Phosphodiesterase Inhibitors

Phosphodiesterase Inhibitors: 

Phosphodiesterase Inhibitors Dr. Mayur M. Maybhate JR III, Dept. of Pharmacology IGGMC, Nagpur.

Introduction: 

Introduction A phosphodiesterase is any enzyme that breaks a phosphodiester bond. There are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases

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Usually, people speaking of Phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below

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The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.

Historical aspects: 

Historical aspects The phosphodiesterase (PDE) story begins with the work of Henry Hyde Salter in 1886 . An asthmatic he noted that when he drank a strong cup of coffee on an empty stomach, his breathing eased, an effect attributed to the bronchodilator properties of caffeine. Although the mechanism of action at the time was unknown, it has since been shown that caffeine was acting as a non-selective, albeit weak, PDE inhibitor

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The different forms or subtypes of phosphodiesterase were initially isolated from rat brains by Uzunov and Weiss in 1972 and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait . This prediction meanwhile has proved to be true in a variety of fields.

Classification : 

Classification The PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. The classification is based on: 1. PDE substrate specificities by enzyme family. Both means it hydrolyzes both cAMP and cGMP. 2. amino acid sequences 3. regulatory properties 4. tissue distribution

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PDEs have different substrate specificities. Some are cAMP selective hydrolases(PDE4, 7 and 8), others are cGMP selective(PDE5, 6 and 9) Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11)

Effect of PDE inhibition: 

Effect of PDE inhibition PDE cAMP/cGMP AMP/GMP - Increased cardiac contractility - Smooth muscle relaxation - Reduced immune and inflammatory activity of cells

PDE inhibitors: 

PDE inhibitors Nonselective PDE inhibitors PDE 1 inhibitors PDE 2 inhibitors PDE 3 inhibitors PDE 4 inhibitors PDE 5 inhibitors

Non selective PDE inhibitors: 

Non selective PDE inhibitors

Theophylline: 

Theophylline Apart from inhibiting adenosine receptors, also nonspecifically inhibits PDE enzyme Wide range of actions CVS – Positive ionotropic, chronotropic SM – relaxant Reduced activity of inflammatory cells

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Oral theophylline used in pts of COPD and mild to moderate asthma Act synergistically with β 2 agonists in asthma

ADRs: 

ADRs ADR Proposed Mechanism Nausea, Vomiting PDE 3 inhibition Headache PDE 3 inhibition Gastric disconfort PDE 3 inhibition Diuresis Adenosine antagonism Cardiac arrythmias PDE 3 inhibition Seizures Adenosine antagonism Narrow margin of safety, therapeutic range – 8-15 mcg/ml

Drug interactions: 

Drug interactions Reduced activity in presence of enzyme inducers like rifampicin, carbamazepine etc. (Dose increased) Increased activity in presence of enzyme inhibitors such as ketoconazole, cimetidine, erythromycin etc. (Dose decreased) Enhances effect of sympathomimetics, digitalis, hypoglycemic, anticoagulant agents

Pentoxifylline: 

Pentoxifylline Theobromine analogue, inhibits PDE enzyme Reduces blood viscosity and improves blood flow in ischemic area through microcirculation

Uses: 

Uses One of the DOC for PVDs Non hemorrhagic stroke Chronic cerebrovascular insufficiency Trophic leg ulcers Diabetic neuropathy

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Also inhibits production of TNF-alfa in AIDS patients Used in dose of 400 mg BD orally

PDE 1 inhibitor - Vinpocetine: 

PDE 1 inhibitor - Vinpocetine Semisynthetic derivative alkaloid of vincamine, an extract from the periwinkle plant. Still an investigational agent having variety of properties

As vasodilator: 

As vasodilator

As Anti-inflammatory agent: 

As Anti-inflammatory agent

ADRs: 

ADRs generally tolerated well Some cases of Agranulocytosis reported 2-5 mg tab. OD, can be increased upto 10 mg/day

PDE 2 Inhibitors - Anagralide : 

PDE 2 Inhibitors - Anagralide - Drug used for the treatment of essential thrombocytosis or overproduction of blood platelets. - also has been used in the treatment of chronic myeloid leukemia

Mechanism of action: 

Mechanism of action Inhibiting the maturation of platelets from megakaryocytes inhibitor of phosphodiesterase-II. It inhibits PDE-3 and phospholipase A2.

Uses: 

Uses the combination of anagrelide and aspirin for the initial management of ET

ADRs: 

ADRs headache, diarrhea, unusual weakness/fatigue, hair loss, nausea and dizziness. Less common side effects include: congestive heart failure, myocardial infarction, cardiomyopathy

PDE 3 inhibitors: 

PDE 3 inhibitors Inamrinone, Milrinone, Levasimendan, Enoximone Bipyridine derivatives also reffered as Nonglycoside Nonsympathomimetic ionotropic agents

Mechanism of action: 

Mechanism of action Selectively inhibits PDE 3, located in heart, results in increased cAMP Positive ionotropic on heart Vasodilatation of vessels (Ionodilator)

Kinetics: 

Kinetics Active orally as well as parenterally Half life 3-6 hrs, excreted via urine

ADRs: 

ADRs Nausea, Vomiting Cardiac arrythmias Thrombocytopenia Altered liver enzymes Milrinone less toxic

Use: 

Use Only used IV for acute heart failure cases in dose of 100 mg, repeat if necessary Potentiates action of β 1 agonist

Cilastazole: 

Cilastazole PDE 3 inhibitor Raises cAMP in vessel wall leading to vasodilatation and inhibition of platelet aggregation (antiplatelet agent)

Use: 

Use Used as an antiplatelet agent mainly in intermittent claudication Also used as adjuvant antianginal agent

Interaction and dosage: 

Interaction and dosage Metabolized by CYP3A4, hence concurrent use of verapamil, diltiazem and ketoconazole etc. should be avoided 100 mg OD orally is usual dose

PDE 4 Inhibitors: 

PDE 4 Inhibitors Enzyme located in respiratory tract, inhibition of which raises cAMP, causing smooth muscle relaxation and reduced release of cytokines, in turn reduces migration and activation of immune cells Also potentiates β 2 agonist in asthma

Roflumilast, Cilomilast: 

Roflumilast, Cilomilast

Dosage,ADRs: 

Dosage,ADRs 500 μ g/day oral alone or in combination with β 2 agonist Nausea, vomiting, Headache, nasopharyngitis, URTI, decreased appetite

Drotaverine: 

Drotaverine Novel PDE 4 inhibitor, Elevated cAMP leads to relaxation of smooth muscles of GIT

Uses and Dosage: 

Uses and Dosage Used as antispasmodic agent in intestinal, biliary, renal colics as well as irritable bowel syndrome and uterine spasms Oral as well as parenteral 40-80 mg TDS

ADRs: 

ADRs Headache, dizziness, flushing Fall in BP on IV injection

PDE 5 inhibitors: 

PDE 5 inhibitors Enzyme located in corporal musculature Inhibition leads to raised cAMP, relaxation of corporal muscles

Sildenafil, Tadanafil: 

Sildenafil, Tadanafil Indicated in treatment of erectile dysfunction in men due to organic or psychological causes No effect in absence of sexual stimulation 1 hr prior to anticipated sexual activity

ADRs: 

ADRs Headache, nasal congestion, flushing, hypotension Disturbance in color vision due to inhibition of PDE 6 in retina Ability to potentiate NO – very cautiously used in pts of angina, HTN using nitrates

Interactions: 

Interactions Reduced activity in presence of enzyme inducers like rifampicin, carbamazepine etc. Increased activity in presence of enzyme inhibitors such as ketoconazole, cimetidine, erythromycin etc.

Off label use: 

Off label use PDE 5 also located in lungs, inhibition leads to raised cAMP leading to vasodilatation Used in pulmonary HTN

Future trends in PDE 5 Inhibitors: 

Future trends in PDE 5 Inhibitors Premature ejaculation Adding PDE5 inhibitors to SSRI drugs (e.g. paroxetine) for the treatment of premature ejaculation could result in better ejaculatory control according to recent studies. Possible mechanism is based on nitric oxide (NO)/cGMP transduction system as a central and peripheral mediator of inhibitory non-adrenergic, non-cholinergic nitrergic neurotransmission in the urogenital system

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Female sexual arousal disorder PDE5 is expressed in clitoral corpus cavernosum and in vaginal smooth muscle and epithelium. Increased levels of cGMP have been shown to occur in human-cultered vaginal smooth muscle cells treated with a PDE5 inhibitor suggesting involvement of the NO/cGMP axis in the female sexual response Therefore it is possible that PDE5 inhibitors could affect female sexual arousal disorder but further research is needed .

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Raynaud's phenomenon Sildenafil has been shown to be effective in treating severe Raynaud's phenomenon associated with systemic sclerosis and digital ulceration. When given sildenafil for 4 weeks subjects had reduced mean frequency and duration of Raynaud attacks and a significantly lowered mean Raynaud’s condition score. The capillary blood flow velocity also increased in each individual patient and the mean capillary flow velocity of all patients increased significantly.

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Stroke Sildenafil has been shown to significantly improve neurovascular coupling without affecting overall cerebral blood flow by increasing brain levels of cGMP, evoking neurogenesis and reducing neurological deficits in rats 2 or 24 hours after stroke. This data suggest that PDE5 inhibitors may have a role in promoting recovery from stroke

Recent advances: 

Recent advances

Spiroquinazolinones as novel, potent, and selective PDE7 inhibitors: 

Spiroquinazolinones as novel, potent, and selective PDE7 inhibitors The latest scientific findings about PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. Taking this into account, the interesting profile as PDE7/PDE4 dual inhibitors of our derivatives makes them as promising drugs to treat a variety of human diseases, predominantly disorders of immune , as multiple sclerosis, and inflammatory systems and also disorders of the CNS such as depression, psychosis, and Alzheimer disease

The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents : 

The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway May have role in neurodegenerative diseases like AD

PDE 10 Inhibitors ???: 

PDE 10 Inhibitors ??? PDE10 is an enzyme that has been shown to be present at high levels in neurons in areas of the brain that are closely associated with many neurological and psychiatric disorders By inhibiting PDE10, levels of cAMP and cGMP are increased within neurons and the ability of these neurons to function properly is thereby improved

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PDE10 inhibitors have been shown to be as effective in vivo as current anti-psychotic drugs

Conclusion: 

Conclusion PDE - Wide distribution in body Various agents and many more in pipeline

References: 

References Bertram G. Katzung , PDE inhibitors in heart failure, Basic and clinical pharmacology:11:216-30;2009 Mark S, PDE 5 inhibitors for erectile dysfunction; Goodman and Gilmans , Pharmacological basis of therapeutics; 12;1511-55; 2010.

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David MJ, Role of PDE inhibitors in asthma; Harrisons Principle of internal medicine; 17; 1688-1745;2009. Tripathi K.D .,PDE inhibitors; Essentials of Medical Pharmacology; 6;242-53;2008. HL Sharma, KK Sharma , Phosphodiesterase inhibitors; Principles of Pharmacology;2;320;2011

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Stehlik J, Movsesian MA, Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure, Expert Opin Investig Drugs ; Jul;15(7):733-42;2009 Mark S, David KG, PDE 5 inhibitors for erectile dysfunction, PubMed ; 2008

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