RECENT ADVANCES IN

DRUGS AFFECTING AUTONOMIC

NERVOUS SYSTEMDr. Jayesh Vaghela

2

OVERVIEW Recent Advances in drugs affecting –

Cholinergic system

Anti cholinergic system

Adrenergic system

Anti adrenergic drugs

3Muscarinic

Receptor Agonist

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

5

ADRs:- Excessive sweating & salivation- Nausea- Rhinitis

C/I :- Asthma- Allergy to cevimeline- Miosis

Dose :o 30 mg three times a day orally

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

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

8

Muscarinic Receptor

Antagonist

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

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

11

LADOSTIGIL Under phase 2 trial

M/A : Novel cholinesterase Brain-selective monoamine oxidase (MAO) inhibitor

Use : Alzheimer’s Disease MCI ( Mild Cognitive Impairment )

12α -1 Receptor

Selective Agonists

14

PHENYLEPHRINE( OPHTHALMIC SOLUTION ) Mydriasis :Constriction of ciliary body blood vessels

→ IOP↓Mydriasis without cycloplegia

→ Preferred for fundus examinationin elder patient

Dose : 2.5 – 5 % topical eye drops Other uses : Nasal decongestant Hypotension or shock

15

METARAMINOL

Acts indirectly by stimulating the release of NE

Use : Hypotension

16

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

17

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

benefitBecause, No demonstration of clinical

benefit

18α -2 Receptor

Selective Agonists

20

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

21

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

22

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

23

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

24

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

25

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

26

TIZANIDINE(ZANAFLEX)

α2 agonist with some properties similar to those of clonidine

Use : As Muscle relaxant

- spasticity associated with cerebral and spinaldisorders

27

BRIMONIDINE( MIRVASO ® ) FDA Approval : Aug – 2013 M/A :

- α2 agonist → Direct local vasoconstriction

Use : Facial erythema of rosacea

ADR :- Erythema, flushing, burning sensation

28β -1 Receptor

Selective Agonists

29

PRENALTEROLNon catecholamine

Approved for reversal of β blockade

30β -2 Receptor

Selective Agonists

31

Short Acting Long Acting

PirbuterolIsoetharineFenoterolProcaterol

ArformoterolCarmoterolIndacaterolRitodrine

ClenbuterolBambuterol

32

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

33

ISOETHARINE

Catecholamine but resistant to metabolism by MAO only metabolized by COMT

Use : Asthma Chronic asthmatic bronchitis

34

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

HydrolysisEsterase

35

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

36

PROCATEROL For inhalation

Rapid onset of action

Lasts for ~5 hours

37

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

38

ARFORMOTEROL

( BROVANA ® )

FDA Approval : Oct – 2006

Long term Twice daily maintenance of bronchodilation in patients with COPD

ADR :- Chest pain, back pain, sinusitis, Diarrhoea.

39

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

40

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

41

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

42

Discontinuation Of Production Of Drugs

( containing CFC gas )Drug name Trade name Last date of

productionAlbuterol + Ipratropium

Combivent Inhalation Aerosol

December 31, 2013

Pirbuterol Maxair Autohaler

December 31, 2013

Metaproterenol Alupent Inhalation Aerosol

June 14, 2010

43β -3 Receptor

Selective Agonists

44

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

45

BRL- 37344 & AD-9677 Under trial

Non catecholamine

Polymorphism in β3 receptor gene → related to risk of obesity

Short- lived transient action

46Indirectly Acting

Sympathomimetics

47

PEMOLINE Structurally similar to methylphenidate

Prominent CNS actions & minimal effect on CVS

Longer plasma half life

Use : In ADHD

Prolonged use : Dependence & hepatic damage

48

MODAFINIL Blocks NE & DA reuptake

Use: To treat Narcolepsy

No abuse potential

49

DROXIDOPA( NORTHERA® ) FDA Approval : Feb 2014 M/A :o Precursor of norepinephrineo 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

50

ADR :oHypertensionoNauseaoHeadache

Dose :o100 mg three times daily orally

51

SIBUTRAMINE Mechanism :Suppress appetite by inhibiting NA & 5-HT reuptake in hypothalamus

Use : As anti-obesity drug

India discontinued From March 2011Serious ADR like cardiovascular event & death

52

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

53

ROPINIROLE ( REQUIP ® )

Dopamine agonist D3 > D2 or D4

Use : Parkinson’s disease Restless leg syndrome

ADR :• Syncope• Bradycardia• Day time sleepiness

54α - Receptor Antagonists

55

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

56

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

57

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

58

BUNAZOSIN

α1-selective antagonist

Use : BPH Lowers blood pressure in patients with hypertension

Available in-

Germany, Japan, Thailand, and Indonesia

59

INDORAMIN α 1 antagonist Competitive antagonism of Histamine & 5-HT receptors

Use : Hypertension BPH Prophylaxis of migraine

ADR : Sedation, dry mouth, failure of ejaculation

60

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 inprefrontal cortex → acts as antipsychotic

61β - Adrenoceptor

Antagonists

62

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

63

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

64

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

65

CARTEOLOL ( CARTROL ® ) Selective β1 Antagonist β2 Agonist Produces NO

Use : Open angle glaucoma Hypertension

Dose : 1 % ophthalmic solution one drop in each eye

66

TILISOLOL Only animal study data is available

Non selective β receptor blocker

K+ channel opener

Long lasting & stable action in treatment of hypertension

67

BOPINDOLOL Prodrug of Pindolol

Non selective β receptor blocker With ISA

M/A :o β1 blockade – Heart - ↓es HR & BPo β2 blockade – JGA – inhibits renin production, water retention

68

BEVANTOLOL Selective β1 receptor antagonist

Use :- Angina pectoris- Hypertension

69

QSYMIA(PHENTERMINE + TOPIRAMATE)

Use : As anti-obesity

ADR : Paraesthesia, Insomnia, dry mouth

Phentermine↓

Releases CA from hypothalamus

↓↓ed appetite &

food consumption

Topiramate↓

↑ed GABA activityInhibits CAase enzyme

70

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

71

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/ucm283120.htm

http://www.frx.com/pi/tudorza_pi.pdf

72

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/2013/204708lbl.pdf

Anoro Ellipta Approval History.

http://www.drugs.com/history/anoro-ellipta.html

73

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/2013/203510s000lbl.pdf. http://www.drugbank.ca/drugs/DB00610

Precedex Dexmedetomidine Hydrochloride injection http://www.drugbank.ca/system/fda_labels/DB00633.pdf?1265922807

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

74