Levocetirizine

A short presentation I gave for my medical school pharmacology. A little rough in places, but I really just wanted to try this service.

1. LEVOCETIRIZINE
A histamine H
1
-receptor antagonist

2. Primary Questions

3. Primary Questions
1.What is the problem?

4. Primary Questions
1.What is the problem?
2.What are the treatment options?

5. Primary Questions
•What is the problem?
•What are the treatment options?
•What is unique about Levocetirizine?

6. Histamine
Endogenous Vasoactive Amine
• Mediates the increase in capillary permeability
associated with the contraction of endothelial
cells in postcapillary venules that occurs with
mild injuries
• Released from granules in mast cells,
basophils, and platelets
• Degranulation is usually a localized event in
response to acute insult, therefore
inflammation remains site specific
Gartner and Hiatt. “Color Textbook of Histology” Second Ed. 2001

7. Histamine
Histamine Receptor Subtypes
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004
Eosinophils, neutrophils, CD4 T-cellsH
4
Presynaptic: brain, neuronsH
3
Gastric mucosa, cardiac muscle,
mast cells, brain
H
2
Smooth muscle, endothelium, brainH
1
DistributionReceptor
subtype

8. Histamine
H
1
Receptors
-Similar to muscarinic and 5-HT
1
receptors
-Mediate pain and itching
-BP changes are caused by vasodilation action
of histamine on arterioles
-Postcapillary vessel separation  Histamine
induced edema (urticaria)
-Agonism can cause bronchoconstriction
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004

9. Allergic Rhinitis

10. Allergic Rhinitis
Clinical Presentation

11. Allergic Rhinitis
Clinical Presentation
Allergic rhinitis is a symptomatic disorder of the
nose induced after allergen exposure by an
IgE-mediated inflammation.
Symptoms include:
-Rhinnorrhea
-Nasal obstruction*
-Nasal itching and sneezing
“Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach.”
Allergy 2009: 64: 85:95

12. Allergic Rhinitis
IgE-mediated inflammation
1. Mast cell sensitization:
• exposure to antigen  production of specific IgE antibodies
• IgE attaches to the surface of mast cells
2. Mast cell degranulation:
• Subsequent exposure  binding of antigen to surface IgE,
signaling granule release of histamine
Mast cell depicted using Single
Particle Tracking (SPT)
Image courtesy of:
http://www.nanopicoftheday.org/
“Lippincott’s Illustrated Review: Pharmacology.” Harvey and Champe Eds. 4th edition. 2009

13. Allergic Rhinitis
Ubiquitous Allergens

14. Allergic Rhinitis
*Nasal Obstruction

15. Allergic Rhinitis
Co-morbidities and Associated Findings
• Asthma
• Otitis Media
• Sinusitis
Reduced Quality of life:
• sleep disturbance
• impaired cognitive function
• depression and anxiety
“Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach.”
Allergy 2009: 64: 85:95

16. Allergic Rhinitis
Burden-of-illness
• $2-5 billion USD annually in direct costs
• $5-9 billion USD annually in indirect costs
“The economic burden of allergic rhinitis: a critical evaluation of the literature.”
Reed SD, Lee TA, McCrory DC. Pharmacoeconomics. 2004;22(6):345-61. Review.

17. Allergic Rhinitis
Burden-of-illness

18. Indirect Costs
•Cost per employee per year for AR: $593
–Stress: $518
–Migraine: $277
–Depression: $273
–Arthritis/rheumatism: $269
–Respiratory infections: $181
–Diabetes: $95
–Coronary heart disease: $40
Allergic Rhinitis
“Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach.”
Allergy 2009: 64: 85:95

19. Prevalence
•10-20% of the general population
•10-40% of the pediatric patient
In all likelihood, these numbers are under
representations due to variability in perceived
impact on lifestyle
Allergic Rhinitis
“Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach.”
Allergy 2009: 64: 85:95

20. Chronic Idiopathic Urticaria

21. Clinical Presentation
Chronic Idiopathic Urticaria

22. Clinical Presentation
Chronic urticaria is a disease consisting of
spontaneous pruritic welts, present on all or
most days for more than 6 weeks
-Angioedema frequently occurs with CIU
-No effective diagnostic screens
-No clear universal therapy
-Frustration and dismay abound in patients
-QoL can be profoundly reduced
Chronic Idiopathic Urticaria
“Chronic idiopathic urticaria.”
Greaves MW. Curr Opin Allergy Clin Immunol. 2003 Oct;3(5):363-8.

23. A Difficult Disease To Treat
“I've had Chronic Idiopathic Urticaria for 6
years and its not going away, but getting
worse. I've been to so many doctors and
specialists! All these doctors do the same
tests and they tell me the same thing ‘there is
no cure and nothing we can do.’”
Chronic Idiopathic Urticaria
http://answers.yahoo.com/question/index?qid=20080928142252AA64Xyf

24. Two Types
•Autoimmune:
- Antibodies formed against IgE receptor FcεR1
- Antibodies formed against IgE (less common)
- Mast cell stimulation  degranulation
2. “True” idiopathic:
- Some autoimmune mechanism as yet
undefined
Chronic Idiopathic Urticaria
http://www.medscape.com/viewarticle/461843

25. Two Types
-The more severe cases typically involve
autoantibodies to the mast cell receptors, but
this pathology constitutes nearly 50% of
cases
-There is no data linking these reactions to
underlying infections or malignancies
-Treatment options are limited to modulating
the reactions: immunosuppressive therapies
aiming to prevent reactions have not been
demonstrated efficacious
Chronic Idiopathic Urticaria
“Chronic urticaria: a role for newer immunomodulatory drugs? “Am J Clin Dermatol. 2003;4(5):297-305.

26. Triggers for CIU may include:
-Medications
-Food allergies*
-Insect stings
-Physical stimuli
Chronic Idiopathic Urticaria
“Urticaria and angioedema. Controlling acute episodes, coping with chronic cases.” Postgrad Med. 2005 May;117(5):25-31.

27. *Elimination Diet:
Chronic Idiopathic Urticaria
online.statref.com

28. *Elimination Diet:
Chronic Idiopathic Urticaria
online.statref.com

29. Treatment Options

30. Control the Allergen, or Consider Drug Therapy
Treatment Options

31. Pharmacotherapy for Allergic Rhinitis
Well-controlled clinical trials have shown the
efficacy and safety of pharmacotherapy:
• Intranasal corticosteroids
• Oral or intranasal antihistamines
• Oral antihistamine/decongestant combinations
• Intranasal ipratropium
• Intranasal cromolyn (42)
• Oral montelukast
Treatment Options
Online.statref.com

32. Pharmacotherapy for Allergic Rhinitis
Well-controlled clinical trials have shown the
efficacy and safety of pharmacotherapy:
• Oral antihistamines
Treatment Options

33. Pharmacotherapy for CIU
Treatment Options

34. Pharmacotherapy for CIU
The cornerstone of treatment for Chronic
Idiopathic Urticaria is antihistamines:
• Oral antihistamines
Treatment Options
Online.statref.com

35. Antihistamine Pharmacology
H
1
Antagonists
1st Generation:
Ethanolamines, Ethylaminediamines,
Piperazine derivatives, Alkylamines,
Phenothiazine derivatives, and others
2nd Generation:
Piperidines, Laratidine, Cetirizine
“3rd” Generation:
Levocetirizine
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004

36. Antihistamine Pharmacology
H
1
Antagonists
1st generation drugs:
-Many enter the CNS readily
-Some are extensively metabolized, primarily
by the liver
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004

37. Antihistamine Pharmacology
H
1
Antagonists
Actions not caused by Histamine receptor block:
-Sedation
-Antinausea and antiemetic actions
-Antiparkinsonism effects - used with antipsychotics
-Anticholinoceptor effects - atropine like effects
-Adrenoceptor-blocking actions
-Serotonin-blocking action
-Local anesthesia
-Inhibition of mast cell release of histamine (?)
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004

38. Antihistamine Pharmacology
1st Generation
Diphenhydramine (Benadryl)
- inverse agonist at H
1
receptor
- anticholinergic
- antiemetic, sedative, hypnotic
- treatment for RA, hives
- cheap, effective, available
- significant drowsiness
“Lippincott’s Illustrated Review: Pharmacology.” Harvey and Champe Eds. 4th edition. 2009

39. Antihistamine Pharmacology
H
1
Antagonists
2nd generation drugs:
-Several are metabolized by CYP3A4, which is
important for drug interactions
-Considerably less lipid soluble, and therefore
do not readily cross the BBB
Katzung. “Basic and Clinical Pharmacology.” 9th edition. 2004

40. Antihistamine Pharmacology
2nd Generation
Cetirizine (Zyrtec)
- racemic compound
- treatment for allergies, hay fever, angioedema,
and urticaria
- available OTC
- less CNS effects than 1st generation
antihistamines
- mild drowsiness
www.wikipedia.org/cetirizine

41. Antihistamine Pharmacology
“Heritage”
- Following administration of hydroxyzine, a 1st
generation antihistamine, the major
metabolite in the blood is cetirizine
- Cetirizine is a racemic mixture of
dextrocetirizine and levocetirizine

42. Antihistamine Pharmacology
Levocetirizine
Levocetirizine is the active R-enantiomer of
cetirizine.
LevocetirizineCetirizine
Images: www.wikipedia.org/cetirizine

43. Antihistamine Pharmacology
Levocetirizine
Levocetirizine is the active R-enantiomer of
cetirizine.
LevocetirizineCetirizine
Images: www.wikipedia.org/cetirizine

44. Antihistamine Pharmacology
Levocetirizine
- While both cetirizine and hydroxyzine possess
high affinity at the H
1
receptor, the R-
configured levocetirizine has much slower
dissociation rate from the H
1
receptor than R-
hydroxyzine, making it an insurmountable
antagonist.
- Levocetrizine and cetirizine have longer half-
lives, and can be administered once daily.
“Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine.”
Curr Med Chem. 2008;15(21):2173-91.

45. Antihistamine Pharmacology
Levocetirizine
-No measurable muscarinic effects
-No induction of liver enzymes
-Almost entirely excreted unchanged by the
kidneys
-In vitro studies indicate a 2-fold increase in
affinity for H
1
receptors over cetirizine
-Clinical studies in the pediatric and geriatric
populations are ongoing, but promising
http://www.rxlist.com/xyzal-drug.htm

46. Antihistamine Pharmacology
Levocetirizine
-High bioavailability
-Rapid onset of action
-Limited distribution
-Physically limited from the CNS by the BBB at
therapeutic doses
“A review of the role of levocetirizine as an effective therapy for allergic disease.”
Expert Opinion on Pharmacotherapy. April 2008, Vol. 9, No. 5, Pages 859-867
“Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the
guinea pig.” British Journal of Pharmacology (2007) 151, 1129–1136; doi:10.1038/sj.bjp.0707318; published online 11 June 2007

47. Antihistamine Pharmacology
Levocetirizine vs Cetirizine
-Studies show significant improvement in
subjective rating of symptoms following a
course of Levocetirizine or Cetirizine
compared to placebo
-One 12 week program demonstrated
statistically significant superiority in relieving
symptoms using cetirizine in 6-12 year old
population*
“The comparison of cetirizine, levocetirizine and placebo for the treatment of childhood perennial allergic rhinitis”
Pediatr Allergy Immunol. 2008 Sep 30. [Epub ahead of print].

48. Antihistamine Pharmacology
Levocetirizine vs Cetirizine: Side Effects
http://www.rxlist.com/xyzal-drug.htm

49. Antihistamine Pharmacology
Levocetirizine vs Cetirizine
http://www.rxlist.com/xyzal-drug.htm

50. Antihistamine Pharmacology
Levocetirizine vs Cetirizine
 negative impact =  patient comfort

51. Antihistamine Pharmacology
Levocetirizine: CIU Therapy

52. Antihistamine Pharmacology
Levocetirizine: CIU Therapy
-Levocetirizine is more efficacious in reducing CIU
symptoms than desloratadine
- Levocetirizine was found not only to be a potent
inhibitor of the histamine-induced weal and flare
reaction, following both initial and repeated doses,
but also to be demonstrably free from disruptive and
sedative effects on objective measures of
psychomotor and cognitive function
Comparison of the efficacy of levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic urticaria patients.
Allergy. 2008 Nov 22. [Epub ahead of print].
Current Medical Research and Opinion. Volume 22, Number 4

53. Antihistamine Pharmacology
Levocetirizine: CIU Therapy
-The effects of levocetirizine against
histamine-induced skin reactions and skin
blood flow are measurably longer than other
antihistamine classes
-24 hours for loratadine and desloratadine, two
days for fexofenadine, and 3-4 days for
cetirizine and levocetirizine
“The effect of 5-days of cetirizine, desloratadine, fexofenadine 120 and 180 mg, levocetirizine, loratadine treatment on the
histamine-induced skin reaction and skin blood flow--a randomized, double-blind, placebo controlled trial]”
Pol Merkur Lekarski. 2006 Nov;21(125):449-53.

54. Antihistamine Pharmacology
Levocetirizine: CIU Therapy
•Levocetirizine is more potent and consistent
than other popular H1 antihistamines
ebastine, fexofenadine, loratadine,
mizolastine for blocking the cutaneous
response to histamine in healthy men
“A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine,
mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects.”
Ann Allergy Asthma Immunol. 2002 Feb;88(2):190-7.

55. Antihistamine Pharmacology
Levocetirizine: CIU Therapy
-Levocetirizine is a cost effective treatment for
CIU
-A net gain of €91.93 per patient per month
compared to placebo
Medscape today: Clinical Drug Investigation
Cost Effectiveness of Levocetirizine in Chronic Idiopathic Urticaria

56. Antihistamine Pharmacology
Allergic Rhinitis

57. Antihistamine Pharmacology
Allergic Rhinitis
• “Consider intranasal corticosteroids, oral
antihistamines, intranasal antihistamines, oral
antihistamine/oral decongestant combination
products, oral leukotriene modifiers, or
intranasal cromolyn as first-line
pharmacotherapy”
- 6 first-line therapies?!? What should you use?
Online.statref.com

58. Antihistamine Pharmacology
Allergic Rhinitis

59. Antihistamine Pharmacology
Allergic Rhinitis
-Tailor the treatment to the patient.
-Be mindful of drug interactions. Levocetirizine is a
particularly safe option in this regard, but the dose
should be reduced in patients with moderate renal
complications, and is contraindicated in patients
with renal failure.
-Utilize side effects if applicable. Drowsiness may
help decrease sleep latency in patients with sleep
difficulty.
-Cost management*

60. Antihistamine Pharmacology
*Cost Management
-According to drugpriceinfo.com:
-Levocetirizine = $79/month
-Cetirizine = $71/month
-Benazepril = $14/month

61. Antihistamine Pharmacology
Allergic Rhinitis
-Levocetirizine
-Reduced side effect profile
-Preliminary indications of comparable if not better
symptom relief
-Societal cost savings*

62. Antihistamine Pharmacology
Allergic Rhinitis
-Long term treatment with Levocetirizine
compared to placebo
-Cost without treatment: 355 euros/month
-Cost with Levocetirizine: 202 euros/month
“Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach.”
Allergy 2009: 64: 85:95

63. Antihistamine Pharmacology
Levocetirizine: Beyond H
1
Antagonism
-Reduces expression of IL-6, IL-8, and GM-CSF
-Reduces percentage representation of cell
phenotypes known to contribute to inflammatory
tissue damage (eosinophils, CD4+CD29+,
CD4+CD212+, and CD4+CD54+) and expands
percentages of CD4+CD25+
-Inhibits production of rhinovirus-induced ICAM-1 and
NF-kappaB expression
“Influence of cetirizine and levocetirizine on two cytokines secretion in human airway epithelial cells.”
Allergy Asthma Proc. 2008 Sep-Oct;29(5):480-5.
“Levocetirizine modulates lymphocyte activation in patients with allergic rhinitis.” Pharmacol Sci. 2008 Oct;108(2):149-56.
“Levocetirizine inhibits rhinovirus-induced ICAM-1 and cytokine expression and viral replication in airway epithelial cells.”
Antiviral Res. 2008 Dec 25. [Epub ahead of print]

64. Antihistamine Pharmacology
Asthma
-Bronchial Hyperreactivity, the cardinal feature
of asthma, is frequently present in patients
with chronic rhinitis
-70% reduction in asthma attacks in children
using Levocetirizine
Levocetirizine in persistent allergic rhinitis and asthma: effects on symptoms, quality of life and inflammatory parameters.
Clin Exp Allergy. 2006 Sep;36(9):1161-7.
Impact of allergic rhinitis on asthma: effects on bronchial hyperreactivity.
Allergy. 2009 Jan 28. [Epub ahead of print]

65. Thank you
Questions?