This document summarizes recent advances in drugs affecting the autonomic nervous system. It discusses several cholinergic drugs including cevimeline, ambenonium chloride, aclidinium bromide, and umeclidinium. It also discusses muscarinic receptor antagonists. Several adrenergic drugs are mentioned including alpha-1, alpha-2, beta-1, beta-2, and beta-3 receptor agonists and antagonists. Indirectly acting sympathomimetic drugs and their uses are also briefly described.

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