Potassium Channel Openers

Student: Dr. Anup PetarePG Guide: Dr. Raakhi Tripathi

History

Akinori Noma first identified potassium channels in cardiac myocytes

HypertensionHair loss

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

Pharmacological actions

Heart & Blood vessels

Smooth muscles

Brain

Endocrine system

Hair growth

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.

Important potassium

channel openers

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

Thank you