This slides were prepared for My Post Graduation activities and seminar most of them are from sources such as slide share, Pub Med, Standard Pharmacology Textbooks .... Feel free to comment/correct/suggest Thank you

1. Potassium Channel Openers
Student: Dr. Anup Petare
PG Guide: Dr. Raakhi Tripathi

2. History
Akinori Noma first identified potassium channels in
cardiac myocytes
HyHpaeirrt elonsssion

3. Potassium channels
Cellular &
cardiac
repolarization
Neuro-transmitter
&
insulin
release
• Most abundant & diverse class of ion
Smooth
muscle
relaxation
channels.
• Membrane spanning proteins
allows efflux of potassium ions
through K+ selective pore.
• Regulated by voltage, calcium,
or neurotransmitters.
• Important role : .
K+

4. Classification of potassium channels
2 TM: Inward rectifier
potassium Channel
4 TM : Underlying cause for leak
currents in neuronal cells
6 TM: Voltage gated
channels

5. 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:
Halothane
Riluzole
Heat & alkaline Ph.
Inhibitors:
Acidic Ph,
Anandamide
Halothane
Arachidonic acid
8 subtypes
Activators:
Retigabine
Inhibitors:
TEA
4AP
Linopirdine
Astemizole
Terfenadine,
Charybdotoxin,
Iberiotoxin
Apamine

6. ATP sensitive
ADP ATP
potassium channels
 Octameric structure with 4 Kir subunits & 4 SUR subunits
 ATP was first modulator studied
Other 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)
Diazoxide did not activate the sarcolemmal cardiac channel
while it did open pancreatic K channel suggesting the possibility
of tissue selectivity.
 Metabolically regulated channels

7. Drugs
Cells
Example of Tissue selectivity
Diazoxide Pinacidil Cromakalim Nicorandil
Pancreatic β
cells
(+++) (-) (-) (-)
Cardiac cells (-) (++) (+) (+)
Vascular
smooth cells
(++) (+++) (+++) (+++)

8. 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

9. 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

10. Mechanism
Open K-ATP
Enhance K+ efflux
Membrane Hyper- polarisation
↓Ca+2 entry
Reduced intracellular calcium
Smooth muscle relaxation

11. Inhibits Ca+2 release from
intracellular stores.
Mechanism
↓ Sensitivity of contractile
elements of vascular smooth
muscles
Other
Neurotransmitter release
from nerve terminals.

12. Pharmacological actions
Heart & Blood
vessels
Smooth muscles
Brain
Endocrine
system
Hair growth

13. Action on Heart & Blood vessels
Mainly arteriolar vasodilation
Cardiac preconditioning effect
Shorten duration of cardiac action potential
Negative ionotropic effect
Cardio protective effects studied in numerous models of myocardial
ischemia

14. 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

15. 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

16. 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
Confirms the presence of K-ATP channels in the intestine and
suggests a new approach for the symptomatic treatment of
diarrhoea.

17. Action on urinary bladder
 ↓ spontaneous contractions in urinary bladder
 ↑ the time interval between voids, ↑ bladder capacity
without affecting voiding efficiency
Potential use in erectile dysfunction
 Relaxes corpus cavernosum, penile tumescene and erection .
 Minoxidil lubricating gel on glans penis > placebo
 Nicorandil vasodilates and release NO

18. Action on Endocrine system
 Decreases insulin secretion from pancreatic β-cells
 Diazoxide used for hypoglycaemia due to hyperinsulinemia in
inoperable islet cell adenoma & islet cell hyperplasia
Action on uterus
 Uterine relaxants
 Potential use in treatment of dysmenorrhea & preterm labor

19. 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

20. 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.

21. 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.

23. 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

24.  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.

25. 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.

26.  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”.

27. 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.

28. 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

29. 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.

30. 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

31. 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

33. 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

34. 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?

35. 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