T5 - IE2 - Pulmonology - Ostrom + Elshahawi - Integrated Asthma Week 4

Bronchial smooth muscle tone: adrenergic system causes....

bronchodilation

Bronchial smooth muscle tone: cholinergic system causes...

bronchoconstriction

Increase adrenergic tone by adding an _____________ _________

- (an) adrenergic agonist

Decrease cholinergic tone by adding an _______________

- (adding an) anticholinergic

Overview of pharmacologic treatment for asthma figure

Two stages of asthma

Early: Bronchoconstriction

Late

Inflammatory response

Asthma drug classes that treat the inflammatory response

Corticosteroids

Mast cell stabilizers

Leukotriene modifiers

Monoclonal anti-IgE antibody

Potential Anti-Inflammatory target figure

cromolyn sodium

INTAL

INTAL

cromolyn sodium

Cromolyn sodium (INTAL) is a _____-______ ________ of mast cell (Cl- channel)

- non-specific stabilizer (of mast cell)

Inhibits cough by their action on airway nerves

Cromolyn sodium (INTAL) inhibits cough by their action on ________ ________

- (action on) airway nerves

No systemic side-effects and no bronchodilator activity

Cromolyn sodium does not have ___________ ____-______ nor _____________ activity

- systemic side-effects

- (nor) bronchodilator (activity)

Cromolyn sodium is used as _____________ use

- prophylactic (use)

Cromolyn sodium prophylactic uses

Adjunctive use for asthma

Exercise-induced asthma

- cold air

Allergic rhinitis

Cromolyn sodium: inhaled drug may cause ______ taste, throat __________, __________

- bad (taste)

- (throat) irritation

- bronchospasm

Cromolyn sodium - medicinal chemistry: ______ __________ _______ are necessary for activity and must be coplanar with a linking chain of no longer than six carbons

- two chromone rings (are necesary)

Cromolyn sodium - medicinal chemistry: two chromone rings are necessary for activity and must be _________ with a linking chain of no longer than ______ carbons

- (must be) coplanar

- (no longer than) six (carbons)

Cromolyn sodium - medicinal chemistry: is a ______________ that is present in the fundamental moiety of khellin

- (is a) bischromone [2 chromone groups]

Cromolyn sodium structure

Glucocorticoids and mineralocorticoids are both formed in the _________ ________

- (formed in the) adrenal cortex

Glucocorticoids affect ______________ _________, but they also have significant _______-______________ activity

- glucose homeostatis

- anti-inflammatory (activity)

Mineralocorticoids affect ________ and __________ _________

- sodium

- water retention

Whereas glucocorticoids affect glucose homeostasis and have significant anti-inflammatory activity

Glucocortiocisd provide the body with levels of ___________ that are compatible with ________

- (levels of) glucose

- (compatible with) life

Be used with caution in patients with diabetes

Glucocorticoids should be used with caution in patients with __________

- (patients with) diabetes

Glucocorticoids therapeutic and adverse effect figure

ICS

inhaled corticosteroid

Inhaled corticosteroids for asthma

Belcomethasone* [BECLOVENT]

Budesonide [RHINOCORT]

Fluticasone propionate [FLOVENT]

Mometasone [NASONEX]

Ciclesonide [ALVESCO] "soft steroid"

- pro drug for des-ciclesonide produced by mucosal esterases

- as potent as beclomethasone or budesonide (no oral bioavailability)

Biclomethasone dipropionate [BECLOVENT] has a highly ___________ _________

- (highly) active metabolite

Ciclesonide [ALVESCO] requires ____________ ___________ in situ

- metabolic activation (in situ)

Oral glucocorticoids

Methylprednisolone

Prednisolone

Prednisone

GC

glucocorticoid

Glucocorticoid nuclear receptors mechanism for asthma

decreases the production of inflammatory cytokines

reduces mucus secretion

reduces bronchial hyperactivity

enhances β-agonist bronchodilation

Glucocorticoid nuclear receptors mechanism for asthma: decreases the production of ____________ ___________; reduces _________ secretion and bronchial ____________; enhances ___-______ ___________

- (production of) inflammatory cytokines

- mucus (secretion)

- (bronchial) hyperactivity

- β-agonist bronchodilation

Glucocorticoid nuclear receptors mechanism for asthma: decreases the __________ of inflammatory cytokines

- production (of inflammatory cytokines)

Glucocorticoid nuclear receptors mechanism for asthma: reduces ____________ secretion

- mucus (secretion)

Glucocorticoid nuclear receptors mechanism for asthma: ___________ bronchial hyperactivity

- reduces (bronchial hyperactivity)

Glucocorticoid nuclear receptors mechanism for asthma: enhances ___-_________ __________

- (enhances) β-agonist bronchodilation

ICS-βAR synergy: ICS induces an ____________ of β-receptor mRNA and protein through a direction action of the activated glucocorticoid receptor on positive _______ within the ________ region of the β-receptor gene

- upregulation (of β-receptor mRNA and protein)

- (positive) GREs

- promoter (region)

ICS-βAR synergy: ICS also directly stimulates cAMP by activating ___-___-______ so can augment ______ ______________

- Gs-AC-cAMP

- βAR bronchodilation

Glucocorticoid Nuclear Receptors Figure

ICS-βAR Synergy Figure

GR

glucocorticoid receptor

Steroid resistance: can occur in patients taking ______ for many years e.g., __________ and _________

- (taking) ICS

- asthma

- COPD

Multiple mechanisms of steroid resistance: most studies indicate changes in _________ _________, _________ of nuclear

translocation of receptor and downstream modifications

- (changes in) binding affinity

- efficiency (of nuclear translocation)

90-95% of patients have reversible IL-2 & IL-4 mediated decreased binding affinity by T-lymphocytes; remainder are totally insensitivity to corticosteroids in all cells

Multiple mechanisms of steroid resistance: most studies indicate changes in binding affinity, efficiency of _________ _________ of receptor and _________ modifications

- nuclear translocation (of receptor)

- downstream (modifications)

Multiple mechanisms of steroid resistance: cigarette smoke downregulates _________-_______, decreasing steroid responsiveness (likely a major cause in ________ patients)

- (downregulates) histone-deacetylase

- COPD (patients)

Multiple mechanisms of steroid resistance: Cigarette smoke _____________ histone-deacetylase, decreasing steroid ___________ (likely a major cause in COPD patients)

- downregulates (histone-deacetylase)

- (steroid) responsiveness

Oral glucocorticoids are the _____ ____________ agents for acute attacks unresponsive to bronchodilators

- most effective (agents for acute attacks)

Oral glucocorticoids are the most effective agents for acute attacks ____________ to bronchodilators

- unresponsive (to bronchodilators)

Often as 10 day course post attack to decrease symptoms and prevent recurrence

Oral glucocorticoids often given as _____ ______ course post attack to _________ symptoms and prevent ____________

- 10 day (course)

- decrease (symptoms)

- (prevent) recurrence

Oral glucocorticoids restores ______ ________, restoring __________ of rescue inhaler

- (restores) βAR sensitivity

- (restoring) effectiveness

Oral glucocorticoids - the bad: only ____-____% of dose reaches lung

- 10-20(%)

Prolonged use -> significant health risks

Oral glucocorticoids - the bad: prolonged use -> ______________ health risks

- significant (health risks)

Avoid long-term use

Oral glucocorticoids long-term adverse effects

Weight gain, decreased bone density

Thinning and muscle weakness of the upper arms and legs

Thin skin, with easy bruising and pink or purple stretch marks

Increased acne, facial hair growth, scalp hair loss in women

Ruddy complexion on the face and neck

Often. skin darkening (acanthuses) on the neck

Children will show obesity and poor height

High blood pressure

Steroid nomenclature: the addition of methyl groups at C-10 and C-13 and of ethyl group at C-17 to the steroid nucleus gives a ___-________ _____ structure called ______

- 21-carbon based (structure)

- pregnane

Steroid nomenclature structures

Steroid nomenclature: all glucocorticoids have at least one ________ ______ in ring A and hydroxyl groups at __-____, __-___, and __-___ as well as 3- and 2-keto groups

- double bond (in ring A)

- C-11

- C-17

- C-21

Steroid nomenclature: All glucocorticoids have at least one double bond in _____ ___ and __________ groups at C-11, C-17, and C-21 as well as 3- and 20-_____ groups.

- ring A

- hydroxyl (groups)

- (3- and 20-)keto (groups)

Receptor structure and glucocorticoid binding figure

Note at least 3 hydrogen bonds are created

Glucocorticoid SAR: natural glucocorticoids also interact with ____________ receptor and therefore, will have ____-_________ properties

- mineralocorticoid (receptor)

- salt-retaining (properties)

A large number of synthetic analogs have been prepared to decrease the mineralocorticoid effects in favor of increasing the glucocorticoid (anti- inflammatory) effect of the steroids.

Glucocorticoid SAR: the pregnane skeleton with an ___-______ backbone

- all-trans (backbone)

Glucocorticoid SAR: the ring __-___-____ system

- A-en-one (system)

∆4-3-one ring A

en: double bond

"-one:" ketone

Glucocorticoid SAR: the ___-____ hydroxyl group must be ______ for both mineralocorticoid and glucocorticoid activity

- C-21 (hydroxyl group)

- (must be) free

Glucocorticoid SAR: the pregnane skeleton cannot be _______ must be ______

- (cannot be) cis

- (must be) trans

Glucocorticoid SAR: An exception to this rule are the C-21 ______ and C-20 _______________ _______ _______ (- SCH2F) derivatives that retain anti-inflammatory activity when applied topically or by inhalation.

- (C-21) chloro

- (C-20) fluoromethyl thio ester

Glucocorticoid SAR: that increase anti-inflammatory and mineralocorticoid activities

17α-OH

9α-F, 9α-Cl

21-OH

Glucocorticoid SAR: that INCREASE anti-inflammatory activity

1-dehydro (∆1) [flattens ring A, delays reduction and degradation)

6α-CH3 or F (double-fold)

11β-OH

Glucocorticoid SAR: that decrease mineralocorticoid activity

6α-CH3

16α or/& 16β-CH3

16α, 17α - acetonide

16α-OH

Glucocorticoid prodrugs figure

Note the addition of the ketone groups

Glucocorticoid prodrugs: glucocorticoids are ___________ despite having at least three hydroxyl groups

- lipophilic (despite having at least three)

The hydroxyl groups can be esterified with an appropriate acid that will either increase or decrease lipophilicity.

Glucocorticoid prodrugs: ___-___ hydroxyl is the _______ to be esterified to form lipophilic prodrugs. Once ________, the hydroxyl gp becomes free to form hydrogen bond to the Arg-564 in the glucocorticoid receptor.

- C-21 (hydroxyl)

- easiest (to be esterified)

- (Once) hydrolyzed

The fact that C-21 lipophilic esters are prodrugs means that they have a longer duration of action. They also have a slower onset, because the lipophilic esters generally are bulky and retard hydrolytic enzymes.

Glucocorticoid prodrugs: the fact that C-21 lipophilic esters are prodrugs means that they have a _________ duration of action. They also have a _______ onset, because the lipophilic esters generally are ________ and retard ________ enzymes.

- longer (duration of action)

- slower (onset)

- bulky

- hydrolytic (enzymes)

Glucocorticoid prodrugs - increasing hydrophilicity: placing an _________ group (e.g., _________ or ______) on the prodrug increase hydrophilicity, yielding water-soluble esters

- ionizable (group)

- carboxylate

- phosphate

Hydrophilic glucocorticoid prodrugs have RAPID onset

Glucocorticoid prodrugs - increasing hydrophilicity: Hydrophilic glucocorticoid prodrugs have _________ onset; they are readily hydrolyzed by ________ ________

- rapid (onset)

- (readily hydrolyzed by) plasma esterase

Hydrophilic prodrugs have more systemic side effects because of their wide distribution that comes from their high solubility in the blood.

Glucocorticoid prodrugs - increasing hydrophilicity: Hydrophilic prodrugs have more ___________ side effects because of their ______ distribution that comes from their ______ solubility in the blood.

- (more) systemic

- wide (distribution)

- high (solubility in the blood)

Glucocorticoid prodrugs - dieters and ketals: provide a _________ ________ of Log P (i.e., increased lipophilicity) and an increased __________ of action because they are ______ to metabolize

- further enhancement (of Log P)

- (increased) duration

- slow (to metabolize)

Glucocorticoid prodrugs - dieters and ketals: dieters structure

Structural comparisons of glucocorticoids figure

Systemic glucocorticoids structure - Hydrocortisone (Cortisol)

Systemic glucocorticoids - Hydrocortisone: is ________, and has both ________ and _________ activity

- endogenous

- glucocorticoid

- mineralocorticoid (activity)

Systemic glucocorticoids - Hydrocortisone: essential functional groups for both mineralocorticoid and glucocorticoid activity is the __________ skeleton with an all-______ backbone

- pregnane (skeleton)

- (all-)trans (backbone)

Hydrocortisone can be used to treat severe asthmatic attacks that do not respond to conventional treatment.

Systemic glucocorticoids - prednisone structure

note the TWO double bonds in ring A vs. hydrocortisone

Systemic glucocorticoids - prednisone: prednisone is hydrocortisone with a ___ ______ _____

- ∆1 double bond

This places TWO double bonds in ring A, which flattens it and increases glucocorticoid action at the expense of mineralocorticoid activity

Systemic glucocorticoids - prednisone: ∆1 double bond; places _____ double bonds in ring A, which ________ it and increases _____________ ____ at the expense of __________ activity

- two (double bonds in ring A)

- flattens (it)

- glucorticoid activity

- (at the expense of) mineralocorticoid

Systemic glucocorticoids - prednisone: a prodrug of prednisolone is __________

- (prednisolone is) prednisone

Systemic glucocorticoids - prednisone: prednisone (a prodrug of prednisolone) is the ___-_____ analog of prednisolone and must be converted in vivo to the active ___-___________ ______, which is necessary to _________ bond to (asparagine) Asn-564 in the glucocorticoid receptor.

- 11-keto (analog of prednisolone)

- 11β-hydroxy compound

- hydrogen (bond to asparagine-564)

Methylprednisolone: adding a __-_______ group to prednisolone increases the _________ activity and effectively _________ mineralocorticoid action

- 6α-methyl (group to prednisolone)

- glucocorticoid (actiivty)

- (effectively) abolishes

Methylprednisolone has _______ the glucocorticoid activity of hydrocortisone (prednisolone has _______ the glucocorticoid activity) with ____ of its mineralocorticoid properties.

Is used almost exclusively as a ________ product and is amiable as the free alcohol for oral administration and and as various esters

- systemic (product)

- fivefold (the glucocorticoid activity)

- (prednisolone has) fourfold

- none (of its mineralocorticoid properties)

- systemic (product)

Inhaled corticosteroids (ICS): good control of _________ __________

- (control of) airway inflammation

Limits long-term adverse effects of SABAs and LABAs

Inhaled corticosteroids (ICS): limits ____-_____ __________ effects of SABAs and LABAs

- (limits) long-term adverse (effects)

Limited systemic absorption so LOW adverse effects

Inhaled corticosteroids (ICS): limited __________ absorption

- (limited) systemic (absorption)

Hence low adverse effects

Inhaled corticosteroids (ICS): problems of administration

Dysphonia (effects voice)

Oropharyngeal candidiasis (thrush)

Cough and irritation -> bronchoconstriction; related to aerosol surfactants

Spacer or rinsing mouth will decrease mucosal absorption

Inhaled corticosteroids (ICS) - problems of administration: dysphonia

affects the voice

Inhaled corticosteroids (ICS) - problems of administration: Thrush

Oropharyngeal candidiasis

Inhaled corticosteroids (ICS) - problems of administration: Cough and irritation leads to...

bronchoconstriction; related to aerosol surfactants

Inhaled corticosteroids (ICS) - problems of administration: spacer or rinsing mouth will...

decrease mucosal absorption

Glucocorticoid drugs for inhalation

I - beclomethasone dipropionate

II - budesonide

III - ciclesonide

V - fluticasone propionate

VI - mometasone

Possible patient counseling points for ICS: the medication is only for __________, it will ____ _____ asthma attack

- (only for) prevention

- NOT stop (asthma attack)

Possible patient counseling points for ICS: symptomatic improvement may not be seen for a ______ ______

- (for a) few weeks