Potassium channel modulators

Editor's Notes

• #3: Types and Classification is highly confusing and such details may not be very useful but for the sake of the seminar, a simplified summary for each type will be given. Since KCO is a major class of K Ch modulators, it will be discussed in a little more detail.
• #4: Ion channels 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 Inherited abnormalities of potassium channels (channelopathies) contribute to a rapidly growing number of cardiac, neurological and other diseases. These include the long QT syndrome associated with mutations in cardiac voltage-gated potassium channels, causing episodes of ventricular arrest that can result in sudden death. Certain familial types of deafness and epilepsy are associated with mutations in voltage-gated potassium channels.
• #5: Voltage-gated potassium channels, which possess six membrane-spanning helices, one of which serves as the voltage sensor, causing the channel to open when the membrane is depolarised. Included in this group are channels of the shaker family, accounting for most of the voltage-gated K+ currents familiar to electrophysiologists, and others such as Ca2+-activated potassium channels and two subtypes that are important in the heart, HERG and LQT channels. Disturbance of these channels, either by genetic mutations or by unwanted drug effects, is a major factor in causing cardiac dysrhythmias, which can cause sudden death. Many of these channels are blocked by drugs such as tetraethylammonium and 4-aminopyridine. Inwardly rectifying potassium channels, so called because they allow K+ to pass inwards much more readily than outwards These have two membrane-spanning helices and a single pore-forming loop (P loop). These channels are regulated by interaction with G-proteins (see Ch. 3) and mediate the inhibitory effects of many agonists acting on G-protein-coupled receptors. Certain types are important in the heart, particularly in regulating the duration of the cardiac action potential (Ch . 21); others are the target for the action of sulfonylureas (antidiabetic drugs that stimulate insulin secretion by blocking them; see Ch. 30) and smooth muscle relaxant drugs, such as cromakalim and diazoxide, which open them (see Ch. 22). Two-pore domain potassium channels, with four helices and two P loops (see review by Goldstein et al., 2001). These show outward rectifcation and therefore exert a strong repolarising influence, opposing any tendency to excitation. They may contribute to the resting K+ conductance in many cells, and are susceptible to regulation via G-proteins; certain subtypes have been implicated in the action of volatile anaesthetics such as halothane (Ch. 40). There is high-affinity block by endogenous polyamines, namely spermine, as well as magnesium ions, that plug the channel pore at positive potentials, resulting in a decrease in outward currents. This voltage-dependent block by polyamines results in efficient conduction of current only in the inward direction.
• #6: Potassium channel terminology is confusing, to put it mildly. Electrophysiologists have named K+ currents prosaically on the basis oftheir functional properties (IKV, IKCa, IKATP, IKIR, etc.); geneticists have named genes somewhat fancifully according to the phenotypes associated with mutations (shaker, The shaker (Sh) gene, when mutated, causes a variety of atypical behaviors in the fruit fly, Drosophila melanogaster. Under ether anesthesia, the fly’s legs will shake (hence the name); even when the fly is unanaesthetized, it will exhibit aberrant movements. When flies with mutations in the Ether-à-go-go gene are anaesthetised with ether, their legs start to shake, like the dancing then popular at the Whisky A Go-Go nightclub in West Hollywood, California. ether-a-go-go, etc.), while molecular biologists have introduced a rational but unmemorable nomenclature on the basis of sequence data (KCNK, KCNQ, etc., with numerical suffxes). The rest of us have to make what we can of the unlovely jargon of labels such as HERG (which—don’t blink—stands for Human Ether-a-go-go Related Gene), TWIK, TREK and TASK.
• #7: The alpha subunit is formed from 6 Trans Membrane segments and is associated with a regulatory beta subunit. 4 alpha subunits form a pore
• #8: 8 subtypes Shaker cognate b (Shab) is a member of the Sh family and the structural alpha subunit of a delayed rectifier K+ channel (Kv2). Shab channel functions to regulate excitability in neurons and muscles, and transmitter release. Shaker cognate l (Shal) is a voltage-dependent A-type K+ channel. Shal roles include neuronal excitability, regulating synaptic plasticity, locomotion, learning, and lifespan. Shaker cognate w (Shaw) is a voltage-gated potassium channel that mediates a non-inactivating potassium current open at resting membrane potential. It is important for controlling excitability of motor neurons and clock neurons. Shaw regulates circadian rhythms and is in a pathway with qsm and Na+ K+ Ca2+ Co-transporter. KCNQ gene Slowpoke Big Potassium (BK) channels SloBK - critical for action potential repolarization and transmitter release, sodium-activated potassium channel Slack, Slick is required for optimal cognitive flexibility
• #9: Four of these subunits cluster to form the active channel. Each subunit is composed of two membrane-spanning helices connected by a P-loop.
• #10: Found in Pancreatic beta cells, Neurons, Cardiac and skeletal muscles, vascular and smooth muscles. Close when ATP is high, ADP opens the channels.
• #11: 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
• #12: 6 subtypes Inhibitors and activators (name them)
• #13: Sulfonylureas: Pg 636 Aminopyridines - Fampridine has been used clinically in Lambert-Eaton myasthenic syndrome and multiple sclerosis. It acts by blocking potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction. Fampridine has been shown to improve visual function and motor skills and relieve fatigue in patients with multiple sclerosis (MS). 4-AP is most effective in patients with the chronic progressive form of MS, in patients who are temperature sensitive, and in patients who have had MS for longer than three years. Common side effects include dizziness, nervousness and nausea, Apamin = neuropeptide bee toxin Charybdotoxin = Scorpion venom, both cause paralysis Iberiotoxin = Indian Red Scorpion Toxin Dendrotoxin = dendrotoxins block VG K Channels and prolong the duration of action potentials and increase acetylcholine release at the neuromuscular junction, which may result in muscle hyperexcitability and convulsive symptoms. Strychnine is a neurotoxin which acts as an antagonist of glycine and acetylcholine receptors. It primarily affects the motor nerves in the spinal cord which control muscle contraction Endogenous openers – Relaxin, Acetyl choline, Adenosine, Prostacyclin, VIP, CGRP,
• #15: Decreased calcium load in heart muscle also leads to cardioprotection. Other mechanisms of action of K+ channel openers• Hyperpolarization induced by KCO inhibits production of 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
• #17: Actions of K channels on heart• (a) Sarcolemmal KATP – shorten duration of cardiac action potential – Negative ionotrophic effect in cardiomyocytes and vasodilation of blood vessels• (b) 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. 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 Cardioprotection by KCOs (as mentioned before) Actions on heart• Antiarrhythmic actions – Prevent arrhythmias related to triggered activity , abnormal repolarization and early or delayed after depolarization. ↑ K+ conductance shortens APD and contributes to extracellular K accumulation . This may be responsible for ischemia induced arrhythmias – May also facilitate re-entrant arrhythmias. Actions on blood vessels• Mainly arteriolar vasodilation Therapeutic uses in cardiovascular conditions• Ishemic heart disease : – Angina , Myocardial infarction• Hypertension• Pulmonary hypertension• Perioperative cardiac protection• Organ perfusion and preservation for transplant (Nicorandil  NO  Vasodilation through cGMP) • Rhythm disturbances• Peripheral vascular disease Respiratory system• In bronchial 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 Role in bronchial asthma• 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 (Levocromakalim, Bimakalim, Rilmakalim ) 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. Actions on urinary bladder• 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 Role in erectile dysfunction• 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 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 (Weak and uncoordinated contractions) KATP channels may be involved in this effect. Actions on endocrine system• 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 Actions on nervous system• 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 Uses of KCOs in 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 Action on hair growth• 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
• #18: Diazoxide• Compound related to chlorthiazide but causes sodium and water retention incidentlly• Potent direct arteriolar dilator, no effect on venules• lowers BP within 3-5 min after rapid IV Pharmacokinetics: – 95% protein bound, should be injected IV – T ½ = 36 hrs• Uses: Hypertensive emergencies in conjunction with a beta blocker and diuretic. HTN, Hypoglycemia–Diazoxide• Dose –• Adverse effects – Hypotension – Reflex tachycardia – Aggravation of angina – Gastric disturbances – Hyperglycemia Minoxidil• Prodrug activated to 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 associated with renal failure resistant to other therapies, almost always given with beta blockers, diuretics – Impotence Minoxidil• Dose: –• Adverse effects – Hypertrichosis – Pleural, pericardial effusion – Reflex tachycardia – Fluid and salt retention Nicorandil• In addition to acting as KCO (arterial dil.) also produces vasodilation by acting as NO donor (venodil)• Decreases preload as well as after load• Unlike nitrates tolerance does not develop to its effects. Increases coronary blood flow without coronary steal. Pharmacokinetics: – Well absorbed orally, no significant first pass metabolism – T ½ = 50 min• Uses: Vasospastic and Chronic stable Angina, Arrhythmias 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. C/ I with Sildenafil (hypotension) Pinacidil• Similar to nicorandil 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 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 Retigabine• Structural analog of 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 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 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
• #19: Nicorandil• In addition to 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 Nicorandil• Dose: –• Adverse effects – Headache – Postural hypotension – Gastric disturbances – Flushing – Rashes and mouth ulceration Pinacidil• Similar to nicorandil in use, properties and adverse effects• Oral bioavailability 57% , T 1/2 = 1-3 hrs• Metabolized by CYP450• Can cause fluid retention• Dose: –
• #20: Flupirtine• Selective Neuronal KCO (SNEPCO)• Triaminopyridine recently marketed in Italy• Opens Kv7.2 –Kv 7.5 Potassium channels• Uses: –• Dose: – Retigabine• Structural analog of 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 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: • Adverse effects – Somnolence, confusion, dizziness, headache Iptakalim• Novel ATP sensitive KCO• Strong antihypertensive effect• Antipsychotic action• Mechanism : – Inhibitory function on excess dopamine and glutamate release – Highly lipophilic crosses BBB• Dose: