiting$cellular$receptors
-
Cell$signalling$is$a$part$of$a$complex$system$of$communication$that$enables$cells$
to$perceive$and$correctly$respond$to$their$environment$and$carry$out$basic$cell$
activity$
-
Cells$receive$information$via$receptors$
Receptor$is$a$molecule$to$which$medication$binds$to$initiate$effect
○
Some$are$outside,$others$are$inside$cell$
○
-
Molecules$that$activate$receptors$are$called$ligands$
Can$be$hormones,$neurotransmitters,$cytokines,$growth$factors$
○
-
The$information$cells$receive$achieved$through$signalling$pathways$
Activating$target$proteins$=$response$
○
-
These$receptors$do$not$exist$just$to$bind$to$drugs,$they$normally$bind$to$
hormones,$NT,$growth$factors$
-
How?
Drug$and$receptor$binds$similar$to$a$lock$and$key$model
Small$changes$in$structure$of$drug/receptor$can$weaken$or$eliminate$
binding
○
-
When$bound,$drugs$may$trigger$series$of second)messenger events
e.g.$conversion$ot$ATP$to$cyclic$AMP,$release$of$intracellular$ calcium,$or$
the$activation$of$specific$G$proteins$&$associated$enzymes
○
Not$all$receptors$are$bound$to$membrane,$some$are$intracellular$
molecules$(e.g.$DNA,$or$enzymes)
○
-
Agents$that$bind$intracellular$components$include$steroid$meds,$vitamins$&$
hormones
-
Receptor$subtypes$are$being$discovered$and$help$fine$tune$pharmacology
e.g.$alpha$and$beta$receptors
Makes$the$drug$action$more$specific$rather$than$affecting$all$
receptors$
§
There$are$even$more$subtypes$of$these$receptors$
§
○
-
Non-specific)cellular)responses: drugs$that$act$independently$of$cellular$
receptors$are$associated$w/$other$mechanisms
e.g.$changing$permeability$of$MBs,$depressing$MB$excitability,$ altering$
activity$of$cellular$ pumps
○
Example:$diuretics$
○
-
4.6$Type$of$Drug-Receptor$Interactions$
When$a$drug$binds$to$its$receptor,$it$may$produce$a$response$mimicking$the$
effect$of$the$endogenous$regulatory$molecule
e.g.$bethanechol$binds$to$acetylcholine$ receptors$and$produce$the$same$
actions$as$acetylcholine
○
-
A$drug$that$produces$the$same$response$as$the$endogenous$substance$is$called$
an agonist
Agonists$sometimes$produce$a$greater$maximum$response$than$the$
endogenous$chemical
○
-
Partial)agonist: describes$a$medication$that$produces$a$weaker$or$less$
efficacious$response$than$an$agonist
-
Antagonist: a$drug$that$will$occupy$a$receptor$and$prevent$the$endogenous$
chemical$from$acting
Antagonist$and$agonist$compete$for$receptors$
○
For$example,$the$drug$atropine$competes$with$acetylcholine$for$specific$
receptors$in$the$autonomic$nervous$system
If$the$dose$is$high$enough,$atropine$will$inhibit$the$effects$of$
acetylcholine$because$acetylcholine$cannot$bind$to$its$receptors
§
○
-
Agonists,$partial$agonists$&$antagonists$are$substances$that$compete$w/$drugs$
for$receptor$binding$and$can$cause$drug-drug$and$food-drug$interactions
-
Functional)antagonists inhibit$effects$of$an$agonist$not$by$competing$for$a$
receptor$but$by$changing$pharmacokinetic$factors
-
??
-
4.7$Pharmacology$of$the$Future
Pharmacology$will$likely$be$customized$to$match$the$genetic$makeup$of$each$
client
-
Pharmacogenetics: the$area$of$pharmacology$that$examines$the$role$of$genetic$
variation$in$drug$response
-
Chapter(4
Thursday,$September$ 13,$2018 5:09$PM
Document Summary
Refers to how a medicine changes the body. Graphical representation of the number of individuals who respond to a drug at different doses. Few individuals respond at very low doses (10 - 20 mg) Largest amount of people respond at 50 mg. Does not show to what extent, only whether a measurable response occurred. For example; some people needed only 20 mg for a 20 mmhg reduction in bp whereas others needed 50 mg, and some even 90 mg. The dose required to provide a specific response in 50% of a group of clients. This is only for half the population - many will need more or less. 4. 2 therapeutic index describes a drug"s margin of safety. Td50 / ed50 = represents the margin of safety of a drug. Will be lethal in 50% of a population (group of animals) Compared to ed50 to determine the safety of a drug. A ratio of the drug"s ld50 to ed50.
