Cellular & cardiac
repolarization
Neuro-transmitter
& insulin release
Smooth muscle
relaxation
Potassium channels
• Most abundant & diverse class of ion channels.
• Membrane spanning proteins allows efflux of potassium ions through K+ selective pore.
• Regulated by voltage, calcium, or neurotransmitters.
• Important role : .
K+
2 TM: Inward rectifier potassium Channel
4 TM : Underlying cause for leak currents in neuronal cells
6 TM: Voltage gated channels
Classification of potassium channels
Classification of potassium channels
2 TM 4 TM 6TM
7 subtypes
Activators:PIP2(Kir3.x) Minoxidil, Cromakalim, Diazoxide, Nicorandil (Kir6.x)
Inhibitors:Mg+2,Polyamines(Kir2.X) Glibenclamide Tolbutamide (Kir6.X)
6 subtypes
Activators:HalothaneRiluzoleHeat & alkaline Ph.
Inhibitors:Acidic Ph, AnandamideHalothaneArachidonic acid
8 subtypes
Activators:Retigabine
Inhibitors:TEA 4APLinopirdineAstemizole Terfenadine, Charybdotoxin,IberiotoxinApamine
ATP sensitive potassium channels
Octameric structure with 4 Kir subunits & 4 SUR subunits ATP was first modulator studiedOther endogenous modulators: pH, fatty acids, NO, various nucleotides and G-proteins Expressed in various tissues: Pancreatic β-cells, brain (SUR1,Kir6.2) Heart, skeletal muscle (SUR2A,Kir6.2) Smooth muscle (SUR2B,Kir6.1/6.2)
Metabolically regulated channels
ADP ATP
Diazoxide did not activate the sarcolemmal cardiac channel while it did open pancreatic K channel suggesting the possibility
of tissue selectivity.
Drugs Cells
Diazoxide Pinacidil Cromakalim Nicorandil
Pancreatic β cells
(+++) (-) (-) (-)
Cardiac cells (-) (++) (+) (+)
Vascular smooth cells
(++) (+++) (+++) (+++)
Example of Tissue selectivity
Modulators of K-ATP channels
Blockers• Sulfonylureas• Aminopyridines• Class III anti-arrhythmics Amiodarone Sotalol Dofetilide• Naturally occuring toxins Strychnine Apamine Charybdotoxin Iberiotoxin Detrotoxin
Openers:• Adenosine, Prostacycline• VIP, cGRP, NO• Diazoxide• Minoxidil• Cromakalim• Levocromakalim• Bimakalim• Aprikalim• Pinacidil• Nicorandil
Potassium channel openers
Endogenous
• VIP• Calcitonin gene related
peptide• Relaxin• Prostcyclin• Acetylcholine
Exogenous• Nicorandil• Minoxidil• Levocromakalim, Bimakalim• Diazoxide• Pinacidil• Aprikalim• Cyclobutenediones: WAY-151616• Tertiary carbonoles: ZD-6169• Dihydropyridine: ZM-244085
Open K-ATP
Enhance K+ efflux
Membrane Hyper- polarisation
↓Ca+2 entry
Reduced intracellular calcium
Smooth muscle relaxation
Mechanism
Inhibits Ca+2 release from intracellular stores.
↓ Sensitivity of contractile elements of vascular smooth muscles
Neurotransmitter release from nerve terminals.
Other Mechanism
Shorten duration of cardiac action potential Negative ionotropic effect
Cardiac preconditioning effect
Mainly arteriolar vasodilation
Action on Heart & Blood vessels
Cardio protective effects studied in numerous models of myocardial ischemia
Potential uses in cardiovascular diseases
Ischemic heart disease : Angina , Myocardial infarction
Hypertension
Pulmonary hypertension
Perioperative cardiac protection
Rhythm disturbances related to delayed repolarization
Peripheral vascular disease
Action on respiratory system
Smooth muscle relaxation
Decreases micro vascular leakage & goblet cell secretion
Decreases dyspnea evoked by inflammatory mediators & airway hyper-responsiveness
Do not develop tolerance on long term use
Action on intestines
Minoxidil ↑ the effect of morphine on gastrointestinal delay in presence of mosapride
Confirms the presence of K-ATP channels in the intestine and suggests a new approach for the symptomatic treatment of
diarrhoea.
Pinacidil and cromakalim administered orally, inhibited the intestinal propulsion of charcoal, and castor oil-induced diarrhoea in mice
Action on urinary bladder
Potential use in erectile dysfunction
↓ spontaneous contractions in urinary bladder
↑ the time interval between voids, ↑ bladder capacity without affecting voiding efficiency
Relaxes corpus cavernosum, penile tumescene and erection .
Minoxidil lubricating gel on glans penis > placebo
Nicorandil vasodilates and release NO
Action on Endocrine system
Action on uterus
Decreases insulin secretion from pancreatic β-cells
Diazoxide used for hypoglycaemia due to hyperinsulinemia in inoperable islet cell adenoma & islet cell hyperplasia
Uterine relaxants Potential use in treatment of dysmenorrhea & preterm labor
Action on Nervous system
Neuroprotective effect
Inhibits Calcium loading, decreases excitability and prevent neuronal injury
Inhibits release of aspartate and glutamate which are released in hypoxia
Potential use in SAH wherein it prevents and reverses vasospasm without affecting systemic hemodynamics
Other potential areas of use include Epilepsy and Alzheimers disease
Action on muscular system
Hyperpolarization of sarcolemmal membranes in smooth muscle cells causing relaxation
Cromakalim and pinacidil shown to be effective in myotonia congenital and myotonic dystrophy
Potentially useful in Hypokalemic periodic paralysis and peripheral vascular disease.
Action on hair growth
Promotes hair growth by direct effect on follicles & improving blood supply to hair follicles by vasodilation
Promotes proliferation & differentiation of epithelial hair shaft.
Increases hair density by induction of anagen phase & increased anagen duration.
Minoxidil stimulates DNA synthesis in epidermal keratinocytes and hair follicles.
Diazoxide
Benzothiadiazine derivative
Mainly interacts with pancreatic β cell membrane K-ATP channel and results in hyperglycemia
Highly plasma protein bound with long half life of 48 hours
Oral dose is 3-8 mg/kg per day (Adults) 8-15 mg/kg per day (Infant)
Used to treat chronic or recurring hypoglycaemia. May be useful inoperable insulinomas and neonatal hyperinsulinism
Potentially useful in Malignant & pulmonary hypertension and Uterine hyperactivity
Adverse effects include,
Nausea, Vomiting,
Fluid retention,
hyperuricemia, hypertrichosis, Hypotension, reflex tachycardia,
thrombocytopenia and leucopenia
Drug interactions seen are,
Decreases glucose lowering effect of sulfonylureas,
Diuretics may increase the effects of diazoxide.
Minoxidil
Prodrug Active metabolite → Minoxidil
sulfate
Available as 2% or 5% solution for topical application
Well absorbed orally as well with half life of 3 -4 hours.
85% metabolized, rest excreted unchanged
Uses: - Alopecia areata & alopecia androgenita - Malignant/refractory hypertension
- Impotence.
Adverse drug reaction
o Allergic and irritant contact dermatitis
o Hair growth at undesirable location
o Reflex tachycardia
o Fluid and salt retention and pleural, pericardial effusion
o Flattened and inverted T waves frequently observed
“Effect of Minoxidil is reversible on stopping drug”.
Nicorandil
Introduced as anti-anginal in 1990
Dual mechanism of action: potassium channel opener + NO donor Preload and afterload decreases
Well absorbed orally, ~completely metabolized by liver
Biphasic elimination: rapid phase T ½ = 1 hour and slow phase T ½ is 12 hours.
Nicorandil
Dose: 5-20 mg BD orally 2-6 mg BD iv.
ADR include. Rashes and moth ulceration, flushing, palpitation, weakness, headache, dizziness, nausea and vomiting, Drug may interact with sildenafil
Uses : Alternative anti-angina drug. Useful in resistant angina
During angioplasty given for acute MI
Pinacidil
Cyanoguanidine group of drug
Oral bioavailability 60 %, T ½ = 1-3 hours
Metabolized by CYP450
Dose = 12.5 mg BD in combination with diuretic
37.5 mg controlled release tablet available.
Flupirtine
Triaminopyridine
Selective Neuronal KCO
Uses: - Fibromyalgia - Musculoskeletal pain (mild to moderate) - Headache (chronic tension headache) -Neurodegenerative disorder
ADR = dizziness , drowsiness , pruritus, dry mouth gastric fullness, nausea, and muscle tremor
Retigabine/ezogabine (Trobalt/Potiga)
Analog of Flupirtine
Used in epilepsy
(broad spectrum antiepileptic)
MOA: activates Kv7.2-Kv7.6
Hyperpolarization of neuronal RMP inhibits
spontaneous/triggered neuronal activity
Bioavailability: 50–60%.
T ½ : 8-10 hours, 80% plasma protein bound
ADR: Somnolence, fatigue, dizziness, confusion,
headache
Iptakalim
Novel potassium channel opener with high selectivity for cardiac and vascular potassium channels
Strong antihypertensive effect
Antipsychotic effect - K ATP channels in brain modulates glutamate and dopamine levels - crosses blood brain barrier (lipopholic)
Use limited to severe and/or refractory hypertension
Future research …
Cardio-protection
1. Are the Mitochondrial K channels the end effectors of cardio-
protection?
2. How does opening mitochondrial K-ATP channel will have ATP
sparing effects?
To conclude….
Most importantly used in alopecia, angina, hypertensive crisis
Newer KCO like retigabine ,flupirtine, iptakalim are promising drugs
Multi-utility drugs but lack specificity in their action
More selective drugs need to be developed.
Potential area of research