Lecture 19

Question 1

What is Rhinitis

Answer 1

When airflow is blocked due to inflammation of the nasal mucous membrane
Symptom of common cold (rhinovirus) and allergic reactions (allergic rhinitis)

Question 2

Things that cause Rhinitis

Answer 2

1) Vasodilation (blood supply increases)
2) Edema (fluid leaking out from between cells)
3) Mucous secretion (rhinorrhea), resulting in a runny nose

Question 3

What can treat rhinorrhea (mucous secretion from rhinitis

Answer 3

Muscarinic receptor antagonist (suppresses parasympathetic nervous system)

Question 4

Main approaches to treat a stuffy nose

Answer 4

1) Sympathomimetic nasal decongestants (rhinitis from common cold)
2) Antihistamines (allergic reaction)

Question 5

Receptors in blood vessels of nose

Answer 5

Alpha 1 and alpha 2 adrenergic receptors (stimulation induces vasoconstriction)
Vasodilation causes swelling inwards resulting in nasal congestion

Question 6

Raynaud’s syndrome

Answer 6

Severe vasoconstriction due to excessive sympathetic tone
Lack of blood flow to extremities

Question 7

Mechanism of Indirect Sympathomimetics

Answer 7

ex. pseudoephedrine and PPA
Indirect sympathomimetics act presynaptic ally on sympathetic terminals to stimulate release of noradrenaline–>release of NA increases stimulation of alpha 1 and alpha 2 receptors–>induces vasoconstriction

Question 8

Mechanism of Direct Sympathomimetics

Answer 8

ex. Phenylephrine
Phenylephrine selectively stimulate the alpha-1 receptor–>inducing vasoconstriction

Question 9

Pathway of Alpha 1-receptor vasoconstriction

Answer 9

Stimulation of alpha-1 receptor–>Activates GPCR–>activates Phospholipase C (PLC)–>increase in IP3 (second messenger)–>IP3 stimulates Ca2+ release–>Ca2+ activation calcium dependent protein kinase–>increasing smooth muscle tone–>vasoconstriction

Question 10

Pathway of Alpha 2-receptor vasoconstriction

Answer 10

Stimulation of alpha-2 receptor–>activates G protein alpha subunit–>inhibits adenylate cyclase–>decrease [cAMP]–> decrease in PKA activity–>increase in smooth muscle tone–>vasoconstriction

Question 11

Downside of Adrenaline injection for asthma exacerbation

Answer 11

Adrenaline is quickly metabolized by monoamine oxidase in blood stream (short action)

Question 12

Alternative to adrenaline injection for asthma exacerbation

Answer 12

Ephedrine
Orally available, longer half life in bloodstream than adrenaline

Question 13

Alternative (bad) to Ephedrine

Answer 13

Amphetamine
Stable and widely available but addictive

Question 14

Treatment for common cold

Answer 14

NONE, just drugs to alleviate symptoms

Question 15

Topically vs orally available sympathomimetics

Answer 15

Topically–>Phenylephrine and PPA
Orally–>Phenylephrine, ephedrine, amphetamine, and PPA

Question 16

Sympathomimetics susceptibility to degradation

Answer 16

Stable to degradation by monoamine oxidase (long lifetime)–>pseudoephedrine, ephedrine, and PPA

Degraded by MAO–> Phenylephrine, adrenaline, and noradrenaline

Completely resistant to catechol-O-methyltransferase (COMT, degrades adrenaline and noradrenaline)–>Phenylephrine, pseudoephedrine, ephedrine, and PPA

Question 17

What sympathomimetic synthesizes methamphetamine

Answer 17

Pseudoephedrine can be made into methamphetamine so is restricted, replaced with phenylephrine (less effective drug)
Methamphetamine causes early aging and meth mouth

Question 18

What is rebound withdrawal

Answer 18

When the body fights the drug administered and attempts to counter its effect, even when the drug is no longer present

Question 19

Effect of inhalation administration

Answer 19

Very fast onset, moderate decongesting effect, very fast offset

Question 20

Effect of nasal spray administration

Answer 20

Very strong decongestant effect, fast onset and fast offset

Question 21

Effect of syrup administration

Answer 21

Very slow onset, moderate decongesting effect, very slow offset

Question 22

Which sympathomimetic has NO effect when taken orally

Answer 22

Phenylephrine (gets metabolized quickly in bloodstream by MAO

Question 23

Decongestants effect on blood pressure

Answer 23

Increase heart rate and blood pressure due to increasing sympathetic drive
Stimulation of beta-1 adrenergic receptors–>minor increase of heart rate
Stimulation of alpha 1 adrenergic receptors (peripheral blood vessels)–>vasoconstriction

Question 24

Why is PPA banned?

Answer 24

Increased risk of hemorrhagic stroke, also associated with heart attacks

Question 25

Side effects of Alpha-1 agonists

Answer 25

Hypertension, stroke, insomnia, nervousness, and loss of appetite

Question 26

Main issue with Pseudoephedrine

Answer 26

Can be synthesized into methamphetamine

Question 27

Types of allergic rhinitis

Answer 27

Seasonal (produces IgE) or perennial (throughout the year)

Question 28

Effect of seasonal allergies

Answer 28

IgE production followed by mast cell degranulation and leukotrienes and histamine release-->histamine binds to H1 receptor

Question 29

What reduces inflammation and allergic rhinitis

Answer 29

Antihistamines (H1 blockers, first generation) to inhibit the action of histamine Leukotriene receptor antagonists to decrease inflammation by blocking action of leukotrienes, but not as effective

Question 30

2 generations of H1 histamine receptor antagonists

Answer 30

1st-->cause sedation, cross BBB (diphenhydramine) 2nd-->non-sedating (terfenadine), cannot cross BBB

Question 31

Tests to see if terfenadine (2nd generation antihistamine) can cross BBB

Answer 31

1) Radiolabeling of terfenadine 2) Measuring of H1 receptor occupancy 3) Behavioural test

Question 32

Outcome of Radiolabeled terfenadine experiment

Answer 32

The concentration of terfenadine in the rats brains after death was very low Terfenadine concentration was highest in the GIT No radiolabeled terfenadine was present in the brain after death

Question 33

Outcome of H1 receptor occupancy in Vivo experiment

Answer 33

H1 receptor antagonists: terfenadine and mepyramine 1) Chlorpheniramine enters the brain (as 3H-mepyramine binding was lower when co-administered with chlorpheniramine) 2) Terfenadine cannot enter the brain (3H-mepyramine binding was the same when co-administered with terfenadine) 3) Absence of terfenadine in the brain is not due to experimental error (both chlorpheniramine and terfenadine showed near complete saturation of peripheral H1 receptors) 4) Terfenadine can act competitively in the brain (in vitro), but cannot pass BBB in vivo

Question 34

H1 receptor occupancy outcome with antihistamines

Answer 34

1) First generation antihistamines (chlorpheniramine and diphenhydramine)-->CAN cross BBB and bind H1 receptors in brain 2) Second generation antihistamines (terfenadine)--> canNOT cross BBB and canNOT bind H1 receptors in the brain

Question 35

Kinetics of H1 receptor block

Answer 35

Chlorpheniramine-->rapid and reversible onset, wears off after a few hours Terfenadine-->slower onset, abnormal recovery, irreversible

Question 36

Explanation of abnormal Terfenadine dose response curve

Answer 36

Flattening (downward shift) of dose-response curve due to terfenadine's slow (negligible) dissociation from the receptors and interaction with spare receptors More spare receptors present while agonist is at 100%, more potent the agonist

Question 37

Terfenadine affinity with H1 receptors

Answer 37

Terfenadine has a very high affinity for H1 receptors with few spare receptors left, and a very strong antagonist block Low concentrations-->enough spare receptors for histamine to achieve maximum effect and surmount terfenadine's antagonist block High concentrations-->nearly all spare receptors are blocked, even high concentrations of histamine cannot achieve maximal effect, so insurmountable block by terfenadine (flattens dose response curve)

Question 38

Behavioural test outcomes

Answer 38

Driving test Terfenadine is NOT sedating as none of the doses affected the driver's performance more than the placebo

Question 39

First vs second generation antihistamines

Answer 39

Same effectiveness Second generation antihistamine + pseudoephedrine achieves stronger decongesting effect (synergistic)

Question 40

Side effects of Terfenadine

Answer 40

Drug-drug interactions with other medications and grapefruit (inhibiting CYP450 enzymes preventing terfenadine metabolism, leading to accumulation) Accumulation of terfenadine can cause ventricular arrythmia

Question 41

Side effects of First generation H1 antagonists

Answer 41

1) Sedation through CNS H1 block 2) Alleviate motion sickness but inhibit salivation through Muscarinic block 3) Postural hypotension through Alpha-1 block 4) Drug-drug interactions through CYP450s competition 5) Allergic reaction

Question 42

Most effective at treating rhinitis

Answer 42

Glucocorticoids are more effective than antihistamines, but have slow onset and slow offset