Recent advances in drugs affecting autonomic nervous system dr jayesh vaghela

1. RECENT ADVANCES IN DRUGS
AFFECTING AUTONOMIC NERVOUS
SYSTEM
Dr. Jayesh Vaghela

2. OVERVIEW
 Recent Advances in drugs affecting –
 Cholinergic system
 Anti cholinergic system
 Adrenergic system
 Anti adrenergic drugs
2

3. Muscarinic
Receptor Agonist
3

4. CEVIMELINE ( EVOXAC® )
 FDA Approval : 01/11/2000
 M/A :
oMuscarinic M3 Cholinergic receptor
agonist
 Metabolised by CYP2D6 and CYP3A3/4
 Excreted in urine
 Use :
oDry mouth in Sjogren’s syndrome
4

5.  ADRs:
- Excessive sweating & salivation
- Nausea
- Rhinitis
 C/I :
- Asthma
- Allergy to cevimeline
- Miosis
 Dose :
o 30 mg three times a day orally
5

6. AMBENONIUM CHLORIDE
( MYTELASE® )
 FDA approval : 11/10/2011
 M/A :
 Competitive, reversible inhibition of AchE by binding
at anionic site
 Inhibit Ach hydrolysis & enhance cholinergic function
 Facilitate impulse transmission because of
accumulation of ACh at the cholinergic synapses
6

7.  Use :
 Myasthenia Gravis
 Advantages :
 Greater residual effect during night & on awakening
 Longer duration of action
 More even strength
 Dose :
 5 mg three to four times a day
7

8. Muscarinic
Receptor
Antagonist
8

9. ACLIDINIUM BROMIDE
(TUDORZA PRESSAIR® )
 U.S. FDA Approval : JULY 2012
 Selective M3 muscarinic receptor
antagonist
 Dose : oral inhalation of 400 mcg, twice daily
 ADR : Headache, Nasopharyngitis, Cough, Sinusitis
 Advantage :
 Reduced potential for systemic side effects
 Wider safety margin
9

10. UMECLIDINIUM + VILANTEROL
(ANORO ELLIPTA®)
 FDA approval : 2013
 Combination of - Umeclidinium ( anticholinergic )
and
- Vilanterol ( β2 agonist )
 Use :
 long-term, once-daily, maintenance treatment of
airflow obstruction in patients with COPD
 Dose : 25 mcg once a day oral inhalation
 ADR :
 Pharyngitis, Sinusitis, LRTI, Constipation
10

11. LADOSTIGIL
 Under phase 2 trial
 M/A :
 Novel cholinesterase
 Brain-selective monoamine oxidase (MAO) inhibitor
 Use :
 Alzheimer’s Disease
 MCI ( Mild Cognitive Impairment )
11

12. α -1 Receptor
Selective Agonists
12

13. PHENYLEPHRINE
( OPHTHALMIC SOLUTION )
 Mydriasis :
Constriction of ciliary body blood vessels
→ IOP↓
Mydriasis without cycloplegia
→ Preferred for fundus examination
in elder patient
Dose : 2.5 – 5 % topical eye drops
 Other uses :
 Nasal decongestant
 Hypotension or shock
14

14. METARAMINOL
 Acts indirectly by stimulating the release of NE
 Use :
 Hypotension
15

15. MIDODRINE
 Midodrine → Desglymidodrine
↓
peak concentrations ~1 hour
 The t1/2 : ~3 hours
 Duration of action : ~4-6 hours
 Midodrine-induced rises in blood pressure associated
with both arterial and venous smooth muscle
contraction
↓
Advantageous in the treatment of patients with
autonomic insufficiency and postural hypotension
16

16.  Frequent complication :- supine hypertension
 Dose : 2.5 -10 mg three times daily
 FDA Approval : 1996
 09/10/2010 :
- Proposal to withdraw approval request
- Post approval studies to verify clinical benefit
Because, No demonstration of clinical benefit
17

17. α -2 Receptor
Selective Agonists
18

18. GUANFACINE
 More selective for α2 receptors than clonidine
 Recent FDA approval of INTUNIV SR form :
 ADHD in children aged 6-17 years
 Pharmacokinetics :
 Well absorbed after oral administration
 Vd = 4-6 L/kg
20

19. M/A :
1) Mainly stimulates α2A receptors at VMC
↓
↓ Central sympathetic outflow
↓
↓ BP & Heart rate
2) Bind with Imidazoline receptor (I1, I2, I3)
↓
G- Protein coupled receptor
↓
IP3 – DAG pathway
↓
↓ Central sympathetic outflow
3) Activates presynaptic α2 receptor
↓
↓ further release of NE 21

20.  50 % - Metabolized, 50% - Urine ( unchanged )
 T1/2 - 12-24 hours
 Efficacy : Guanfacine = Clonidine
 Advantage :
 ADRs & withdrawal syndrome ⇒ Pattern is similar, but
milder & less frequent
22

21. DEXMEDETOMIDINE
( PRECEDEX® )
 FDA Approval : 01/12/2006
 M/A :
 α – 2 selectivity : Slow i.v. ( 10 – 300 mcg/kg )
 α – 1 & 2 activity : Rapid i.v. or High dose (>1000 mcg/kg)
 Use :
o Sedation of initially intubated and mechanically ventilated
patients in ICU
23

22.  Note :
 The α2 -mediated effects (sedation and decreased
sympathetic activity)
⇓
adverse effects of clonidine in treatment for
hypertension
but beneficial effects of Dexmedetomidine in the
controlled setting of the surgical patient
 Because -
 Sedation without respiratory depression
 Suppression of sympathetic nervous system activity
helps to avoid swings in blood pressure
 Analgesic properties 24

23. GUANABENZ
 Centrally acting α2 agonist
 M/A: similar to clonidine
& guanfacine
 T1/2 = 4-6 hours
 Metabolism : Liver
 ADR : ( similar to clonidine )
• Dry mouth
• Sedation
25

24. TIZANIDINE
(ZANAFLEX)
 α2 agonist with some properties similar to those of clonidine
 Use :
 As Muscle relaxant
- spasticity associated with cerebral and spinal
disorders
26

25. BRIMONIDINE
( MIRVASO® )
 FDA Approval : Aug – 2013
 M/A :
- α2 agonist → Direct local vasoconstriction
 Use :
 Facial erythema of rosacea
 ADR :
- Erythema, flushing, burning sensation
27

26. β -1 Receptor
Selective Agonists
28

27. PRENALTEROL
Non catecholamine
Approved for reversal of β blockade
29

28. β -2 Receptor
Selective Agonists
30

29. 31
Short Acting Long Acting
Pirbuterol
Isoetharine
Fenoterol
Procaterol
Arformoterol
Carmoterol
Indacaterol
Ritodrine
Clenbuterol
Bambuterol

30. PIRBUTEROL
 Onset of action : 10 minute
 Duration of action : 4-6 hrs
 The only preparation available in
breath-activated MDI → device meant to optimize
medication delivery by releasing a spray of
medication only on the patient's initiation of
inspiration
32

31. ISOETHARINE
 Catecholamine but resistant to metabolism by MAO
only metabolized by COMT
 Use :
 Asthma
 Chronic asthmatic bronchitis
33

32. BITOLTEROL (TORNALATE)
 Lung :
Bitolterol Colterol or Terbutylnorepinephrine
 Use :
 Bronchodilation in chronic lung disorders
 FDA approval : Dec 1984
 Withdrawn from market in 2011 :
o Ineffective if used too often ⇒ more severe breathing
difficulty that does not improve
34
Hydrolysis
Esterase

33. FENOTEROL
 Rapid onset of action
 Effect lasts for 4-6 hours
 Withdrawn from the market
 The possible Asthma-related deaths
 Dysrhythmias and cardiac effects are due to effects
on β1 adrenergic receptors
35

34. PROCATEROL
 For inhalation
 Rapid onset of action
 Lasts for ~5 hours
36

35. INDACATEROL ( ONBREZ® )
 Longer acting β2 receptor agonist
 FDA approval : July 1, 2011
 Use :
 long term Once daily maintenance
therapy in COPD
 Dose :
 150 mcg once a day oral inhalation
 Advantages :
 Longer acting
 Higher intrinsic activity than salmeterol
37

36. ARFORMOTEROL
( BROVANA® )
 FDA Approval : Oct – 2006
 Long term Twice daily maintenance of bronchodilation
in patients with COPD
 ADR :
- Chest pain, back pain, sinusitis, Diarrhoea.
38

37. CARMOTEROL
 Pure (R,R)-isomer & non-catechol
 Potent and selective β2 agonist
 Rapid onset and long duration of action over 24 hours
 Once a day dosing
 Indications : asthma and COPD
39

38. BAMBUTEROL
 FDA Approval : 6th November 2006
 Prodrug of terbutaline
 Slowly metabolised
 Longer acting : 24 hr
 Use : Only in chronic asthma
 Dose : 10-20 mg OD
40

39. CLENBUTEROL
 Approved to be used in
horses only
 ↑es force of contraction of skeletal muscles
 Particularly known for its abuse
 Anabolic property → use by sportsmen to improve
performance
41

40. Discontinuation Of Production Of Drugs
( containing CFC gas )
Drug name Trade name Last date of
production
Albuterol +
Ipratropium
Combivent
Inhalation Aerosol
December 31,
2013
Pirbuterol Maxair Autohaler December 31,
2013
Metaproterenol Alupent Inhalation
Aerosol
June 14, 2010
42

41. β -3 Receptor
Selective Agonists
43

42. MIRABEGRON ( BETMIGA® )
 β3 receptor agonist
 FDA approval : 28th June, 2012
 Use :
 Urge urinary incontinence,
 Urgency,
 Increase in urinary frequency
 M/A :
 Relaxes detrusor muscles during storage phase
 Dose : 25 mg once a day
 ADR :
Hypertension, UTI, Nasopharyngitis, headache
44

43. BRL- 37344 & AD-9677
 Under trial
 Non catecholamine
 Polymorphism in β3 receptor gene → related to risk of
obesity
 Short- lived transient action
45

44. Indirectly Acting
Sympathomimetics
46

45. PEMOLINE
 Structurally similar to methylphenidate
 Prominent CNS actions & minimal effect on CVS
 Longer plasma half life
 Use : In ADHD
 Prolonged use : Dependence & hepatic damage
47

46. MODAFINIL
 Blocks NE & DA reuptake
 Use: To treat Narcolepsy
 No abuse potential
48

47. DROXIDOPA
( NORTHERA® )
 FDA Approval : Feb 2014
 M/A :
o Precursor of norepinephrine
o Peripheral arterial and venous vasoconstriction.
o ↑ed B.P.
 Use :
o Orthostatic dizziness in patients with orthostatic
hypotension
- Primary autonomic failure
- Dopamine beta-hydroxylase deficiency
- Non-diabetic autonomic neuropathy
49

48.  ADR :
oHypertension
oNausea
oHeadache
 Dose :
o100 mg three times daily orally
50

49. SIBUTRAMINE
 Mechanism :
Suppress appetite by inhibiting NA & 5-HT reuptake in
hypothalamus
 Use :
 As anti-obesity drug
 India discontinued From March 2011
Serious ADR like cardiovascular event & death
51

50. ROTIGOTINE ( NEUPRO® )
 FDA approval : 2007
 Dopamine agonist
 Use :
 Parkinson’s disease
 Restless leg syndrome
 Dose :
 Transdermal delivery system containing 1 – 8 mg per
24 hours
 ADR : Nausea, vomiting, somnolence, application site
reactions
52

51. ROPINIROLE ( REQUIP® )
Dopamine agonist D3 > D2 or D4
 Use :
 Parkinson’s disease
 Restless leg syndrome
 ADR :
• Syncope
• Bradycardia
• Day time sleepiness
53

52. α - Receptor
Antagonists
54

53. ALFUZOSIN ( UROXATRAL® )
 α1-selective antagonist
 T1/2 : 4 hours
 Twice or thrice a day dosing needed
 C/I : Hepatic failure
 Dose : 10 mg two or three times a day
55

54. SILODOSIN
 Selective for α 1A
 Main metabolite is a glucuronide formed by UGT2B7
 Approved for - BPH
 Lesser effects on blood pressure
 Silodosin - 4 mg and 8 mg capsules.
 ADR :
- Retrograde ejaculation, orthostatic hypotension
56

55. URAPIDIL
 M/A :
 Blocks postsynaptic α1 receptors ⇒ ↓ed TPR
 Central effect ( 5-HT1A receptor )
 Use :
 Severe Hypertension
- Hypertensive emergency
- During and/or after surgery
 Dose strength :
 25 mg / 5 ml
 50mg / 10 ml
57

56. BUNAZOSIN
 α1-selective antagonist
 Use : BPH
 Lowers blood pressure in patients with hypertension
 Available in-
Germany, Japan, Thailand, and Indonesia
58

57. INDORAMIN
 α 1 antagonist
 Competitive antagonism of Histamine & 5-HT
receptors
 Use :
 Hypertension
 BPH
 Prophylaxis of migraine
 ADR :
 Sedation, dry mouth, failure of ejaculation
59

58. IDAZOXAN
 Antagonist at α2-adrenoceptors.
 Antagonist at I1 imidazoline receptors
 Agonist at I2 imidazoline receptors
 Use :
 Depression ( under investigation )
 Schizophrenia ( as adjunctive )
- α2- antagonist → ↑es DA neurotransmission in
prefrontal cortex → acts as antipsychotic
60

59. β - Adrenoceptor
Antagonists
61

60. BUCINDOLOL
 Under trial
 M/A :
 3rd generation Non selective β – adrenoceptor
antagonist
 α – 1 selective blocker
 Intrinsic Sympathomimetic Activity ( ISA )
 Reduces after load
 Use : CHF
62

61. CELIPROLOL
 low lipid solubility
 weak vasodilation & bronchodilation
 Smooth muscle relaxant
 Promotes NO production,
↓
 Inhibits oxidative stress
 Intrinsic sympathomimetic activity at the β2 receptor
 Devoid of membrane-stabilizing activity
63

62. NEBIVOLOL (BISTOLIC®)
 FDA approval : 19 Feb – 2010
 3rd generation Highly selective β1 blocker
 Dose : 5 mg once a day
 Devoid of - ISA
- Membrane stabilizing activity
- α1 receptor blocking property
 Advantages :
 Once a day dose
 ↑ed efficacy, tolerability
 Antioxidant property
 Favourable CH & lipid metabolism
64

63. CARTEOLOL ( CARTROL® )
 Selective β1 Antagonist
 β2 Agonist
 Produces NO
 Use :
 Open angle glaucoma
 Hypertension
 Dose :
 1 % ophthalmic solution one drop in each eye
65

64. TILISOLOL
 Only animal study data is available
 Non selective β receptor blocker
 K+ channel opener
 Long lasting & stable action in treatment of
hypertension
66

65. BOPINDOLOL
 Prodrug of Pindolol
 Non selective β receptor blocker
 With ISA
 M/A :
o β1 blockade – Heart - ↓es HR & BP
o β2 blockade – JGA – inhibits renin production, water
retention
67

66. BEVANTOLOL
 Selective β1 receptor antagonist
 Use :
- Angina pectoris
- Hypertension
68

67. QSYMIA
(PHENTERMINE + TOPIRAMATE)
 Use : As anti-obesity
 ADR :
 Paraesthesia, Insomnia, dry mouth 69
Phentermine
↓
Releases CA from
hypothalamus
↓
↓ed appetite & food
consumption
Topiramate
↓
↑ed GABA activity
Inhibits CAase enzyme

68. FUTURE ADVANCES :
Beta adrenergic antagonists as antimalarial drugs :
 Hormones that regulate CVS ⇒ also affect malarial parasite
infestation
 Gs subtype of GPCRs ⇒ regulate P. falciparum entry into
blood RBCs
 beta blockers ⇒ prevent entry of P. falciparum into blood
RBCs
70

69. References
 Westfall T.C. & Westfall D.P. Adrenergic agonists and
antagonists,Goodman & Gilman’s the pharmacological basis of
therapeutics-12th edition.Pg-277-333
 SharmaK.K. and Sharma K.K.-principle of pharmacology,Drugs
affecting sympathetic nervous system,2nd edition,Pg-155-190
 Tripathi KD,Medical pharmacology,Adrenergic system and drugs,
7th edition,Pg-124-139
 Mytelase (ambenonium chloride) Tablets. Detailed View: Safety
Labeling Changes Approved By FDA Center for Drug Evaluation
and Research (CDER) – November 2011.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm2831
20.htm
 http://www.frx.com/pi/tudorza_pi.pdf
71

70.  Midodrine Hydrochloride Tablets.
http://www.drugs.com/pro/midodrine.html
 guanfacine - oral, Tenex.
http://www.medicinenet.com/guanfacine-oral/article.htm
 Guanabenz Acetate Tablets USP.
http://www.drugs.com/pro/guanabenz.html
 tizanidine - oral, Zanaflex.
http://www.medicinenet.com/tizanidine-oral/article.htm
 Brimonidine
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/20470
8lbl.pdf
 Anoro Ellipta Approval History.
http://www.drugs.com/history/anoro-ellipta.html
72

71.  pharma.us.novartis.com/product/pi/pdf/arcapta.pdf
 http://www.brovana.com/about/about-brovana.html
 Phenylephrine Hydrochloride Ophthalmic Solution.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/20351
0s000lbl.pdf. http://www.drugbank.ca/drugs/DB00610
 Precedex Dexmedetomidine Hydrochloride injection
http://www.drugbank.ca/system/fda_labels/DB00633.pdf?126592
2807
 pirbuterol-aerosol inhaler, Maxair.
http://www.medicine.et.com/pirbuterol-aerosol_inhaler/article.htm
 bitolterol mesylate, Tornalate.
http://www.medicinenet.com/bitolterol_mesylate/article.htm
 Safety and Efficacy Study of Ladostigil in Mild to Moderate
Probable Alzheimer's Disease.
http://clinicaltrials.gov/show/NCT01354691
73

72. 74