Lecture 11: Colds Allergies

Front 1

phenylpropanolamine (PPA)

Back 1

-indirect sympathomimetics
-release NA from terminal which then acts on
alpha 1/2-R's
-given oral, topical
-not broken down by MAO/COMT

Front 2

phenylephrine

Back 2

-direct sympathomimetics
-act on alpha 1-R
-given oral, topical
-broken down by MAO
-not broken down by COMT

Front 3

(pseudo)ephedrine (Sudafed™)

Back 3

-indirect sympathomimetics
-release NA from terminal which then acts on
alpha 1/2-R's
-given oral
-not broken down by MAO/COMT

Front 4

diphenhydramine

Back 4

first-generation, sedating antihistamine
H1-R blocker

Front 5

terfenadine/Hismanal

Back 5

2nd generation non-sedating antihistamine
H1-R blocker

Front 6

sympathomimetic

Back 6

-drugs that increase or mimic (nor)adrenergic transmission
ex) nasal decongestants

Front 7

rhinitis=
causes(3)
caused by (2)

Back 7

-inflammation of nasal mucosal membrane
-vasodilation, mucous secretion, edema
-cold, allergies

Front 8

Vasodilation and edema=

Back 8

stuffy nose

Front 9

Mucus secretion (rhinorrhea)=

Back 9

runny nose

Front 10

vasodilation cause nasal cavity to

Back 10

decrease
*vasoconstriction alleviates this

Front 11

Three main approaches for a congested nose

Back 11

• Sympathomimetic
• Antihistamine (H1-R antagonists not H2)
• Other

Front 12

you have alpha 1 and alpha 2 receptors on smooth muscle if u stimulate them=

Back 12

vasoconstriction

Front 13

alpha 1 stimulation

Back 13

coupled to PLC-->IP3-->calcium-->activated Ca-dependent kinase = vasoconstriction

Front 14

alpha 2 stimulation

Back 14

coupled to adenylate cyclase--> decreases cAMP--> decreased PKA =vasoconstriction

Front 15

NA is a ___agonist
is it broken down by MAO/COMT

Back 15

direct
yes
* can be decongestant, not given as treatment though

Front 16

*Sudafed™ is an isomer of

Back 16

ephedrine

Front 17

ephedrine has ___isomers

Back 17

4
*ie 2 chiral centers

Front 18

Pseudoephedrine direct precursor for____

Back 18

methampehtamine

Front 19

____animal model for decongestants
limitation

Back 19

ferrets
need for anesthesia

Front 20

major problem with decongestants

Back 20

rebound effect
withdrawal from drug causes opposite effects of the drug

Front 21

Nasal resistance alternates every __ hours

Back 21

2-4

Front 22

one advantage of taking thing systemically/orally is that you can unblock

Back 22

eustacian tube

Front 23

Do anticongestants work when taken orally?

Back 23

if phenylephrine, no because broken down by MAO in blood stream

Front 24

How does PPA increase BP?

Back 24

acts presynaptically to increase NA
-Beta 1 receptors in the heart activated and cause heart to work more
-alpha 1 on BV's and when activated cause constriction

Front 25

Phenylephrine was ineffective in changing BP- why?

Back 25

could be reflex bradycardia but if u look at graph theres no change in HR so most likely due to MAO

Front 26

Why was PPA banned?

Back 26

increase risk of stroke in young women why? PPA similar to amphetamine and women were using it as an appetite suppressant
also heart attacks increased

Front 27

why would selective alpha 2 agonist be better nasal decongestants

Back 27

-Direct α1 receptor stimulation can produce
• hypertension
• stroke
• insomnia, nervousness
• loss of appetite
-Pseudoephedrine-may be used as diversion to methamphetamine

Front 28

possible concern of alpha 2 agonist

Back 28

if you act on presynaptic alpha 2 inhibitory autoreceptors then NA release decrease, might be a worry if took alpha 2 agonist orally (if put into nose then may not be problem)

Front 29

allergic rhinitis can be seasonal or ___(throughout the year)

Back 29

perennial

Front 30

mast cells release

Back 30

histamine
inflammatory mediators

Front 31

do antihistamines work in allergy rhinits

Back 31

yes

Front 32

do antihistamines work in the common cold

Back 32

no clear effect

Front 33

are histamines produced in the nose during cold

Back 33

no

Front 34

Nasal secretions during colds have an increase in
___ but not histamine

Back 34

kinins

Front 35

(3) ways to see if terfenadine gets pass the BBB

Back 35

-radiolabel
-give drug in vivo and figure out how many receptors were occupied
-behavioral tests to see if it produced sedation

Front 36

results for radiolabel study of terfenadine

Back 36

Brain concn was very low
Drug was excreted via gut

Front 37

key assumption when giving drug in vivo and figuring out how many receptors were occupied

Back 37

drug given in vivo is still present in the in vitro binding assay

Front 38

when people asked "can we be sure that terfenadine did not reach the brain in pharmacological concentrations" they gave drug in vivo and figured out how many receptors were occupied, results?

Back 38

-its not getting into the brain in high enough conc to interact with the receptors ie not reaching pharmacologically significant levels
-it does act noncompetitive in the brain though

Front 39

in last flash experiment, chlorpheniramine was used as a ___

Back 39

+ control to show the assay worked
* its a H1 anatagonist getting thru BBB and increases KD

Front 40

in the experiment discussed they also asked "But did they give enough terfenadine?" answer?

Back 40

yes
*Both chlorpheniramine and terfenadine almost completely saturated these peripheral
histamine receptors at the doses given

Front 41

does terfendaine compete with 3H-mepryamine for brain histamine receptors

Back 41

terfenadine had similar affinity in brain and periphery tissue
terfenadine can act competitively in brain if it reaches
so it is a competitive antagonist

Front 42

IC50 =

Back 42

[drug] that inhibits binding by 50%
low IC50 means high affinity

Front 43

When given systemically, do antihistamines reach the brain? (will they inhibit in vivo binding of 3H-mepyramine to mouse brain?)

Back 43

given systemically, only classic (1st generation) antihistamines inhibited in vivo binding of 3H-mepyramine to mouse brain

Front 44

kinetics of chlorpheniramine

Back 44

rapid onset, reversible
competitive antagonist
causes right shift

Front 45

kinetics of terfenadine

Back 45

slow onset, irreversible
shifts right but more complicated, its a right downward shift

Front 46

reason for terfenadine

Back 46

reminder: its a competitive antagonist and has slow dissociation from receptor (acting irreversibly)
-you dont have to occupy all receptors to get response you can activate 1% of them and can get max response this known as receptor reserve/spare receptors. this is reason for downward shift

Front 47

so you need these (3) to get the downward shift

Back 47

slow dissociation (irreversible)
spare receptors
competitive antagonist

Front 48

explain terfenadine and spare receptors

Back 48

-terfenadine binding to half receptors and it doesn't come off so half of receptors put out of action and u need 10% to get max response
-however there's a point when u increase the conc that it takes out more than 90% of the receptors and then it cant have max response anymore

Front 49

Terfenadine vs. diphenhydramine: effects on driving

Back 49

diphenhydramine is worse

Front 50

Are newer, non-sedating antihistamines more effective for allergies?

Back 50

-no
-first and second generation are both equally effective

Front 51

2nd generation antihistamine (desloratadine) ± pseudoephedrine in allergic rhinitis - which is more effective?

Back 51

both together=most effective

Front 52

-An industrial solvent and coolant
-Prolonged exposure causes severe tissue damage
-Excessive ingestion causes a number of unpleasant though not usually life-threatening side-effects
-major component of acid rain
-Found in biopsies of pre-cancerous tumours and lesions
-Variations are a suspected contributor to the El Nino weather effect
-Taken by elite athletes to improve performance

Back 52

DHMO (dihydrogen monoxide)

Front 53

too much terfenadine causes

Back 53

potentially fatal ventricular arrhythmia

Front 54

is Terfenadine metabolite good

Back 54

yes
it doesnt cross BBB

Front 55

Possible side effects of H1 antagonists (6)

Back 55

MUSCARINIC block: dry mouth, alleviates motion sickness
CNS H1 block: sedation
ALLERGY: some are allergic to drug
Competition for HEPATIC MICROSOMAL ENZYMES: drug interactions
ALPHA1 block: postural hypotension
Na CHANNEL block: local anesthetic

Front 56

sleep aids commonly contain a

Back 56

H1 blocker

Front 57

Possible side effects of SECOND-generation H1 antagonists

Back 57

Competition for HEPATIC MICROSOMAL ENZYMES: drug interactions

Front 58

Glucocorticosteroids (Nasal inhaler) ___ effective than antihistamines

Back 58

More
*Not immediate, Slow offset

Front 59

Summary of main points:
-Two main causes of rhinitis(=nasal inflammation) are colds and allergies.
-Allergies involve histamine release but also other inflammatory mediators.
-Colds: little if any histamine involvement, best treated with decongestant.
-Route of administration can affect onset and offset
-Some side effects can be beneficial.
-About 30% of allergy sufferers are not helped adequately by antihistamines.
-For moderate-severe seasonal allergic rhinitis, glucocorticosteroids are the drugs of choice.

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