Potassium channel openers

Potassium channel openers

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  Potassium channel openers Dr. Naser Ashraf Tadvi Associate Professor Dept. of Pharmacology Kamineni Institute of Medical Sciences, Narketpally
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  Objectives • Potassium channels – Types – Distribution – KATP channels – Modulators • Potassium channel openers – Classification – Mechanism of action – Pharmacological actions – Uses – Adverse effects – Important drugs
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  Ion Channels • Ionchannels are protein molecules that form pores on the plasma membrane and intracellular organelle of all cells. • They exploit the ionic gradient between cytosolic side and Extracellular space • Responsible for transfer of ions • Regulate the shape and frequency of Action potential • Potassium channels form most abundant and diverse class of ion channels
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  Potassium channels • Theyare membrane spanning proteins allowing efflux of potassium ions through K+ selective pore. • Their activity may be regulated by voltage, calcium, or neurotransmitters • Play important role in cellular and cardiac repolarization, smooth muscle relaxation, neurotransmitter and insulin release.
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  Classification of potassiumchannels • Grouped into families based on their structure as well as physiological & pharmacological criteria . • Mainly classified into three families – 2 TM: Inward rectifier potassium channels – 4 TM : Underlying cause for leak currents in neuronal cells – 6 TM: includes voltage gated channels • These channels are composed of two subunits namely primary pore forming α-subunit and an associated regulatory subunit.
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  α –subunit β –subunits Composite model of a voltage-dependent K+ channel.
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  2TM family subtypes (Inward rectifier) 2TM Family Subtype Activators Inhibitors KIR1.X 1.1 KIR2.X 2.1 to 2.4 Mg2+, polyamines KIR3.X 3.1 to 3.4 PIP2 G Protein activated KIR4.X 4.1-4.2 KIR5.X 5.1 KIR6.X 6.1 – 6.2 Minoxidil , Glibenclamide, ATP Associated cromakalim, tolbutamide sensitive subunit SUR1, diazoxide, SUR2A,2B nicorandil KIR7.X 7.1
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  4TM family ofK channels • This family is underlying cause of leak currents in the neuronal cells • The primary pore forming α-subunit has two pore domains • These two pore domain channels have emerged as potential target for inhalational anaesthetic agents. • Halothane seems to highly efficacious in activating these subtypes TREK AND TASK
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  4TM family subtypes 4TMfamily Subtypes Activators inhibitors TWIK 1-3 Acid PH TREK TREK 1,2 & Halothane, Riluzole, Heat, TRAAK Arachidonic Acid,pH TASK 1,3,5 Halothane, alkaline PH Anandamide TALK 1,2,4 ALKALINE PH THIK 1-2 Halothane TRESK 1 Arachidonic acid TWIK: TANDOM OF PORE DOMAINS IN A WEAK INWARD RECTIFYING K CHANEL TREK:TWIK RELATED POTASSIUM CHANNEL TASK: TWIK RELATED ACID SENSITIVE POTASSIUM CHANNEL TALK: TWIK RELATED ALKALINE PH ACTIVATED K CHANNEL THIK: TANDEM PORE DOMAIN HALOTHANE INHIBITED CHANNEL TRESK: TWIK RELATED SPINAL CORD POTASSIUM CHANNEL
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  6 TM familyof potassium channels 6 TM FAMILY Activators Inhibitors Kv1.x (Shaker) TEA, 4-AP, Margatoxin Kv2.x (Shab) TEA Kv3.x (Shal) TEA, 4-AP Kv4.x (Shaw) Kv7.x (KCNQ) Retigabine TEA, Linopirdine Kv10.x- Kv12.x (EAG) Astemizole, terfenadine Kca1.x,Kca4.x Kca5.x TEA, Charybdotoxin , (SloBK, Slack,slick) Iberiotoxin Kca2.x, Kca3.x Charybdotoxin, apamin (KCNMB1-4) 4AP: 4 AMINO PYRIDINE, TEA: TETRAETHYL AMMONIUM,
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  ATP sensitive potassiumchannels • Present in the pancreas , heart, brain, smooth muscle, and skeletal muscle. • close when ↑ATP , ↑ ADP: opens the channels • Structure : octameric with – 4 KIR6 subunits and 4 SUR subunits
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  Structure of KATPchannels SUR subunit has 3 transmembrane domains. TMD0,TMD1 & TMD2 , and 2 nucleotide binding domains NBD1 in between TMD1 & TMD2 , NBD2: in COOH terminus
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  Tissue specific distributionof different subunits of KATP TISSUE SUBUNITS Pancreatic β- cells SUR1 KIR6.2 Neurons SUR1 KIR6.2 Cardiac & skeletal SUR2A KIR6.2 muscles Vascular & smooth SUR2B Kir6.1/kir6.2 muscles
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  Modulators of KATPchannels Blockers Openers • Sulfonylureas • Adenosine, prostacycline • Aminopyridines • VIP, CGRP, NO • Naturally occuring toxins • Diazoxide – Apamin, charybdotoxin • Minoxidil – Iberiotoxin,detrotoxin • Cromakalim – Strychinine • Levocromakalim • Class III antiarrhythmics • Bimakalim – Amiodarone • Aprikalim – Sotalol • Pinacidil – Dofetilide • Nicorandil • Minoxidil
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  Exogenous potassium channelopeners • Benzopyrans : Levocromakalim, Bimakalim • Benzothiadiazines :Diazoxide • Cyanoguanidines : Pinacidil • Nicotinamides: Nicorandil • Pyrimidines: Minoxidil • Thioformamides: aprikalim • Cyclobutenediones: WAY-151616 • Tertiary carbonoles: ZD-6169 • Dihydropyridine : ZM-244085
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  Endogenous potassium channelopeners • Vasoactive Intestinal Polypeptide • Calcitonin Gene Related Peptide • Adenosine • Relaxin : • Prostacyclin : • Acetyl choline:
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  Chemical Structure 6 3 1
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  Tissue selectivity ofKCOs • WAY-133537, ZD-6169: Uroselective • Rimakalim , BRL55834: Bronchoselective
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  MOA of potassiumchannel openers Potassium channel openers Open KATP Enhance K+ efflux Membrane Hyperpolarization ↓ Ca 2+ entry Reduced intracellular calcium Smooth muscle relaxation
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  Other mechanisms ofaction of K+ channel openers • Hyperpolarization induced by K ATP CO inhibits production of 1,4,5 IP3and hence Ca2+ release from intracellular stores • Hyperpolarization may also be linked with ↓ sensitivity of contractile elements of vascular smooth muscles • ↓ neurotransmitter release from nerve terminals
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  Pharmacological actions &Uses of potassium channel openers
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  Pharmacological actions • Heartand blood vessels • Smooth muscles – Respiratory – Intestine – Urinary bladder – Uterus • Endocrine system • Nervous system • Hair growth
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  Actions on heart •Sarcolemmal KATP – shorten duration of cardiac action potential – Negative ionotrophic effect in cardiomyocytes and vasodilation of blood vessels • Mitochondrial KATP – Channels open in response to ischemia – Trigger ↑mitochondrial ROS production amplify cell signalling pathway – Leads to gene transcription and cell growth – Also prevents disruption of mitochondrial structure and function
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  Actions on heart •Cardiac preconditioning effect – Brief episode of ischemia can result in an increase resistance to subsequent more severe episodes of ischemia – This ischemic preconditioning to brief ischemia may occur due to adenosine by activation of KATP
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  Actions on heart •Antiarrhythmic actions – Prevent arrhythmias related to triggered activity , abnormal repolarization and early or delayed after depolarization – Prolonged QT syndrome, drug induced ventricular arrhythmias nicorandil and pinacidil were effective – ↑ K+ conductance shortens APD and contributes to extracellular K accumulation . This may be responsible for ischemia induced arrhythmias – May also facilitate re-entrant arrhythmias
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  Actions on bloodvessels • Mainly arteriolar vasodilation
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  Therapeutic uses incardiovascular conditions • Ishemic heart disease : – Angina , Myocardial infarction • Hypertension • Pulmonary hypertension • Perioperative cardiac protection • Organ perfusion and preservation for transplant • Rhythm disturbances • Peripheral vascular disease
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  Respiratory system • Inbronchial asthma – Hyperpolarization of smooth muscles, neurons and secretory cells – Reduce bronchial hyper-responsiveness by direct effect on smooth muscle relaxation and through inhibition of excitatory NANC transmission
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  Role in bronchialasthma • Broncho-relaxation • Prevention of bronchoconstriction • ↓ microvascular leakage & goblet cell secretion • ↓ dyspnoea evoked by inflammatory mediators & airway hyperesponsiveness • Do not develop bronchial hyper-reactivity & tolerance on long term use
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  Comparison of potenciesPotassium channel openers used in Bronchial Asthma Compound IC-AHR Ozone – MAP AHR Levocromakalim 22 - 10 Bimakalim 0.5 0.3 2 Rilmakalim 0.2 - 10
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  Action on intestines •Minoxidil ↑the effect of morphine on gastrointestinal delay in presence of mosapride • Pinacidil and cromakalim administered orally, inhibited the intestinal propulsion of charcoal, and castor oil-induced diarrhoea in mice. • This confirms the presence of KATP channels in the intestine and suggests a new approach for the symptomatic treatment of diarrhoea.
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  Actions on urinarybladder • KATP channels also found in the bladder smooth muscle. • A-251179, a potent novel KATP channel opener related to pinacidil has shown high selectivity towards these channels • ↓ed spontaneous contractions in urinary bladder. • prolongs the time interval between voids by ↑ bladder capacity without affecting voiding efficiency • This novel compound represents an interesting area to be explored for the application of KATP channel openers
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  Role in erectiledysfunction • Potassium channel openers hyperpolarize and relax corpus cavernosum • Produce penile tumescene and erection • Minoxidil lubricating gel on glans penis was more effective than placebo or NTG in facilitating erection with less side effects • Nicorandil like compounds additional vasodilation due to NO release
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  Actions on uterus •Capable of producing glibenclamide sensitive relaxation of uterine smooth muscle • May be of used as uterine relaxants & have some place in treatment of dysmenorrhoea, and preterm labour • Hypoxia may contribute to uterine dystocia KATP channels may be involved in this effect.
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  Actions on endocrinesystem • KATP Channels essential in regulating insulin secretion from pancreatic β-cells • Diazoxide used in management of hypoglycemia due to hyperinsulinemia in inoperable islet cell adenoma, & islet cell hyperplasia • Interesting finding is that diazoxide has also demonstrated antidiabetic activity on prolonged use in type II diabetes
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  Actions on nervoussystem • Strong neuroprotective effect when injected prior to ischemic or epileptic insult • Inhibit release of Aspartate and glutamate, which are released during hypoxia with neuronal depolarization • Also inhibit Ca2+ loading , decreases excitability and prevent neuronal injury
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  Uses of KCOsin neurological diseases • Subarachnoid haemorrhage : – prevent and reverse vasospasm by relaxing basilar artery without affecting systemic hemodynamics • Epilepsy • Alzheimers disease • Antinociceptive effect – Mediated through release of endorphins and enkephalins and activation of opioid receptors
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  Role in musculardiseases • Cromakalim and pinacidil shown effect in Myotonia congenita and myotonic dystrophy • Hypokalemic periodic paralysis • Peripheral vascular disease
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  Action on hairgrowth • Promote hair growth by direct effect on hair follicles and also by improving blood supply to hair follicles (vasodilation) • Minoxidil stimulates DNA synthesis in epidermal keratinocytes and hair follicles • ↑ proliferation and differentiation of epithelial hair shaft • ↑hair density by induction of anagen phase and ↑ anagen duration
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  Important potassium channel openers
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  Diazoxide • Compound relatedto chlorthiazide • Potent direct vasodilator • Pharmacokinetics: – 95% protein bound, should be injected IV – T ½ = 36 hrs • Uses: – malignant and pulmonary hypertension – Hypoglycemia – Uterine hyperactivity
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  Diazoxide • Dose – Hypertension : 13 mg/ kg I.V Bolus every 5-15 minutes – Hypoglycemia: 3-8 mg/kg QID • Adverse effects – Hypotension – Reflex tachycardia – Aggravation of angina – Gastric disturbances – Hyperglycemia
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  Minoxidil • Prodrug activatedto active metabolite minoxidil sulfate • Pharmacokinetics – Well absorbed orally – T ½ = 3-4 hrs – 85 % metabolized rest excreted unchanged • Uses – Alopecia areata & alopecia androgenita – Malignant / refractory hypertension – Impotence
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  Minoxidil • Dose: – 2.5 mg – 80 mg BD orally – 2% gel or 5 % gel also available apply 1 ml BD in alopecia • Adverse effects – Hypertrichosis – Pleural, pericardial effusion – Reflex tachycardia – Fluid and salt retention
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  Nicorandil • In additionto acting as KCO also produces vasodilation by acting as NO donor • Decreases preload as well as after load • Pharmacokinetics: – Well absorbed orally, no significant first pass metabolism – T ½ = 50 min • Uses: Angina, Arrhythmias
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  Nicorandil • Dose: – 10-40 mg orally BD – 2-6 mg/ i.v /hr • Adverse effects – Headache – Postural hypotension – Gastric disturbances – Flushing – Rashes and mouth ulceration
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  Pinacidil • Similar tonicorandil in use, properties and adverse effects • Oral bioavailability 57% , T 1/2 = 1-3 hrs • Metabolized by CYP450 • Can cause fluid retention • Dose: – 12.5 mg BD , in combination with diuretic – 37.5 mg controlled release tablet available
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  Flupirtine • Selective Neuronal KCO (SNEPCO) • Triaminopyridine recently marketed in Italy • Opens Kv7.2 –Kv 7.5 Potassium channels • Uses: – Mild to moderate pain especially associated with muscle tension – Retinal ischemia, stroke, migraine – Neurodegenerative disorder • Dose: – 100-300 mg/day
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  Retigabine • Structural analogof flupirtine • Used in epilepsy (broad spectrum antiepileptic) • Mechanism of action – Activates voltage dependent neuronal potassium channels Kv7.2-Kv7.6 – Hyperpolarizes neuronal resting membrane potential leading to inhibition of spontaneous or synaptically trigerred neuronal activity
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  Retigabine • Pharmacokinetics – 60 % bioavailability , Low first pass metabolism – 80% plasma protein binding , T ½ = 8 hrs – Does not induce or inhibit CYP450 – Metabolized by acetylation • Dose: 600-1200 mg/day • Adverse effects – Somnolence, confusion, dizziness, headache
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  Iptakalim • Novel ATP sensitive KCO • Strong antihypertensive effect • Antipsychotic action • Mechanism : – Inhibitory function on excess dopamine and glutamate release – Highly lipophilic crosses BBB • Dose: 5 – 20 mg
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  Take home message •Potential area of research • Multi- utility drugs but lack specificity in action • Need of developing selective drugs • Most important uses are alopecia, angina, hypertensive crisis • Newer KCOs like retigabine, flupirtine iptakalim are promising drugs
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  Thank You
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  References 1. Hibino H,Inanobe A, Furutani K, Murukami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: Their structure, function and physiological roles.Physiol Rev. 2010;90:291-366. 2. Enyedi P, Czirjak G. molecular background of leak K+ currents: two pore domain potassium channels. Physiol Rev. 2010;90:559-605. 3. Barrese V, Miceli F, Soldovieri MV, Ambrosino P, Lannotti FA, Cilio MR, et.al. Neuronal Potassium channel openers in the management of epilepsy: Role potential of retigabine. Clinical Pharmacology: Advances and Applications. 2010;2:225-36.
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  References 4. Jahangir A,Terzie A. KATP channel therapeutics at bed side. Journal of Molecular and Cellular Cardiology . 2005;39:99-112. 5. Sandhiya S, Dkhar SA. Potassium channels in health disease and development of potassium channel modulators. Indian J Med Res. 2009;129:223-32. 6. Lawson K. Potassium channel openers as potential therapeutic weapons in ion channel disease. Kidney International. 2000;57:838-45.
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  References 7. Pollesello P,Mebazaa A. ATP dependent potassium channels as key target for the treatment of myocardial and vascular dysfunction. Current Opinion in Critical Care. 2004;10:436-41. 8. Challinor Rogers JL, McPherson GA. Potassium channel openers and other regulators of KATP channels. Clinical and Experimental Pharmacology and Physiology. 1994;21:583-97.
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  References 9. Fozart JR,Manley PW. Potassium channel openers: Agents for the treatment of airway hyperreactivity . Prog Respir Res. 2001;31:77-80. 10. Graffi M, Longobardi C, Giovannini A, Viscardi D, Costa F, Palomba R. Analgesia and S.N.E.P.C.O. (Selective Neuronal Potassium Channel Openers): our experience with flupirtine. 5th International Meeting - Dialogues on anaesthesia and intensive care (Napoli, 18-19 november 2011). 11. Sun T, Zhao C, Gang Hu, Ming li. Iptakalim: A potential antipsychotic drug with novel mechanisms?. European Journal of Pharmacology. 2010; 634: 68–76.