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RECENT ADVANCES IN
DRUGS AFFECTING AUTONOMIC
NERVOUS SYSTEMDr. Jayesh Vaghela
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OVERVIEW Recent Advances in drugs affecting –
Cholinergic system
Anti cholinergic system
Adrenergic system
Anti adrenergic drugs
3Muscarinic
Receptor Agonist
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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
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ADRs:- Excessive sweating & salivation- Nausea- Rhinitis
C/I :- Asthma- Allergy to cevimeline- Miosis
Dose :o 30 mg three times a day orally
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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
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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
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Muscarinic Receptor
Antagonist
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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
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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
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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
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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
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METARAMINOL
Acts indirectly by stimulating the release of NE
Use : Hypotension
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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
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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
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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
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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
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50 % - Metabolized, 50% - Urine ( unchanged ) T1/2 - 12-24 hours Efficacy : Guanfacine = Clonidine Advantage : ADRs & withdrawal syndrome ⇒ Pattern is similar, but milder & less frequent
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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
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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
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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
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TIZANIDINE(ZANAFLEX)
α2 agonist with some properties similar to those of clonidine
Use : As Muscle relaxant
- spasticity associated with cerebral and spinaldisorders
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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
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PRENALTEROLNon catecholamine
Approved for reversal of β blockade
30β -2 Receptor
Selective Agonists
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Short Acting Long Acting
PirbuterolIsoetharineFenoterolProcaterol
ArformoterolCarmoterolIndacaterolRitodrine
ClenbuterolBambuterol
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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
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ISOETHARINE
Catecholamine but resistant to metabolism by MAO only metabolized by COMT
Use : Asthma Chronic asthmatic bronchitis
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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
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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
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PROCATEROL For inhalation
Rapid onset of action
Lasts for ~5 hours
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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
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ARFORMOTEROL
( BROVANA ® )
FDA Approval : Oct – 2006
Long term Twice daily maintenance of bronchodilation in patients with COPD
ADR :- Chest pain, back pain, sinusitis, Diarrhoea.
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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
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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
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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
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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
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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
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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
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PEMOLINE Structurally similar to methylphenidate
Prominent CNS actions & minimal effect on CVS
Longer plasma half life
Use : In ADHD
Prolonged use : Dependence & hepatic damage
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MODAFINIL Blocks NE & DA reuptake
Use: To treat Narcolepsy
No abuse potential
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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
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ADR :oHypertensionoNauseaoHeadache
Dose :o100 mg three times daily orally
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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
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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
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ROPINIROLE ( REQUIP ® )
Dopamine agonist D3 > D2 or D4
Use : Parkinson’s disease Restless leg syndrome
ADR :• Syncope• Bradycardia• Day time sleepiness
54α - Receptor Antagonists
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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
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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
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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
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BUNAZOSIN
α1-selective antagonist
Use : BPH Lowers blood pressure in patients with hypertension
Available in-
Germany, Japan, Thailand, and Indonesia
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INDORAMIN α 1 antagonist Competitive antagonism of Histamine & 5-HT receptors
Use : Hypertension BPH Prophylaxis of migraine
ADR : Sedation, dry mouth, failure of ejaculation
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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
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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
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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
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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
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CARTEOLOL ( CARTROL ® ) Selective β1 Antagonist β2 Agonist Produces NO
Use : Open angle glaucoma Hypertension
Dose : 1 % ophthalmic solution one drop in each eye
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TILISOLOL Only animal study data is available
Non selective β receptor blocker
K+ channel opener
Long lasting & stable action in treatment of hypertension
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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
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BEVANTOLOL Selective β1 receptor antagonist
Use :- Angina pectoris- Hypertension
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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
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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
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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
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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
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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
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