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Amlodipine

Systematic (IUPAC) name

3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-

1,4-dihydropyridine-3,5-dicarboxylate

Identifiers

CAS number 88150-42-9

ATC code C08 CA01

PubChem 2162

DrugBank APRD00520

ChemSpider 2077

Chemical data

Formula C20H25Cl N 2O5 

Mol. mass 408.879 g/mol

SMILESeMolecules &

PubChem

Pharmacokinetic data

Bioavailability 64 to 90%

Metabolism Hepatic

Half life 30 to 50 hours

Excretion Renal

Therapeutic considerations

Pregnancy cat.C(AU) C(US)

Legal statusPOM(UK) ℞ -

only(US)

Routes Oral (tablets)

Amlodipine (as besylate, mesylate or maleate) is a long-acting calcium channel blocker (dihydropyridine class) used as an anti-hypertensive and in the treatment of angina. Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle.

Amlodipine is marketed as Dailyvasc in the Philippines by Xeno Pharmaceuticals, and by Pfizer as Norvasc in North America, Australia and some European countries, and as Istin in the United Kingdom. Generic brands (sold under names such as Perivasc in Australia) are also available.

indications

hypertension prophylaxis of angina

Cautions

hepatic impairment pregnancy

Contraindications

cardiogenic shock unstable angina significant aortic stenosis breast feeding

Side effects

Some side effects[1] of the use of amlodipine may be:

Very often: peripheral edema (feet and ankles) - in 1 of 10 users Often: dizziness; palpitations; muscle-, stomach- or headache; dyspepsia; nausea -

in 1 in 100 users Sometimes: blood disorders, development of breasts in men (gynecomastia),

impotence, depression, insomnia, tachycardia - in 1 in 1,000 users Rarely: erratic behavior, hepatitis, jaundice - in 1 in 10,000 users Very rarely: hyperglycemia, tremor, Stevens-Johnson syndrome - in 1 in 100,000

users

Dose

Hypertension or angina: 2.5 or 10 mg once daily (initial treatment can start as low as 2.5 mg per day).

[edit] Salts

In the United Kingdom tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salt. Tablets containing different salts are therefore considered interchangeable.

The efficacy and tolerability of a fixed-dose combination of amlodipine 5mg and perindopril 4mg, an angiotensin converting enzyme (ACE) inhibitor, has recently been confirmed in a prospective, observational multicenter trial 1250 hypertensive patients.[2]

[edit] Drug metabolism and excretion

Amlodipine is almost entirely metabolised to inactive metabolites. Ten per cent of the parent substance and 60% of the metabolites are excreted in urine.

[edit] Patent loss

Pfizer patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007[3]. A number of generic versions are now available.

[edit] See also

Amlodipine/benazepril Amlodipine Besylate

[edit] References

1. ̂ Source: Sandoz product information sheet2. ̂ Bahl VK, Jadhav UM, Thacker HP. Management of Hypertension with the

Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice: Results from the STRONG Prospective, Observational, Multicenter Study. American Journal of Cardiovascular Drugs May 22, 2009; 9 (3): 135-42 Link text

3. ̂ Kennedy, Val Brickates (2007-03-22). "Pfizer loses court ruling on Norvasc patent". MarketWatch. http://www.marketwatch.com/news/story/pfizer-loses-court-ruling-norvasc/story.aspx?guid=%7B9819D67E-B76B-431D-835C-FB8D6D8327B7%7D.

Felodipine

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Felodipine

Systematic (IUPAC) name

3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-

3,5-dicarboxylate

Identifiers

CAS number 72509-76-3

ATC code C08 CA02

PubChem 3333

DrugBank APRD00374

Chemical data

Formula C18H19Cl2N O 4 

Mol. mass 383.069 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability >95% [1]

Metabolism Hepatic

Half life  ??

Excretion Renal

Therapeutic considerations

Pregnancy cat.C(US)

Legal status℞ Prescription only

Routes Oral

Felodipine is a calcium channel blocker (calcium antagonist), a drug used to control hypertension (high blood pressure). It is marketed with the brand name Plendil by AstraZeneca. The formulation patent for the substance expired in 2007.

AstraZeneca dropped Plendil from its support and AZ&Me free Rx access program in October 2008.

[edit] Interactions

Recent findings have suggested that felodipine in combination with grapefruit juice can cause toxic effects. Oral administration of felodipine is first metabolized in the gastrointestinal tract and liver by the enzyme CYP3A4. Grapefruit juice contains bergamottin which is found to have an inhibiting effect over this enzyme and as a result the bioavailability of the drug increases, raising the risk for abnormal side effects. [2]

[edit] References

1. ̂ Blychert E. (1992). "Felodipine pharmacokinetics and plasma concentration vs effect relationships". Blood Press Suppl. 2: 1–30.

2. ̂ Jawad Kiani, Sardar Z Imam (October 30 2007). "Medicinal importance of grapefruit juice and its interaction with various drugs". Nutr J. 6 (33): 33. doi:10.1186/1475-2891-6-33. PMID 17971226. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2147024. Retrieved 2008-04-09.

Nicardipine

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Nicardipine

Systematic (IUPAC) name

2-[benzyl(methyl)amino]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-

dihydropyridine-3,5-dicarboxylate

Identifiers

CAS number 55985-32-5

ATC code C08 CA04

PubChem 4474

DrugBank APRD00088

Chemical data

Formula C26H29N3O6 

Mol. mass 479.525 g/mol

Physical data

Melt. point 6 °C (43 °F)

Pharmacokinetic data

Bioavailability  ?

Protein binding >95%

Metabolism  ?

Half life 8.6 hours

Excretion  ?

Therapeutic considerations

Pregnancy cat.?

Legal status

Routes  ?

Nicardipine hydrochloride (Cardene) is a medication used to treat high blood pressure and angina. It belongs to the class of calcium channel blockers.

Nicardipine is a dihydropyridine calcium-channel blocking agent used for the treatment of vascular disorders such as chronic stable angina, hypertension, and Raynaud's phenomenon. It is available in oral and intravenous formulations. Its mechanism of action and clinical effects closely resemble those of nifedipine and the other dihydropyridines (amlodipine, felodipine), except that nicardipine is more selective for cerebral and coronary blood vessels. Furthermore, nicardipine does not intrinsically decrease myocardial contractility and may be useful in the management of congestive heart failure. Nicardipine also has a longer half-life than nifedipine. Nicardipine was approved by the FDA in December 1988. The patent for both Cardene and Cardene SR expired in October 1995.

It has been used in percutaneous coronary intervention.[1]

Nicardipine must be used with caution in patients with renal failure because of possible kidney shutdown

[edit] References

1. ̂ Huang RI, Patel P, Walinsky P, et al. (November 2006). "Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention". Catheter Cardiovasc Interv 68 (5): 671–6. doi:10.1002/ccd.20885. PMID 17034064. http://dx.doi.org/10.1002/ccd.20885.

Nifedipine

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Nifedipine

Systematic (IUPAC) name

3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-

dicarboxylate

Identifiers

CAS number 21829-25-4

ATC code C08 CA05

PubChem 4485

DrugBank APRD00590

ChemSpider 4330

Chemical data

Formula C17H18N2O6 

Mol. mass 346.335 g/mol

Physical data

Melt. point 173 °C (343 °F)

Pharmacokinetic data

Bioavailability 45-56%

Protein binding 92-98%

Metabolism Gastrointestinal, Hepatic

Half life 2 hours

Excretion Renal: >50%, Biliary: 5-15%

Therapeutic considerations

Pregnancy cat.C: (USA)

Legal status

Routes Oral

Nifedipine (brand name Adalat, Nifedical, and Procardia) is a dihydropyridine calcium channel blocker. Its main uses are as an antianginal (especially in Prinzmetal's angina) and antihypertensive, although a large number of other uses have recently been found for this agent, such as Raynaud's phenomenon, premature labor, and painful spasms of the esophagus in cancer and tetanus patients. It is also commonly used for the small subset of pulmonary hypertension patients whose symptoms respond to calcium channel blockers.

Dosing

Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine (such as Adalat OROS). A more novel release system is GITS (Gastro-Intestinal Therapeutic System), which - according to Bayer - provides 24-hour continuous release through an osmotic push system. Recent trials with GITS include INSIGHT (for blood pressure)[1] and ACTION (for angina).[2]

Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the lowering of CYP3A4 activity.[3]

Uses

Approved uses

The approved uses for nifedipine are the long-term treatment of hypertension (high blood pressure) and angina pectoris. In hypertension, recent clinical guidelines generally favour diuretics and ACE inhibitors, although calcium channel antagonists are still favoured as primary treatment for older black patients.[4]

Sublingual nifedipine has previously been used in hypertensive emergencies. This was found to be dangerous, and has been abandoned. Sublingual nifedipine causes blood-

pressure lowering through peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, the FDA reviewed all data regarding the safety and efficacy of sublingual nifedipine for hypertensive emergencies in 1995, and concluded that the practice should be abandoned because it was neither safe nor efficacious. [5][6]

Off-label uses

Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it is comparable with magnesium sulfate and beta-agonists (such as ritodrine) with fewer side-effects.[7] Its role vis à vis atosiban is not established.

Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.[8]

Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures.[9]

Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema.[10]

Oral nifedipine has also been found to cause iron loss in the urine of small animals.[11] A NIH NIDDK study[12] is currently seeing if the drug can increase the removal of iron into the urine in humans as well, thus becoming a possible treatment for iron overload.

History

Nifedipine (initially BAY a1040) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s.[13]

The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine.[14] This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctations in blood pressure) and at high doses of 80 mg a day and more.[15]

References

1. ̂ Brown MJ, Palmer CR, Castaigne A, et al. (2000). "Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT)". Lancet 356 (9227): 366–72. doi:10.1016/S0140-6736(00)02527-7. PMID 10972368.

2. ̂ Poole-Wilson PA, Kirwan BA, Vokó Z, de Brouwer S, van Dalen FJ, Lubsen J (2006). "Safety of nifedipine GITS in stable angina: the ACTION trial". Cardiovas Drugs Ther 20 (1): 45–54. doi:10.1007/s10557-006-6312-4. PMID 16552473.

3. ̂ Odou P, Ferrari N, Barthélémy C, et al. (2005). "Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms". Journal Clinical Pharm Ther 30 (2): 153–8. doi:10.1111/j.1365-2710.2004.00618.x. PMID 15811168.

4. ̂ Hypertension: management of hypertension in adults in primary care. Clinical guideline CG34. National Institute for Health and Clinical Excellence (NICE), June 2006. Fulltext index. ISBN 1-86016-285-1.

5. ̂ Grossman E, Messerli FH, Grodzicki T, Kowey P (1996). "Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies?". JAMA 276 (16): 1328–31. doi:10.1001/jama.276.16.1328. PMID 8861992.

6. ̂ Varon J, Marik PE (2003). "Clinical review: the management of hypertensive crises". Critical care (London, England) 7 (5): 374–84. doi:10.1186/cc2351. PMID 12974970.

7. ̂ King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B (2003). "Calcium channel blockers for inhibiting preterm labour". Cochrane database of systematic reviews (Online) (1): CD002255. doi:10.1002/14651858.CD002255. PMID 12535434.

8. ̂ Thompson AE, Pope JE (2005). "Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis". Rheumatology (Oxford, England) 44 (2): 145–50. doi:10.1093/rheumatology/keh390. PMID 15546967.

9. ̂ Ezri T, Susmallian S (2003). "Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure". Dis. Colon Rectum 46 (6): 805–8.

Nisoldipine

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Nisoldipine

Systematic (IUPAC) name

isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Identifiers

CAS number 63675-72-9

ATC code C08 CA07

PubChem 4499

DrugBank APRD00635

Chemical data

Formula C20H24N2O6 

Mol. mass 388.414 g/mol

Pharmacokinetic data

Bioavailability  ?

Protein binding 99%

Metabolism  ?

Half life 7-12 hours

Excretion  ?

Therapeutic considerations

Pregnancy cat.C(US)

Legal status℞ -only (US)

Verapamil

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Verapamil

Systematic (IUPAC) name

(RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-dimethoxyphenyl)ethyl]-

(methyl)amino]-2-isopropylpentanenitrile

Identifiers

CAS number 52-53-9

ATC code C08 DA01

PubChem 2520

DrugBank APRD00335

ChemSpider 2425

Chemical data

Formula C27H38N2O4 

Mol. mass 454.602 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 35.1%

Metabolism Hepatic

Half life 2.8-7.4 hours

Excretion Renal: 11%

Therapeutic considerations

Pregnancy cat.C(US)

Legal status℞ Prescription only

Routes Oral, Intravenous

Verapamil (brand names: Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS) is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches.[1] It is also an effective preventive medication for migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class 4 antiarrhythmic, more effective than digoxin in controlling ventricular rate, and was approved by the United States Food and Drug Administration in 1981.

Mechanism and uses

Verapamil's mechanism in all cases is to block voltage-dependent calcium channels.

In cardiac pharmacology, calcium channel blockers are considered class IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrio-ventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias.

Calcium channels are also present in the smooth muscle that lines blood vessels. By relaxing the tone of this smooth muscle, calcium-channel blockers dilate the blood vessels. This has led to their use in treating hypertension and angina pectoris.

The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts.

Pharmacokinetic details

Given orally, 90–100% of Verapamil is absorbed, but due to high first-pass metabolism, bioavailability is much lower (10–35%). It is 90% bound to plasma proteins and has a volume of distribution of 3–5 L/kg−1. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a non-linear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis.

Verapamil has been reported to be effective in both short-term[2] and long-term treatment of mania and hypomania.[3] Addition of magnesium oxide to the verapamil treatment

protocol enhances the antimanic effect.[4] It has on occasion been used to control mania in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium (which has a small but significant incidence of causing cardiac malformation), Verapamil is usable as an alternative, albeit presumably a less effective one.

Side effects

Some possible side effects of the drug are headaches, facial flushing, dizziness, swelling, increased urination, fatigue, nausea, ecchymosis, lightheadedness, and constipation.

[edit] Uses in cell biology

Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein.[5] This is useful as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It's also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorochromes such as Hoechst 33342.

Veterinary use

Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given post-operatively in rabbits who have suffered trauma to abdominal organs to prevent formation of these intra-abdominal adhesions.

Potential Use in the Treatment of Malaria

Recent resistance to the anti-malarial drug chloroquine has hindered the treatment of malaria in Southeast Asia, South America and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. It has been shown that verapamil, when used in combination with chloroquine, enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.[6][7]

References

1. ̂ Ellen Beck; William J. Sieber; Raul Trejo (2005). "Management of Cluster Headaches". American Family Physician 71 (4): 717–724. http://www.aafp.org/afp/20050215/717.html.

2. ̂ AJ Giannini, J Houser, MC Giannini, RH Loiselle (01 Dec 1984). "Antimanic effects of verapamil". American Journal of Psychiatry 141 (12): 1602–1605. PMID 6439057. http://ajp.psychiatryonline.org/cgi/content/abstract/141/12/1602.

3. ̂ AJ Giannini, RS Taraszewski, RH Loiselle (01 Dec 1987). "Verapamil and lithium in maintenance therapy of manic patients". Journal of Clinical Pharmacology 27 (12): 980–986. PMID 3325531. http://jcp.sagepub.com/cgi/content/abstract/27/12/980.

4. ̂ AJ Giannini, AM Nakoneczie, SM Melemis, J Ventresco, M Condon (2000). "Magnesium oxide augmentation of verapamil maintenance therapy in mania". Psychiatry Research 93: 83–87. doi:10.1016/S0165-1781(99)00116-X.

5. ̂ Bellamy WT. (1996). "P-glycoproteins and multidrug resistance". Annu Rev Pharmacol Toxicol 36: 161–83. doi:10.1146/annurev.pa.36.040196.001113. PMID 8725386.

6. ̂ Martin, S. K., A. M. Oduola, and W. K. Milhous (1987). "Reversal of chloroquine resistance in Plasmodium falciparum by verapamil". Science 235: 899–901. doi:10.1126/science.3544220. PMID 3544220.

7. ̂ Krogstad, D.J., et al (1987). "Efflux of Chloroquine from Plasmodium falciparum: Mechanism of Chloroquine Resistance". Science 238: 1283. doi:10.1126/science.

Diltiazem

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Diltiazem

Systematic (IUPAC) name

cis-(+)-[2-(2-dimethylaminoethyl)-5-(4-methoxyphenyl)

-3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9,

11-trien-4-yl]ethanoate

Identifiers

CAS number 42399-41-7

ATC code C08 DB01

PubChem 39186

DrugBank APRD00473

ChemSpider 35850

Chemical data

Formula C22H26N2O4S 

Mol. mass 414.519 g/mol

Pharmacokinetic data

Bioavailability 40%

Metabolism Hepatic

Half life 3-4.5 hours

Excretion Renal

Biliary

Lactic (in lactiferous females)

Therapeutic considerations

Pregnancy cat.D: (USA)

Legal status

Routes Oral

Diltiazem is a member of the group of drugs known as benzothiazepines, which are a class of calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia. It is also an effective preventive medication for migraine. It is a class 3 anti-anginal drug, and a class IV antiarrhythmic. It incites very minimal reflex sympathetic changes. It is based upon a 1,4-thiazepine ring.

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.

Contents

[hide] 1 Brand names 2 Mechanism 3 Nontherapeutic effects and toxicities 4 Indications 5 Contraindications and precautions 6 Drug interactions 7 Potential future indications

8 References

[edit] Brand names

Progor Herben Altiazem Cardizem Cartia XT Tiazac Tiazac XC Tiamate Tildiem in particular in Europe Adizem Viazem Dilatam Dilzem Angiozem Dilatem Dilcardia

Diltelan Diltime Dyalec Filazem Tildiem Vasmulax Zandil Zemtrial Angizem CD Angizem Dilcontin SR in India (Sustained Release) Dilt-CD Dilt-XR

[edit] Mechanism

Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. Its pharmacological activity is somewhat similar to verapamil.[1]

Potent vasodilator of coronary vessels.

Vasodilator of peripheral vessels. This reduces peripheral resistance and afterload.

Negative inotropic effect. Diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption.

Negative chronotropic effect. Diltiazem causes a modest lowering of heart rate. This effect is due to slowing of the SA (sinoatrial) node. It results in reduced myocardium oxygen consumption.

Negative dromotropic effect. By slowing conduction through the AV (atrioventricular) node, diltiazem increases the time needed for each beat. This results in reduced myocardium oxygen consumption by the body.

[edit] Nontherapeutic effects and toxicities

Reflex sympathetic response. Caused by the peripheral dilation of vessels and the resulting drop in BP; the response works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Symptoms include hypotension, bradycardia, dizziness, flushing.[2]

[edit] Indications

Angina:

Stable angina (exercise-induced) . Diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.[3][4]

Variant angina . Diltiazem is effective due to its direct effects on coronary dilation.

Unstable angina (preinfarction, crescendo). Diltiazem may be particularly effective if the underlying mechanism is vasospasm.

Supraventricular tachycardias. Diltiazem appears to be as effective as verapamil in treating reentrant supraventricular tachycardia.[5]

Atrial fibrillation [6] or atrial flutter.

Hypertension. Because of its vasodilatory effects, diltiazem is useful for treating hypertension. Calcium channel blockers are well-tolerated, and especially effective in treating low-renin hypertension.[7]

[edit] Contraindications and precautions

CHF. Patients with reduced ventricular function may not be able to counteract the inotropic and chronotropic effects of diltiazem, the result being an even higher compromise of function.

SA node or AV conduction disturbances. Use of diltiazem should be avoided in patients with SA or AV nodal abnormalities, because of its negative chronotropic and dromotropic effects Low blood pressure. Patients with systolic blood pressures below 90 mm Hg should not be treated with diltiazem.

Wolff-Parkinson-White syndrome. Diltiazem may paradoxically increase ventricular rate in patients with WPW syndrome because of accessory conduction pathways.

Diltiazem is relatively contraindicated in the presence of sick sinus syndrome, atrioventricular node conduction disturbances, bradycardia, impaired left ventricle function, peripheral artery occlusive disease, chronic obstructive pulmonary disease, and Prinzmetal's angina.

[edit] Drug interactions

Beta-blockers

Intravenous diltiazem should be used with caution with beta-blockers, because while the combination is most therauputically beneficial, there are rare instances of dysrhythmia and AV node block [8].

Quinidine

Quinidine should not be used concurrently with calcium channel blockers because of reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes.

Miscellaneous

Inhibition of hepatic enzymes. Diltiazem and verapamil inhibit hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, possibly resulting in drug interactions.

[edit] Potential future indications

Recent research has shown that diltiazem is able to reduce cocaine cravings in drug-addicted rats.[1] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signalling in the brain.[9] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[10] and reduces the development of tolerance.[11]

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with equal effectiveness. When applied topically, it is made into a cream form using either vaseline or Phlogel. Phlogel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates. [12][13] Like all non-surgical treatments of anal fissure it does not address the long term problem of increased basal anal tone and does not decrease the subsequent recurrence rate that can vary between 40 to 60%.

[edit] References

1. ̂ O'Connor SE, Grosset A, Janiak P. The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem. Fundamental and Clinical Pharmacology. 1999;13(2):145-53. PMID 10226758

2. ̂ Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Annals of Emergency Medicine. 1993 Feb;22(2):196-200. PMID 8427431

3. ̂ Grossman E, Messerli FH. Calcium antagonists. Progress in Cardiovascular Disease. 2004 Jul-Aug;47(1):34-57. PMID 15517514

4. ̂ Claas SA, Glasser SP. Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris. Expert Opinion on Pharmacotherapy. 2005 May;6(5):765-76. PMID 15934903

5. ̂ Gabrielli A, Gallagher TJ, Caruso LJ, Bennett NT, Layon AJ. Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience. Critical Care Medicine. 2001 Oct;29(10):1874-9. PMID 11588443

6. ̂ Wattanasuwan N, Khan IA, Mehta NJ, et al. (February 2001). "Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and

digoxin vs. IV diltiazem alone". Chest 119 (2): 502–6. PMID 11171729. http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11171729.

7. ̂ Basile J. The role of existing and newer calcium channel blockers in the treatment of hypertension. Journal of Clinical Hypertension. 2004 Nov;6(11):621-29. PMID 15538095

8. ̂ http://www.ncbi.nlm.nih.gov/pubmed/107747859. ̂ Mills K, Ansah TA, Ali SF, Mukherjee S, Shockley DC. Augmented behavioral

response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers. Life Sciences. 2007 Jul 26;81(7):600-8. PMID 17689567

10. ̂ Kishioka S, Ko MC, Woods JH. Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys. European Journal of Pharmacology. 2000 May 26;397(1):85-92. PMID 10844102

11. ̂ Verma V, Mediratta PK, Sharma KK. Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers. Indian Journal of Experimental Biology. 2001 Jul;39(7):636-42. PMID 12019755

12. ̂ Nash GF, Kapoor K, Saeb-Parsy K, Kunanadam T, Dawson PM. The long-term results of diltiazem treatment for anal fissure. International Journal of Clinical Practice. 2006 Nov;60(11):1411-3. PMID 16911570

13. ̂ Sajid MS, Rimple J, Cheek E, Baig MK. The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis. International Journal of Colorectal Disease. 2008 Jan;23(1):1-6. PMID 17846781

Amrinone

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Amrinone

Systematic (IUPAC) name

5-amino-3,4'-bipyridin-6(1H)-one

Identifiers

CAS number 60719-84-8

ATC code C01 CE01

PubChem 3698

Chemical data

Formula C10H9N3O 

Mol. mass 187.198 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability n/a

Protein binding 10 to 49%

Metabolism Hepatic

Half life 5 to 8 hours

Excretion Renal (63%) and fecal (18%)

Therapeutic considerations

Pregnancy cat.C(US)

Legal status℞ -only (US)

Routes Intravenous

Amrinone (INN) or inamrinone (USAN, changed in 2000 to prevent confusion with amiodarone [1] ), trade name Inocor, is a type 3 pyridine phosphodiesterase inhibitor.[2]

Contents

[hide] 1 Uses 2 Actions 3 Indications 4 Contraindications 5 Precautions 6 Side effects 7 Routes 8 Pediatric dosage

9 References

[edit] Uses

It is used in the treatment of congestive heart failure.

It has been studied for use before coronary artery bypass surgery.[3]

[edit] Actions

Increases cardiac contractility, vasodilator. Acts by inhibiting the breakdown of both cAMP and cGMP by phosphodiesterase (PDE III) inhibitor

[edit] Indications

Short-term management of severe CHF (not used long term because of increased mortality, probably due to heart failure)

[edit] Contraindications

Patients with history of hypersensitivity to the drug

[edit] Precautions

May increase myocardial ischemia. Blood pressure, pulse, and EKG should be constantly monitored. Amrinone should only be diluted with normal saline or 1/2 normal saline; no dextrose solutions should be used. Furosemide should not be administered into an IV line delivering Amrinone.

[edit] Side effects

Thrombocytopenia, hepatotoxicity, arrhythmia, nausea, & vomiting

[edit] Routes

IV bolus and infusion as described earlier

[edit] Pediatric dosage

Safety in children has not been established

[edit] References

1. ̂ "Amrinone Becomes Inamrinone". USP Quality Review (United States Pharmacopeia) 73. March 2000. http://www.usp.org/hqi/practitionerPrograms/newsletters/qualityReview/qr732000-03-01.html.

2. ̂ Hamada Y, Kawachi K, Yamamoto T, et al. (August 1999). "Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone". Japanese circulation journal 63 (8): 605–9. PMID 10478810. http://joi.jlc.jst.go.jp/JST.JSTAGE/jcj/63.605?from=PubMed.

3. ̂ Kikura M, Sato S (January 2002). "The efficacy of preemptive Milrinone or Amrinone therapy in patients undergoing coronary artery bypass grafting". Anesth. Analg. 94 (1): 22–30, table of contents. PMID 11772795. http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=11772795.

Cinnarizine

Cinnarizine

Systematic (IUPAC) name

1-benzhydryl-4-cinnamyl-piperazine

Identifiers

CAS number 298-57-7

ATC code N07 CA02

PubChem 2761

DrugBank APRD00332

Chemical data

Formula C26H28N2 

Mol. mass 368.514 g/mol

Pharmacokinetic data

Bioavailability  ?

Metabolism  ?

Half life 3..4h

Excretion  ?

Therapeutic considerations

Pregnancy cat.?

Legal status

Routes  ?

Cinnarizine is an anti-histaminic drug which is mainly used for the control of vomiting due to motion sickness. It is marketed under the brand Stugeron or Stunarone. Cinnarizine was first synthesized by Janssen Pharmaceutica in 1955. It is not available in the United States or Canada.

It acts by interfering with the signal transmission between vestibular apparatus of the inner ear and the vomiting centre of the hypothalamus. The disparity of signal processing between inner ear motion receptors and the visual senses is abolished, so that the

confusion of brain whether the individual is moving or standing is reduced. Vomiting in motion sickness is actually a physiological compensatory mechanism of the brain to keep the individual from moving so that it can adjust to the signal perception.[citation needed]

Cinnarizine could be also viewed as a nootropic drug because of its vasorelaxating abilities (due to calcium channel blockage), which happen mostly in brain. It is also effectively combined with other nootropics, primarily piracetam; in such combination each drug potentiate the other in boosting brain oxygen supply.[citation needed]

Cinnarizine can be used in scuba divers without an increased risk of central nervous system oxygen toxicity.[1]

[edit] References

1. ̂ Arieli R, Shupak A, Shachal B, Shenedrey A, Ertracht O, Rashkovan G (1999). "Effect of the anti-motion-sickness medication cinnarizine on central nervous system oxygen toxicity". Undersea and Hyperbaric Medicine 26 (2): 105–9. PMID 10372430. http://archive.rubicon-foundation.org/2307. Retrieved 2009-03-30.

Barrett RJ, Zolov B (December 1960). "A clinical evaluation of cinnarizine (Mitronal) in various allergic disorders". J Maine Med Assoc 51: 454–7. PMID 13687289.

Towse G (September 1980). "Cinnarizine--a labyrinthine sedative". J Laryngol Otol 94 (9): 1009–15. doi:10.1017/S0022215100089787. PMID 7000939.

Fasudil

Fasudil

Systematic (IUPAC) name

5-(1,4-diazepane-1-sulfonyl)isoquinoline

Identifiers

CAS number 103745-39-7

ATC code C04 AX32

PubChem 3547

Chemical data

Formula C14H17N3O2S 

Mol. mass 291.36 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability well absorbed

Metabolism metabolized quickly to hydroxyfasudil

Half life 0.76 hours. Active metabolite

(hydroxyfasudil) 4.66 hours.

Excretion  ?

Fasudil Hydrochloride (INN) is a potent Rho-kinase inhibitor and vasodilator[1]. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage,[2] as well as to improve the cognitive decline seen in stroke victims. It has been found to be effective for the treatment of pulmonary hypertension. [3] It was demonstrated in February of 2009 that Fasudil could also be used to enhance memory and improve the prognosis of Alzheimers patients.[4]

Pregabalin

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Pregabalin

Systematic (IUPAC) name

(S)-3-(aminomethyl)-5-methylhexanoic acid

Identifiers

CAS number 148553-50-8

ATC code N03 AX16

PubChem 5486971

DrugBank APRD01198

ChemSpider 4589156

Chemical data

Formula C8H17N O 2 

Mol. mass 159.23 g.mol-1

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability ≥90%

Protein binding Nil

Metabolism Negligible

Half life 5–6.5 hours

Excretion Renal

Therapeutic considerations

Licence dataUS   Daily   Med :link

Pregnancy cat.B3 (Au), C (U.S.)

Legal statusS4 (Au), POM (UK), Schedule V (U.S.)

Routes Oral(main), IV, Insufflation

  (what is this?)  (verify)

Pregabalin (INN) (pronounced /pr ɨˈɡ æbəl ɨ n/ ) is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults.[1] It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union.[1] It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica.

Recent studies have shown that pregabalin is effective at treating chronic pain in disorders such as fibromyalgia [2] and spinal cord injury.[3] In June 2007, pregabalin became the first medication approved by the U.S. Food and Drug Administration specifically for the treatment of fibromyalgia.[4]

It is considered to have a low potential for abuse, and a limited dependence liability if misused, and is thus classified as a Schedule V drug in the U.S.[5] Especially in higher doses, pregabalin acts as a GABA agonist[citation needed], similar to other CNS depressants such as benzodiazepines (diazepam & triazolam), barbiturates(phenobarbital & butalbital) & others(eszopiclone & carisoprodol).

Lyrica is one of four drugs which a subsidiary of Pfizer in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer illegally promoted the drugs and caused false claims to be submitted to government healthcare programmes for uses that were not medically accepted.[6]

Contents

[hide] 1 History 2 Indications 3 Adverse effects 4 Pharmacology

o 4.1 Pharmacodynamics o 4.2 Pharmacokinetics

5 Drug interactions 6 Abuse 7 References

8 External links

[edit] History

Pregabalin was initially developed by medicinal chemist Richard Bruce Silverman at Northwestern University in the United States. The drug was approved in the European Union in 2004. Pregabalin received U.S. Food and Drug Administration (FDA) approval for use in treating epilepsy, diabetic neuropathy pain, and post-herpetic neuralgia in December 2004, and appeared on the U.S. market in fall 2005.[7]

In June 2007, the FDA approved Lyrica as a treatment for fibromyalgia. It was the first drug to be approved for this indication and remained the only one, until duloxetine (Cymbalta) gained FDA approval for the treatment of fibromyalgia in June 2008.[citation

needed]

[edit] Indications

Pregabalin is indicated for:

Treatment of neuropathic pain from diabetic neuropathy or post herpetic neuralgia. There is not enough data to state that it should be used in all neuropathic pain.

Adjunctive therapy in adults with partial seizures with or without secondary generalization

Fibromyalgia Generalized anxiety disorder (approved in the European Union).[8]

[edit] Adverse effects

Adverse drug reactions associated with the use of pregabalin include:[9][10]

Very common (>10% of patients): dizziness, drowsiness Common (1–10% of patients): visual disturbance (including blurred vision,

diplopia), ataxia, dysarthria, tremor, lethargy, memory impairment, euphoria, constipation, dry mouth, peripheral edema, loss or decrease of libido, erectile dysfunction, weight gain

Infrequent (0.1–1% of patients): depression, confusion, agitation, hallucinations, myoclonus, hypoaesthesia, hyperaesthesia, tachycardia, excessive salivation, sweating, flushing, rash, muscle cramp, myalgia, arthralgia, urinary incontinence, dysuria, thrombocytopenia, kidney calculus

Rare (<0.1% of patients): neutropenia, first degree heart block, hypotension, hypertension, pancreatitis, dysphagia, oliguria, rhabdomyolysis, suicide.[11]

Pregabalin may also cause dependency and withdrawal effects may occur after long-term use. When prescribed for seizures, quitting "cold turkey" can increase the strength of the seizures and possibly cause the seizures to reoccur. Withdrawal symptoms include restlessness, insomnia, and anxiety. Withdrawal symptoms are similar to benzodiazepine withdrawal but the severity of the withdrawal depends on how much pregabalin has been

taken and how long it has been taken. Pregabalin should be reduced gradually when finishing treatment.[citation needed]

[edit] Pharmacology

[edit] Pharmacodynamics

Like gabapentin, pregabalin binds to the α2δ (alpha2delta) subunit of the voltage-dependent calcium channel in the central nervous system. This reduces calcium influx into the nerve terminals. Pregabalin also decreases the release of neurotransmitters such as glutamate, noradrenaline, and substance P (Australian Medicines Handbook). Pregabalin increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity.[citation needed] Glutamic acid decarboxylase (GAD) is the enzyme that converts the excitatory neurotransmitter glutamate into the inhibitory GABA in a single step. For this reason, pregabalin greatly potentiates benzodiazepines, barbiturates & other depressants.

[edit] Pharmacokinetics

Absorption: Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within one hour. Pregabalin oral bioavailability is estimated to be greater than or equal to 90% and is independent of dose. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25 to 30% and a delay in Tmax to approximately 2.5 hours. Administration with food, though, has no clinically significant effect on the extent of absorption.[12]

Distribution: Pregabalin has been shown to cross the blood-brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the volume of distribution of pregabalin for an orally administered dose is approximately 0.56 L/kg and is not bound to plasma proteins.[12]

Metabolism: Pregabalin undergoes negligible metabolism in humans.[13] Approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methy pregabalin is the major metabolite.[12]

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.[12] Renal clearance of pregabalin is 73 mL/minute.[verification

needed]

[edit] Drug interactions

No pharmacokinetic interactions have been demonstrated in vivo. The manufacturer notes some potential pharmacological interactions with opioids (pregabalin is synergistic with

opioids in lower doses), benzodiazepines, barbiturates, ethanol(alcohol), and other drugs that depress the central nervous system.[9]

[edit] Abuse

Pregabalin is a Schedule V drug, classified as a CNS depressant. The potential for abuse of pregabalin is significantly less than the potential with benzodiazepines.[14]

[edit] References

1. ^ a b Benkert, O., Hippius, H. et al.: Kompendium der Psychiatrischen Pharmakotherapie, 6. Auflage, Springer Medizin Verlag, Heidelberg, 2007. (german) ISBN 9783540344018

2. ̂ Crofford LJ, Rowbotham MC, Mease PJ, et al. (2005). "Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial". Arthritis Rheum 52 (4): 1264–73. doi:10.1002/art.20983. PMID 15818684. Free full text

3. ̂ Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK (2006). "Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial". Neurology 67 (10): 1792–800. doi:10.1212/01.wnl.0000244422.45278.ff. PMID 17130411.

4. ̂ U.S. Food and Drug Administration (June 21, 2007). "FDA Approves First Drug for Treating Fibromyalgia". Press release. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01656.html. Retrieved 2008-01-14.

5. ̂ Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of pregabalin into schedule V. Final rule. Fed Regist 2005;70(144):43633-5. PMID 16050051

6. ̂ Pfizer agrees record fraud fine7. ̂ Dworkin RH, Kirkpatrick P (June 2005). "Pregabalin" (PDF on free subscription).

Nature Reviews Drug Discovery 4: 455-6. doi:10.1038/nrd1756. http://www.nature.com/nrd/journal/v4/n6/pdf/nrd1756.pdf.

8. ̂ "Pfizer's Lyrica Approved for the Treatment of Generalized Anxiety Disorder (GAD) in Europe". Press release. http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/03-27-2006/0004327379. Retrieved 2007-07-04.

9. ^ a b Pfizer Australia Pty Ltd. Lyrica (Australian Approved Product Information). West Ryde: Pfizer; 2006.

10. ̂ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

11. ̂ Medication Guide12. ^ a b c d "Summary of product characteristics". European Medicines Agency. 19

August 2009. http://www.emea.europa.eu/humandocs/PDFs/EPAR/lyrica/emea-combined-h546en.pdf. Retrieved 8 September 2009.

13. ̂ Susan L. McElroy,. Antiepileptic Drugs to Treat Psychiatric Disorders. p. 370.}

Risedronic acid

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Risedronic acid

Systematic (IUPAC) name

(1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonic acid

Identifiers

CAS number 105462-24-6

ATC code M05 BA07

PubChem 5245

DrugBank APRD00410

Chemical data

Formula C7H11N O 7P2 

Mol. mass 283.112 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 0.63%

Protein binding ~24%

Metabolism None

Half life 1.5 hours

Excretion Renal and fecal

Therapeutic considerations

Pregnancy cat.B3(AU) C(US)

Legal statusPOM(UK) ℞ -only (US)

Routes Oral

Risedronic acid (INN) or risedronate sodium (USAN, trade name Actonel) is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Procter & Gamble and Sanofi-Aventis.

[edit] Administration

Risedronate is taken orally, usually 5 mg daily or 35 mg weekly. Notably, if risedronate lodges in the esophagus, it can lead to esophageal ulcers. Therefore, it is recommended that risedronate be taken with the body upright, and followed by a glass of water. Moreover, risedronate is poorly absorbed when taken with food, so it is recommended that no food or drink other than water be taken for 2 hours before and 30 minutes after taking risedronate. Risedronate has a faster esophageal transit time and different chemical chain which results in less gastrointestinal side-effects than other drugs in this class. The dosage instructions also show that risedronate can be taken with less water than other drugs in the class.

[edit] Controversies

In January 2006 P&G and its marketing partner Sanofi-Aventis filed a Lanham Act false claims lawsuit against rival drugmakers Roche and GlaxoSmithKline claiming false advertising about Boniva.[1] The manufacturers of Boniva, a rival bisphosphonate, were accused in the suit of causing a "serious public health risk" through misrepresentation of scientific findings. In a ruling on September 7 2006 U.S. District Judge Paul A. Crotty rejected P&G's attempted injunction. P&G was criticized for attempting to "preserve its market share by denigrating Boniva". Judge Crotty wrote that "Roche was clearly entitled to respond with its own data, provided that the data was truthfully and accurately presented".[2]

In 2006 P&G faced controversy over its handling of clinical research involving risedronate (News Reports and discussion).

In common with other bisphosphonate drugs, risedronate appears to be associated with the rare side effect osteonecrosis of the jaw, often preceded by dental procedures inducing trauma to the bone.

Bosentan

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Bosentan

Systematic (IUPAC) name

4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-

yl)pyrimidin-4-yl]benzene-1-sulfonamide

Identifiers

CAS number 147536-97-8

ATC code C02 KX01

PubChem 104865

DrugBank APRD00829

Chemical data

Formula C27H29N5O6S 

Mol. mass 551.614 g/mol

SMILESeMolecules &

PubChem

Pharmacokinetic data

Bioavailability 50%

Protein binding >98%

Metabolism Hepatic

Half life 5 hours

Excretion  ?

Therapeutic considerations

Pregnancy cat.X

Legal status℞ Prescription only

Routes Oral

Bosentan (BOZENTAN) is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer.

Mechanism of action

Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, bosentan decreases pulmonary vascular resistance. Bosentan has a slightly higher affinity for ET-A than ET-B.

[edit] Clinical uses

Bosentan is indicated mainly for the treatment of pulmonary hypertension. In 2007, Tracleer (bosentan) was approved in the European Union also for reducing the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.

In the United States, Tracleer® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class II-IV symptoms, to improve exerciseability and decrease the rate of clinical worsening. [1]

Methyldopa

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Methyldopa

Systematic (IUPAC) name

(S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid

Identifiers

CAS number 555-30-6

ATC code C02 AB01

PubChem 4138

DrugBank APRD01106

Chemical data

Formula C10H13N O 4 

Mol. mass 211.215 g/mol

Pharmacokinetic data

Bioavailability approximately 50%

Metabolism Hepatic

Half life 105 minutes

Excretion Renal for metabolites

Therapeutic considerations

Pregnancy cat.a drug of choice in PIH

Legal status℞ Prescription only

Routes Oral, IV

Methyldopa (L-α-Methyl-3,4-dihydroxyphenylalanine; Aldomet, Aldoril, Dopamet, Dopegyt, etc) is a psychoactive drug used as a sympatholytic or antihypertensive. Its use is now deprecated following introduction of alternative safer classes of agents. However,

it continues to have a role in otherwise difficult to treat hypertension and gestational hypertension (also known as as pregnancy-induced hypertension (PIH)).

Contents

[hide] 1 Indications 2 Pharmacology 3 Pharmacokinetics 4 History 5 Side Effects

o 5.1 Rebound / Withdrawal 6 See Also

7 References

[edit] Indications

Methyldopa is used in the clinical treatment of the following disorders:

High blood pressure (HBP) or hypertension (HTN) Preeclampsia and eclampsia or hypertensive disorder of pregnancy (HDP) Gestational hypertension (GH) or pregnancy-induced hypertension (PIH)

[edit] Pharmacology

Methyldopa has a dual mechanism of action:

It acts as a DOPA decarboxylase inhibitor (DDCI) or inhibitor of the enzyme DOPA decarboxylase (DDC), also known as aromatic L -amino acid decarboxylase (AAAD), which uses the precursor L -DOPA (Levodopa) to produce the neurotransmitter dopamine, as well as norepinephrine (noradrenaline) and epinephrine (adrenaline). This action results in reduced dopaminergic and adrenergic neurotransmission in the peripheral nervous system (PNS) which causes therapeutic benefits like hypotension, though also the central nervous system (CNS) which induces adverse side effects such as depression, anxiety, apathy, anhedonia, and parkinsonism, among others.

It is metabolized to the compound to α-methylnorepinephrine (Levonordefrin; Nordefrin), an α2-adrenergic receptor agonist. Activation of the α2-adrenergic receptor, which is located primarily as an inhibitory pre-synaptic autoreceptor and heteroreceptor, results in suppression of the sympathetic nervous system (SNS), causing therapeutic benefits like hypotension.

[edit] Pharmacokinetics

Methyldopa has variable absorption from the gastrointestinal tract (GT) of approximately 50%. It is metabolized in the liver and intestines and is excreted in urine.

[edit] History

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Nonetheless, one of methyldopa's still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

[edit] Side Effects

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.[1] Side effects may include:

Psychological o Depression and/or even suicidal ideation, as well as nightmareso Apathy and/or anhedonia, as well as dysphoriao Anxiety , especially of the social anxiety varianto Decreased alertness, awareness, and wakefulnesso Impaired attention, focus, and concentrationo Decreased desire, drive, and motivationo Fatigue or lethargy and/or malaise or lassitudeo Sedation or drowsiness and/or somnolence or sleepinesso Agitation or restlessnesso Cognitive and memory impairment o Derealization and/or depersonalization, as well as mild psychosiso Sexual dysfunction including impaired libido, desire, and drive

Physiological o Dizziness , lightheadedness, or vertigoo Miosis or pupil constrictiono Xerostomia or dry moutho Gastrointestinal disturbances such as diarrhea and/or constipationo Headache or migraineo Myalgia or muscle aches, arthralgia or joint pain, and/or paresthesia ("pins

and needles")o Restless legs syndrome (RLS)

o Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, and/or balance or postural instability

o Akathisia , ataxia, dyskinesia as well as even tardive dyskinesia, and/or dystonia

o Bell's palsy or facial paralysiso Sexual dysfunction consisting of impaired erectile dysfunction and/or

anorgasmiao Hyperprolactinemia or excess prolactin, gynecomastia ("man boobs") or

breast enlargement in males, and/or amenorrhoea or absence of menstrual cycles in females

o Bradycardia or decreased heart rateo Hypotension or decreased blood pressure (though this may also be

considered a therapeutic benefit)o Orthostatic hypotension (also known as postural hypotension)o Hepatitis , hepatotoxicity, or liver dysfunction or damageo Pancreatitis or inflammation of the pancreaso Haemolytic anaemia or deficiency in red blood cells (RBCs)o Myelotoxicity or bone marrow suppression, potentially leading to

thrombocytopenia or blood platelet deficiency and/or leukopenia or white blood cell (WBC) deficiency

o Hypersensitivity such as lupus erythematosus, myocarditis, and/or pericarditis

o Lichenoid reactions such as skin lesions and/or rashes

Tizanidine

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Tizanidine

Systematic (IUPAC) name

5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine

Identifiers

CAS number 51322-75-9

ATC code M03 BX02

PubChem 5487

DrugBank APRD00128

ChemSpider 5287

Chemical data

Formula C9H8Cl N 5S 

Mol. mass 253.712

SMILES eMolecules & PubChem

Synonyms4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-8-thia-7,9-

diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-amine

Pharmacokinetic data

Bioavailability  ?

Protein binding 30%

Metabolism CYP 1A2

Half life 2.54 hours

Excretion  ?

Therapeutic considerations

Pregnancy cat.?

Legal statusRx-Only, Unscheduled

Routes Oral, Intranasal, Injection

Tizanidine (brandnames Zanaflex, Sirdalud) is a drug that is used as a muscle relaxant. It is a centrally acting α-2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, spastic diplegia, back pain, or certain other injuries to the spine or central nervous system. It is also prescribed off-label for migraine headaches, as a sleep aid, and as an anticonvulsant. It is also prescribed for some symptoms of fibromyalgia [1] .

Tizanidine may cause hypotension, so caution is advised when it is used in patients who have a history of orthostatic hypotension. Use caution with this drug as it can be very strong even at the 2 mg dose. Also use caution when switching from gel cap to tablet form and vice versa.

Contents

[hide] 1 Availability 2 Side effects 3 Interactions

4 References

[edit] Availability

Tizanidine is available in tablets with "cor 138" on one side and 2 scores on the back that create an X, or R179 on one side and a single score through the middle of the back, or a white oval pill with R180 on one side and 2 scores on the back that create an X, or a round white tablet with E 44 on one side, and is double scored on the other side. It is also found as a circular white pill with the number 503 on one side and X-scored on the back[2].

Tizanidine is supplied as 2 and 4 mg tablets for oral administration, and in gel cap form in doses of 2 mg, 4 mg, and 6 mg.

The tablets are composed of the active ingredient, tizanidine hydrochloride (2.288 mg equivalent to 2 mg tizanidine base and 4.576 mg equivalent to 4 mg tizanidine base), and the inactive ingredients, silicon dioxide colloidal, stearic acid, microcrystalline cellulose and anhydrous lactose.

[edit] Side effects

Tizanidine use occasionally causes drug induced liver injury. In controlled clinical studies, approximately 5% of patients treated with Zanaflex had elevations of liver function tests (ALT, AST) to greater than 3 times the upper limit of normal (or 2 times if baseline levels were elevated).[citation needed]

Tizanidine use has been associated with hallucinations. Visual hallucinations and delusions have been reported in 5 of 170 patients (3%) in two North American controlled clinical studies.[citation needed]

If therapy needs to be discontinued, especially in patients who have been receiving high doses for long periods, the dose should be decreased slowly to minimize the risk of withdrawal and rebound hypertension, tachycardia, and hypertonia.

[edit] Interactions

Concomitant use of tizanidine and moderate or potent CYP1A2 inhibitors is contraindicated. Concomitant use of tizanidine with fluvoxamine, a potent CYP1A2 inhibitor in man, resulted in a 33-fold increase in the tizanidine AUC (plasma drug concentration-time curve) by fluvoxamine.

Rilmenidine

Rilmenidine

Systematic (IUPAC) name

N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine

Identifiers

CAS number 54187-04-1

ATC code C02 AC06

PubChem 68712

Chemical data

Formula C10H16N2O 

Mol. mass 180.247 g/mol

Pharmacokinetic data

Bioavailability  ?

Protein binding 7%

Metabolism Minimal

Half life 8 hours

Excretion Renal, unchanged

Therapeutic considerations

Pregnancy cat.?

Legal status

Routes Oral

Rilmenidine is a prescription medication administered to treat hypertension.[1] It is marketed under the brand names HYPERIUM and Tenaxum.

Each tablet contains 1.544 mg rilmenidine dihydrogen phosphate, an amount equivalent to 1 mg rilmenidine base.

[edit] Mode of action

Rilmenidine, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. Rilmenidine shows greater selectivity for imidazoline receptors than for cerebral alpha2-adrenergic receptors, distinguishing it from reference alpha2-agonists.

[edit] Indications

Hypertension.

[edit] Contraindications

Severe depression, severe renal failure (creatinine clearance <15 ml/min), as a precaution in the absence of currently available studies.

[edit] Warning

Therapy should never be interrupted suddenly; the dosage should be reduced gradually.

[edit] Precautions

As with all antihypertensive agents, regular medical monitoring is required when rilmenidine is administered to patients with a recent history of cardiovascular disease (stroke, myocardial infarction).

Alcohol consumption should be avoided during treatment. In patients with renal failure, no dosage adjustment is necessary if creatinine

clearance is greater than 15 mL/min. In the absence of documented experiments in this area, rilmenidine is not

recommended for prescription to children. Pregnancy: as with all new molecules, administration of rilmenidine should be

avoided in pregnant women, although no teratogenic or embryotoxic effects have been observed in animal studies.

Lactation: rilmenidine is excreted in breast milk, and its use is therefore not recommended during lactation.

Effects on the ability to drive motor vehicles or operate machinery: double-blind, placebo-controlled studies have not shown rilmenidine to have any effect on alertness at therapeutic doses (1or 2 daily administrations of 1 mg). If these doses are exceeded, or if rilmenidine is combined with other drugs capable of reducing alertness, vehicle drivers or machine operators should be warned of the possibility of drowsiness.

[edit] Drug interactions

Combinations not recommended: combination with MAOIs is not recommended; combination with tricyclic antidepressants requires prudence, as the antihypertensive activity of rilmenidine may be partly antagonized.

[edit] Side effects

At a dose of 1 mg given as a single daily administration during controlled trials, the incidence of side effects was comparable to that observed with placebo.

At a dose of 2 mg per day of rilmenidine, controlled comparative studies versus clonidine (0.15 to 0.30 mg/day) or alpha2-methyldopa (500 to 1000 mg/day) demonstrated that the incidence of side effects was significantly lower with rilmenidine than with either clonidine or a-methyldopa.

Side-effects are rare, non-severe, and transient at therapeutic doses: asthenia, palpitations, insomnia, drowsiness, fatigue on exercise, epigastric pain, dryness of the mouth, diarrhea, skin rash; and exceptionally, cold extremities, postural hypotension, sexual disorders, anxiety, depression, pruritus, edema, cramps, nausea, constipation, hot flushes.

[edit] Dosage and route of administration

The recommended dosage is 1 tablet per day as a single morning administration. If results are not adequate after 1 month of treatment, the dosage may be increased to 2 tablets per day, given in divided doses (1 tablet morning and evening) before meals. As a result of its good clinical and biological acceptability, rilmenidine may be administered to both elderly and diabetic hypertensive patients. In patients with renal failure, no dosage adjustment is necessary in principle when the creatinine clearance is greater than 15 mL/min.

Treatment may be continued indefinitely.

[edit] Overdosage

No cases of massive absorption have been reported. Likely symptoms in such an eventuality would be marked hypotension and lowered alertness. In addition to gastric lavage, sympathomimetic agents may also required. Rilmenidine is only slightly dialysable.

Celiprolol

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Celiprolol

Systematic (IUPAC) name

(RS)-N'-{3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl}-N,N-

diethylurea

Identifiers

CAS number 56980-93-9

ATC code C07 AB08

PubChem 2663

Chemical data

Formula C20H33N3O4 

Mol. mass 379.49 g/mol

Pharmacokinetic data

Bioavailability 30-70%

Metabolism  ?

Half life 5 hours

Excretion  ?

Therapeutic considerations

Pregnancy cat.?

Legal status

Routes  ?

Celiprolol (brand names Cardem, Celectol, Celipres, Celipro, Celol, Cordiax, Dilanorm, Selectol) is a medication in the class of beta blockers, used in the treatment of high blood pressure.

Oxprenolol

Oxprenolol

Systematic (IUPAC) name

(RS)-1-[2-(allyloxy)phenoxy]-3-(isopropylamino)propan-2-ol

Formula C15H23N O 3 

Mol. mass 265.348

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 20-70%

Metabolism Hepatic

Half life 1-2hours

Excretion Renal

Lactic (In lactiferous

females)

Therapeutic considerations

Pregnancy cat.C(AU)

Legal status℞ Prescription only

Routes oral

Oxprenolol (Trasacor, Trasicor, Coretal, Laracor, Slow-Pren, Captol, Corbeton, Slow-Trasicor, Tevacor, Trasitensin, Trasidex) is a non-selective beta blocker with some intrinsic sympathomimetic activity. It is used for the treatment of angina pectoris and abnormal heart rhythms. It is also used for treating high blood pressure.

Oxprenolol is a lipophilic beta blocker which passes the blood-brain barrier more easily than water soluble beta blockers. As such, it is associated with a higher incidence of CNS-related side effects than hydrophilic ligands such as atenolol, sotalol and nadolol.[1]

Oxprenolol is a potent beta-blocker and should not be administered to asthmatics because it can cause irreversible airway failure and inflammation.[citation needed]

Propranolol

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Propranolol

Systematic (IUPAC) name

(RS)-1-(isopropylamino)-3-(1-naphthyloxy)propan-2-ol

Identifiers

CAS number 525-66-6

ATC code C07 AA05

PubChem 4946

DrugBank APRD00194

ChemSpider 4777

Chemical data

Formula C16H21N O 2 

Mol. mass 259.34 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 26%

Metabolism hepatic (extensive)

Half life 4-5 hours

Excretion renal <1%

Therapeutic considerations

Licence dataUS FDA:link

Pregnancy cat.C(AU) C(US)

Legal statusPrescription Only (S4)(AU) POM(UK) ℞ -

only(US)

Routes oral, iv

Propranolol (INN) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. It is the only drug proven effective for the prophylaxis of migraines in children. Propranolol is available in generic form as propranolol hydrochloride, as well as an AstraZeneca and Wyeth product under the trade names Inderal, Inderal LA, Avlocardyl (also available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL, Sumial, Anaprilinum (depending on marketplace and release rate).

[edit] History and development

Scottish scientist and St. Andrews graduate James W. Black successfully developed propranolol in the late 1950s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of a methoxy bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models.

Newer, more selective beta-blockers (such as nebivolol) are now used in the treatment of hypertension.

[edit] Indications

An 80 mg capsule of Propranolol.

Propranolol is indicated for the management of various conditions including:[1]

Hypertension Angina pectoris Tachyarrhythmias Myocardial infarction Control of tachycardia/tremor associated with anxiety, hyperthyroidism or lithium

therapy. Essential tremor Migraine prophylaxis Cluster headaches prophylaxis Tension headache (Off the label use) Tetralogy of Fallot Phaeochromocytoma (along with α blocker) There has been some experimentation in psychiatric areas:[2]

o Treating the excessive drinking of fluids in psychogenic polydipsia,[3][4]

o Antipsychotic -induced akathisia,[5]

o Aggressive behavior of patients with brain injuries [6] o Post-traumatic stress disorder

Glaucoma

While once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes. [7]

Propranolol is also used to lower portal vein pressure in portal hypertension and prevent oesophageal variceal bleeding.

[edit] Off-label and investigational use

Propranolol is often used by musicians and other performers to prevent stage fright.

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder. [8][9][10]. Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. Studies have shown that individuals given propranolol immediately after a traumatic experience show less severe symptoms of PTSD compared to their respective control groups that did not receive the drug (Vaiva et al., 2003). However, results remain inconclusive as to the success of propranolol in treatment of PTSD.

Recent evidence (June 2008) suggests that propranolol can be used to treat severe hemangiomas [11] . This treatment may prove superior to corticosteroids, as propranolol has far less side effects.

Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on P. falciparum and so the treatment of malaria. In vitro positive effects until recently had not been matched by useful in vivo anti-parasite activity against P. vinckei,[12] or P. yoelii nigeriensis.[13] However a single study from 2006 has suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role for combination therapies.[14]

[edit] Precautions and contraindications

Propranolol should be used with caution in patients with:[1]

Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked. Also, propranolol may affect blood sugar levels

Peripheral vascular disease and Raynaud's syndrome, which may be exacerbated Phaeochromocytoma , as hypertension may be aggravated without prior alpha

blocker therapy Myasthenia gravis , may be worsened Other drugs with bradycardic effects

Propranolol is contraindicated in patients with:[1]

Reversible airways disease, particularly asthma or chronic obstructive pulmonary disease (COPD)

Bradycardia (<60 beats/minute) Sick sinus syndrome Atrioventricular block (second or third degree) Shock Severe hypotension Uncontrolled congestive heart failure Cocaine toxicity [per American Heart Association guidelines, 2005]

[edit] Adverse effects

Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers (see beta blocker).

[edit] Pregnancy and lactation

Propranolol, like other beta blockers, is classified as Pregnancy category C in the United States and ADEC Category C in Australia. Beta-blocking agents in general reduce perfusion of the placenta which may lead to adverse outcomes for the neonate, including pulmonary or cardiac complications, or premature birth. The newborn may experience additional adverse effects such as hypoglycemia and bradycardia.[citation needed]

Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.[citation needed]

[edit] Pharmacokinetics

Propranolol is rapidly and completely absorbed, with peak plasma levels achieved approximately 1–3 hours after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will therefore increase its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active.

Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life and may be up to 12 hours, if the single dose is high enough (e.g., 80 mg). Effective plasma concentrations are between 10–100 ng/mL.

Toxic levels are associated with plasma concentrations above 2000 ng/ml.

[edit] Mechanism of action

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine on both β1- and β2-adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong membrane stabilizing activity (only at high blood concentrations, eg overdosage). The drug is also characterized as an adrenoreceptor partial agonist, especially the S-(-) enantiomer. Probably owing to the effect at the α1-adrenoceptor, the racemate and the individual enantiomers of propranolol have been shown to substitute for cocaine in rats with the most potent enantiomer being S-(-)-Propranolol. Research has also shown that propranolol has inhibitory effects on the norepinephrine transporter, stimulates norepinephrine release and partially agonizes serotonin receptors, the two former indirectly while the latter directly.[15] Both enantiomers of the drug have local anesthetic (termed topical) effect.

[edit] Interactions

Beta blockers, including propranolol, have an additive effect with other drugs which decrease blood pressure, or which decrease cardiac contractility or conductivity. Clinically-significant interactions particularly occur with:[1]

verapamil epinephrine β 2-adrenergic receptor agonists clonidine ergot alkaloids isoprenaline non-steroidal anti-inflammatory drugs quinidine cimetidine lidocaine phenobarbital rifampicin Fluvoxamine slows down the metabolism of propranolol significantly leading to

increased blood levels of propranolol.[16]

[edit] Dosage

The usual maintenance dose ranges for oral propranolol therapy vary by indication:

Hypertension, angina, essential tremor o 120–320 mg daily in divided doseso Sustained-release formulations are available in some markets.

Tachyarrhythmia, anxiety (GAD), hyperthyroidism o 10–40 mg 3–4 times daily

Performance anxiety o 5–10 mg 30min or 1.5hrs before and after performance, optionally 5–

10 mg night before. Up to 40 mg if necessary, but side-effects may present. [17]

Timolol

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Timolol

Systematic (IUPAC) name

(S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-

yl)oxy]propan-2-ol

Identifiers

CAS number 26839-75-8

ATC code C07 AA06

PubChem 5478

DrugBank APRD00229

Chemical data

Formula C13H24N4O3S 

Mol. mass 316.421 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 60%

Metabolism Hepatic: 80%

Half life 2.5-5 hours

Excretion Renal

Therapeutic considerations

Pregnancy cat.C(AU) C(US)

Legal status℞ Prescription only

Routes oral, Ophthalmic

Timolol maleate is a non-selective beta-adrenergic receptor blocker. In its oral form (Blocadren), it is used to treat high blood pressure and prevent heart attacks, and occasionally to prevent migraine headaches. In its ophthalmic form (brand names Timoptol in Italy; Timoptic), it is used to treat open-angle and occasionally secondary glaucoma by reducing aqueous humour production through blockage of the beta receptors on the ciliary epithelium. The pharmacological mechanism by which it actually does this is still unknown.

Side effects

The most serious possible side effects include cardiac arrhythmias and severe bronchospasms. Timolol can also lead to fainting, congestive heart failure, depression, confusion, worsening of Raynaud's syndrome and impotence.

Usual dosage

Children and Adults: Ophthalmic: Initial: 0.25% solution, instill 1 drop twice daily; increase to 0.5% solution if response not adequate; decrease to 1 drop/day if *controlled; do not exceed 1 drop twice daily of 0.5% solution Adults: Oral:

Hypertension: Initial: 10 mg twice daily, increase gradually every 7 days, usual dosage: 20-40 mg/day in 2 divided doses; maximum: 60 mg/day

Prevention of myocardial infarction: 10 mg twice daily initiated within 1-4 weeks after infarction

Migraine headache: Initial: 10 mg twice daily, increase to maximum of 30 mg/day

Formulations

Gel-forming solution, ophthalmic, as maleate (Timoptic-XE): 0.25% (2.5 mL, 5 mL); 0.5% (2.5 mL, 5 mL)

Solution, ophthalmic, as hemihydrate (Betimol): 0.25% (5 mL, 10 mL, 15 mL); 0.5% (5 mL, 10 mL, 15 mL) [contains benzalkonium chloride]

Solution, ophthalmic, as maleate: 0.25% (5 mL, 10 mL, 15 mL); 0.5% (5 mL, 10 mL, 15 mL) [contains benzalkonium chloride]

Timoptic: 0.25% (5 mL, 10 mL); 0.5% (5 mL, 10 mL) [contains benzalkonium chloride]

Solution, ophthalmic, as maleate [preservative free] (Timoptic OcuDose): 0.25% (0.2 mL);0.5% (0.2 mL) [single use]

Tablet, as maleate (Blocadren): 5 mg, 10 mg, 20 mg

For ophthalmic use, timolol is also available combined with other medications:

Combigan - timolol and brimonidine Cosopt - timolol maleate and dorzolamide hydrochloride DuoTrav - timolol and travoprost

Pindolol

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Pindolol

Systematic (IUPAC) name

(RS)-1-(1H-indol-4-yloxy)-3-(isopropylamino)propan-2-ol

Identifiers

CAS number 13523-86-9

ATC code C07 AA03

PubChem 4828

DrugBank APRD00678

Chemical data

Formula C14H20N2O2 

Mol. mass 248.321 g/mol

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability 50% to 95%

Metabolism Hepatic

Half life 3–4 hours

Excretion Renal

Therapeutic considerations

Pregnancy cat.C(AU) B(US)

Legal status℞ Prescription only

Routes oral, iv

Pindolol (Visken, Betapindol, Blockin L, Blocklin L, Calvisken, Cardilate, Decreten, Durapindol, Glauco-Visken, Pectobloc, Pinbetol, Prindolol, Pynastin) is a beta blocker.

Contents

[hide] 1 Pharmacology 2 Pharmacokinetics 3 Indications 4 Investigational Use 5 Contraindications 6 Side Effects 7 Dosage

8 References

[edit] Pharmacology

Pindolol is a nonselective beta blocker with partial beta-adrenergic receptor agonist activity. It possesses ISA (Intrinsic Sympathomimetic Activity). This means that pindolol particularly in high doses exerts effects like epinephrine or isoprenaline (increased pulse rate, increased blood pressure, bronchodilation), but these effects are limited. Pindolol also shows membrane stabilizing effects like quinidine, possibly accounting for its antiarrhythmic effects. It also functions as a 5-HT1A receptor weak partial agonist / antagonist.

[edit] Pharmacokinetics

Pindolol is rapidly and well absorbed from the GI tract. It undergoes some first-pass-metabolization leading to an oral bioavailability of 50 to 95%. Patients with uremia may have a reduced bioavailability. Food does not alter the bioavailability, but may increase the resorption. Following an oral single dose of 20mg peak plasma concentrations are reached within 1 to 2 hours. The effect of pindolol on pulse rate (lowering) is evident after 3 hours. Despite the rather short halflife of 3 to 4 hours, hemodynamic effects persist for 24 hours after administration. Plasma halflives are increased to 3 - 11.5 hours in patients with renal impairment, to 7 - 15 hours in elderly patients, and from 2.5 to 30 hours in patients with liver cirrhosis. Approximately 2/3 of pindolol are metabolized in the liver giving hydroxylates, which are found in the urine as gluconurides and ethereal sulfates. The remaining 1/3 of pindolol is excreted in urine in unchanged form.

[edit] Indications

Angina pectoris and hypertension. The use of pindolol in the treatment of unstable angina may be less effective compared to beta blockers without ISA.

In some other countries also arrhythmias and prophylaxis of acute stress reactions.

[edit] Investigational Use

Augmentation therapy of clinical depression: Pindolol is sometimes added to a standard antidepressant therapy,[1] if the patient fails to respond to the standard therapy alone. Fluoxetine is the most commonly used standard antidepressant. The results of augmentation therapy are encouraging. It is not known whether pindolol has antidepressive activities as monotherapeutic agent.

Augmentation therapy of premature ejaculation: According to a recent study, pindolol can be effectively added to a standard anti-premature-ejaculation therapy, which usually consists of daily doses of an SSRI antidepressant such as fluoxetine or paroxetine. Augmentation of pindolol results in substantial increase of ejaculatory latency, even in those who previously did not experience in an improvement with the SSRI monotherapy. (source: Once-Daily High-Dose Pindolol for Paroxetine-Refractory Premature Ejaculation : A Double-Blind, Placebo-Controlled and Randomized Study. MOHAMMAD REZA SAFARINEJAD. Journal of clinical psychopharmacology 2008, vol. 28, no1, pp. 39-44)

[edit] Contraindications

See the article on propranolol.

[edit] Side Effects

See the article on Propranolol.

[edit] Dosage

Usual doses are 5 mg 3 or 4 times daily or 15 to 20 mg in one single dose daily. Slow Release forms (20 mg) may be available to increase patient compliance. The maximum daily dose is 60 mg for hypertension and 40 mg for angina. Treatment should be started with low doses and slowly increased according to the clinical response. The initial and maintenance doses should be reduced in patients with severe liver disease. In some countries pindolol exists as injection concentrate for the emergency treatment of serious arrhythmias. In these cases 0.4 to 1 mg is injected i.v. under strict ECG-monitoring. Further treatment, if necessary, should then be oral.

The recommendation for augmentation in depressive patients is 2.5 mg (or possibly 5 mg) three times daily.

Rasagiline

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Rasagiline

Systematic (IUPAC) name

(R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine

Identifiers

CAS number 1875-50-9

ATC code N04 BD02

PubChem 3052776

Chemical data

Formula C12H13N 

Mol. mass 171.238 g/mol

Pharmacokinetic data

Bioavailability 36%

Protein binding 88 – 94%

Metabolism Hepatic (CYP1A2-mediated)

Half life 3 hours

Excretion Renal and fecal

Therapeutic considerations

Licence dataEU EMEA:link, US FDA:link

Pregnancy cat.C(US)

Legal status℞ -only (US)

Routes Oral

Rasagiline (trade name Azilect) is an irreversible inhibitor of monoamine oxidase [1] used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases.[2] It is selective for MAO type B over type A by a factor of fourteen.[3]

It was developed by Teva Neuroscience [4] , initially investigated by Prof. Moussa Youdim and Prof. John Finberg of the Faculty of Medicine, Technion   – Israel Institute of Technology.[5]

Contents

[hide] 1 Mechanism of Action 2 Metabolism 3 Usage

o 3.1 Monotherapy in Early PD o 3.2 Adjunct Therapy in Advanced PD o 3.3 Safety

4 References

[edit] Mechanism of Action

Human cells contain two forms of monoamine oxidase, MAO-A and MAO-B. Both are found in the brain, but MAO-B is far more prevalent and is responsible for the breakdown of dopamine after its release into the synapse. Parkinson's disease is characterized by the death of cells that use dopamine to transmit their signals, this results in a decrease in synaptic signal strength and concommitant symptomology. By inhibiting the breakdown of dopamine in the synapse, rasagiline permits the signaling neurons to reabsorb more of it for reuse later, somewhat compensating for the diminished quantities manufactured.

Selegiline was the first MAO inhibitor approved for use in Parkinson's disease in the United States. It is chemically similar to methamphetamine and its metabolic breakdown path eventually yields l-methamphetamine derivatives that have been associated with cardiac and psychiatric effects in some patients. The chief metabolite of rasagiline is 1(R)-aminoindan[6] which has no amphetamine characteristics. Some clinicians believe rasagiline will be better tolerated in sensitive patients for these reasons. Aminoindan inhibits both MAO-A and MAO-B in a reversible manner, although considerably weaker than rasagiline.[3]

Laboratory studies show that rasagiline has in vitro and in vivo neuroprotective effects but its neuroprotective effect in Parkinson's disease patients is unknown at present. These studies show that MAO-B can, under some circumstances, create a harmful chemical

called MPP+ that in turn creates free radicals. These studies show that amphetamines may block this neuroprotective effect; since rasagiline does not metabolize to amphetamines or their metabolites it may have superior neuroprotective properties when compared to selegiline. There is uncertainty because the mechanism of cell death in human PD may or may not involve the actions of free radicals, but there is suggestive evidence that the drug slows disease progression.

[edit] Metabolism

Rasagiline is broken down via CYP1A2 [7] , part of the cytochrome P450 metabolic path in the liver. It is probably contraindicated in patients with hepatic insufficiency and its use should be monitored carefully in patients taking other drugs that alter the normal effectiveness of this metabolic path. Examples include but are not limited to fluvoxamine, cimetidine, ciprofloxacin and omeprazole.

[edit] Usage

[edit] Monotherapy in Early PD

A study called TVP-1012 (an early name for rasagiline) in Early Monotherapy for Parkinson's Disease Outpatients (TEMPO) enrolled 404 patients. A double-blind, randomized, delayed start study, it evaluated patients for a year using a placebo and doses of 1 mg and 2 mg per day. The initial six-month placebo controlled part of the study yielded data that led organizers to conclude both rasagiline doses were superior to placebo. The evaluation compared patients' Unified Parkinson's Disease Rating Scale (UPDRS) scores. The UPDRS is a standard method of measuring PD severity. Starting at six months the placebo treated group received the higher dosage of rasagiline (2 mg) until the conclusion of the study at twelve months and patients' UPDRS scores were compared again. Patients who had consistently received the higher dose had significantly better scores than patients who had received the placebo, and somewhat better scores than other groups. These data suggest but do not prove a neuroprotective effect. Some patients entered an open-label follow up study. About half of them did not require additional dopaminergic therapy two years later. Over a six and a half year period the mean deterioration in UPDRS scores for patients receiving some level of rasagiline therapy was 2-3 points. Other clinical studies of placebo treated patients with early PD reported a diminution of 8-12 points per year.

[edit] Adjunct Therapy in Advanced PD

An eighteen week double-blind placebo-controlled study called the Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily (LARGO) compared the drug to entacapone and a placebo in 687 patients experiencing motor fluctuations, a hallmark symptom of PD.[8] Rasagiline at a 1 mg dose significantly reduced daily off time (1.18 hours) compared to the placebo (0.4 hours) and increased on time without dyskinesia by 0.85 hours. This was approximately the same benefit granted by entacapone.

The Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "OFF" (PRESTO) study monitored 472 patients treated with levodopa for motor fluctuations despite attempts to optimize dopaminergic therapy.[9] PRESTO did not have an active comparison drug; its patients randomly received a 0.5 mg dose, a 1 mg dose, or a placebo. Patients receiving both doses of rasagiline experienced less significantly less off time (1.4 hours and 1.8 hours) than did those who received the placebo.

These studies suggest patients with advanced and fluctuating PD benefit in the short term from rasagiline therapy but do not comment on long term effects.

[edit] Safety

Between the TEMPO, LARGO and PRESTO studies 530 patients were treated with the recommended dosage of 1 mg/day for a total of 212 patient-years. The number of patients who discontinued participation due to adverse symptoms was not significantly different between active drug and placebo.

Although rasagiline is an inhibitor of MAO-B, some concern still exists regarding possible drug interactions with medications that are normally considered contraindicated when taken with general MAO inhibitors since adequate studies to establish rasagiline's selectivity for MAO-B have not been conducted.[4] The concern revolves around a possible serotonin-syndrome effect, which was not known to occur during clinical trials despite patients being allowed to take certain antidepressant drugs that are normally contraindicated with general MAO inhibitors. Concern for a possible interaction between rasagiline and tyramine also exists, although no dietary restrictions were imposed during the TEMPO, PRESTO and LARGO studies and no hypertensive crises resulted due to the possible interaction of tyramine and rasagiline.[10]

CAS# 136236-51-6

Selegiline

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Selegiline

Systematic (IUPAC) name

(R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine

Identifiers

CAS number 14611-51-9 [14611-52-0] (HCl)

ATC code N04 BD01 QN06 AX90

PubChem 26757

DrugBank APRD00525

ChemSpider 24930

Chemical data

Formula C13H17N 

Mol. mass 187.281 g/mol

Pharmacokinetic data

Bioavailability 4.4% (oral, fasted), 20% (oral, after food),

18% (patch)

Protein binding 90%

Metabolism liver

Half life 1.5 hours (oral, single dose), 9 hours (oral,

chronic)

Excretion urine

Therapeutic considerations

Pregnancy cat.C (US)

Legal statusprescription only (unscheduled) (US)

Routes Oral, transdermal, buccal

  (what is this?)  (verify)

Selegiline (l-deprenyl, Eldepryl, Zelapar, or Anipryl veterinary) is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary.[1] The drug was researched by Jozsef Knoll et al. (Hungary). Selegiline belongs to a class of drugs called phenethylamines. Selegiline consists of a l-desoxyephedrine (levomethamphetamine) skeleton with a propargyl group attached to the nitrogen atom.

History

Selegiline was discovered in Hungary in the 1960s. Joseph Knoll, a chair of pharmacology at the Semmelweis University in Budapest, was interested in the physiology of "drive" and the differences between high- and low-performing individuals. For his research, he required a molecule that combined amphetamine-like psychostimulant effect with a "psycho-energic" effect of monoamine oxidase inhibitors (MAOI). To do that, he decided to combine in the same molecule the structural features of the MAOI pargyline and the psychostimulant amphetamine. Knoll was a close friend of Meszaros, the research director of Chinoin, a Hungarian pharmaceutical company (later part of Sanofi). For this project, Meszaros put Knoll in contact with a chemist called Ecsery who worked in Chinoin in the field of phenethylamines. Escery made about 30 compounds, and Knoll selected the molecule of E-250 (deprenyl) based on its surprising properties. "The great discovery" (in Knoll's words) was that the new molecule did not increase blood pressure, unlike amphetamine, and moreover, it inhibited the blood pressure raising effect of amphetamine. The first publication on deprenyl in Hungarian appeared in 1964, followed by a paper in English in 1965. Deprenyl is a racemic compound, a mixture of two isomers called enantiomers. For the further pharmaceutical development, Knoll chose the (-)-enantiomer of deprenyl, which caused less hypermotility than the opposite (+)-enantiomer. This (-)-enantiomer (l-deprenyl, R-deprenyl) later has come to be called selegiline.[2]

In 1971, Knoll showed that selegiline selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" that plagues non-selective MAO inhibitors. A few years later, two Parkinson's researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinson's disease. One of their colleagues, Moussa Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, the Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease. [2][3]

In 1967, a Hungarian psychiatrist Ervin Varga observed that racemic deprenyl given in large doses has an antidepressant action.[4] This study was largely forgotten until the 2000s when Sommerset Pharmaceuticals developed selegiline patch for depression.

Uses

The main use of selegiline is in the treatment of Parkinson's disease. It can be used on its own or in a combination with another agent, most often L-DOPA.[5] For the newly diagnosed Parkinson's patients, selegiline appears to slow the progression of the disease. It delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months.[6] The idea behind adding selegiline to levodopa is to decrease the dose of levodopa and thus reduce the motor complications of levodopa therapy.[7] Comparisons of patients on levodopa + placebo vs levodopa + selegiline showed that selegiline allowed to reduce the dose of levodopa by about 40%. Selegiline + levodopa also delayed the time point when the levodopa dose had to be increased from 2.6 to 4.9 years.[6] As a result there were fewer motor complications in selegiline groups.[7] In one trial, selegiline + levodopa completely halted the progress of Parkinson's disease over 14 months, while in the placebo + levodopa group the deterioration of the patients' condition continued. However, the interpretation of this trial as proving neuroprotective action of selegiline has been questioned.[6]

As of February 28, 2006, selegiline has also been approved by the Food and Drug Administration (FDA) to treat major depression using a transdermal patch (Emsam Patch).[8] Selegiline is also used (at extremely high dosages relative to humans) in veterinary medicine to treat the symptoms of Cushing's disease and so-called "cognitive dysfunction" in dogs.[9] As of June 26, 2006, a selegiline transdermal patch is being tested for its effectiveness in treating ADHD.[10]

Several clinical studies are currently underway to evaluate Selegiline's effectiveness in helping people stop smoking tobacco or marijuana.[11][12]

Side effects

Due to the primary metabolites of L-amphetamine and L-methamphetamine, Selegiline shares many side effects seen with these sympathomimetic stimulants. Minor side effects such as dizziness, dry mouth, difficulty falling or staying asleep, muscle pain, rash, nausea and constipation have been seen. More serious side effects such as severe headache, tachycardia, arrhythmia, hallucinations, chorea, or difficulty breathing should be investigated by health professionals immediately. [13]

Pharmacokinetics

Selegiline has a low oral bioavailability.

Selegiline's oral bioavailability is drastically increased in females taking oral contraceptives (10- to 20-fold).[14] This could lead to loss of MAO-B selectivity in favor of an MAO-A selectivity, which in turn would make patients suspectible to the usual risks of unselective MAOIs such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergics such as SSRIs.[14]

[edit] Metabolites

[edit] Desmethylselegiline

Desmethylselegiline may have neuroprotective antiapoptotic properties. A large multicenter study suggests a decrease of in the disease progression of parkinsonism but may have reflected other symptomatic response.[15] Desmethylselegiline is metabolized by CYP2C19.[16]

[edit] L-amphetamine and L-methamphetamine

Selegiline is partly metabolized to l-methamphetamine, one of the two enantiomers of methamphetamine in vivo.[17] A characteristic metabolic pattern was noted, exemplified by a ratio of l-methamphetamine to l-amphetamine of about 2.8.[18] This stereoisomer is not considered psychoactive and has little abuse potential.[19] The stimulatory effect on locomotor activity and dopamine synthesis may be contributed to by the action of l-methamphetamine. If anyone is prescribed and takes selegiline, they can and will test positive for amphetamine/methamphetamine on most drug tests, however the prescription for selegine would explain the reason why they test positive for amphetamine/methamphetamine.

[edit] Mechanism of Action

Selegiline is a selective inhibitor of MAO-B; MAO-B metabolizes dopamine and phenylethylamine.[20] Selegiline exhibits little therapeutic benefit when used independently, but enhances and prolongs the anti-Parkinson effects of levodopa.[21]

[edit] Legal Issues

Possibly due to the structural similarity to illegal stimulants, selegiline has been classified as a controlled substance in Japan and thus can only be obtained with a prescription or special government license.

In E for Ecstasy [22] (a book examining the uses of the street drug Ecstasy in the UK) the writer, activist and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.[23]

Selegiline is not a controlled substance in the US but a prescription is required to obtain it within the US.

[edit] Emsam

February 28, 2006 - The Food and Drug Administration approved Emsam (selegiline), the first transdermal patch for use in treating major depression. The once a day patch works by delivering selegiline through the skin and into the bloodstream. At its lowest strength, Emsam can be used without the dietary restrictions that are needed for all oral MAO inhibitors that are approved for treating major depression. It comes in three sizes that deliver 6, 9, or 12 mg of selegiline per 24 hours. The patch is a matrix containing three layers consisting of a backing, and adhesive drug layer, and a release liner that is placed against the skin. EMSAM was developed by Somerset Pharmaceuticals, Inc. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement that provides Bristol-Myers Squibb with distribution rights to market EMSAM after approval in the United States.

[edit] Zelapar

Zelapar is a transmucosal preparation for human administration of selegiline. The quickly-dissolving lozenge is placed between cheek and gum and the medication enters the bloodstream directly. Because hepatic first-pass metabolism is bypassed, the effective dose is lower than oral (swallowed) selegiline. GI side effects are reportedly reduced compared to oral (swallowed) selegiline. Zelapar is manufactured by Valeant Pharmaceuticals [2].

Didanosine

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Didanosine

Systematic (IUPAC) name

9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3H-purin-6-one

Identifiers

CAS number 69655-05-6

ATC code J05 AF02

PubChem 50599

DrugBank APRD00240

Chemical data

Formula C10H12N4O3 

Mol. mass 236.227 g/mol

Pharmacokinetic data

Bioavailability 30 to 54%

Protein binding Less than 5%

Metabolism  ?

Half life 1.5 hours

Excretion Renal

Therapeutic considerations

Pregnancy cat.B2(AU) B(US)

Legal statusPOM(UK) ℞ -only (US)

Routes Oral

Didanosine (2',3'-dideoxyinosine, ddI, DDI) is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy (HAART).

History

The related pro-drug of didanosine, 2'3'-dideoxyadenosine (ddA), was initially synthesized by M.J. Robins and R.K. Robins in 1964. Subsequently, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan in the National Cancer Institute (NCI) found that ddA and ddI could inhibit HIV replication in the test tube and conducted initial clinical trials showing that didanosine had activity in patients infected with HIV. On behalf of the NCI, they were awarded patents on these activities. Since the NCI does not market products directly, the National Institutes of Health (NIH) awarded a ten-year exclusive licensed to Bristol-Myers Squibb Co. (BMS) to market and sell ddI as Videx tablets.

Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the Food and Drug Administration (FDA) on Oct 9, 1991. Its FDA approval helped bring down the price of zidovudine (AZT), the initial anti-HIV drug.

Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.

At the end of its ten-year license, BMS re-formulated Videx as Videx EC and patented that, which reformulation the FDA approved in 2000. The new formulation is a smaller capsule containing coated microspheres instead of using a buffering compound. It is approved by the FDA for once-a-day dosing. Also at the end of that ten-year period, the NIH licensed didanosine to Barr Laboratories under a non-exclusive license, and didanosine became the first generic anti-HIV drug marketed in the United States.

One of the patents for ddI expired in the United States on 2006-08-29, but other patents extend beyond that time.

[edit] Mechanism of action

Didanosine (ddI) is a nucleoside analogue of adenosine. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has hypoxanthine attached to the sugar ring. Within the cell, ddI is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes. Like other anti-HIV nucleoside analogs, it acts as a chain terminator by incorporation and inhibits viral reverse transcriptase by competing with natural dATP.

[edit] Pharmacokinetics

Oral absorption of didanosine is fairly low (42%)[1] but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach.[1] The half-life in plasma is only 1.5 hours,[1] but in the intracellular environment more than 12 hours. An enteric-coated formulation is now marketed as well. Elimination is predominantly renal; the kidneys actively secrete didanosine, the amount being 20% of the oral dose.

[edit] Drug interactions

A significant interaction has also been recorded with allopurinol, and administration of these drugs together should be avoided.[1]

Indinavir and delavirdine show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times.[1]

Ketoconazole , itraconazole, ciprofloxacin should be administered at a different time from didanosine due to interactions with the buffering agent.[1]

Administration with drugs with overlapping toxicity, such as zalcitabine and stavudine, is not recommended.[2]

Alcohol can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.[1]

[edit] Adverse effects

The most common adverse events with didanosine are diarrhea, nausea, vomiting, abdominal pain, fever, headache and rash. Peripheral neuropathy occurred in 21-26% of participants in key didanosine trials.[1]

Pancreatitis is rarely observed but has caused occasional fatalities, and has black box warning status. Other reported serious adverse events are retinal changes, optic neuritis and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.

[edit] Resistance

Drug resistance to didanosine does develop, though slower than to zidovudine (AZT). The most common mutation observed in vivo is L74V in the viral pol gene, which confers cross-resistance to zalcitabine; other mutations observed include K65R and M184V .[1][3]

Zalcitabine

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Zalcitabine

Systematic (IUPAC) name

4-amino-1-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-

2-one

Identifiers

CAS number 7481-89-2

ATC code J05 AF03

PubChem 24066

DrugBank APRD00562

Chemical data

Formula C9H13N3O3 

Mol. mass 211.218 g/mol

Pharmacokinetic data

Bioavailability >80%

Protein binding <4%

Metabolism Hepatic

Half life 2 hours

Excretion Renal (circa 80%)

Therapeutic considerations

Pregnancy cat.D(AU) C(US)

Legal statusPOM(UK) ℞ -only (US)

Routes Oral

Zalcitabine (2'-3'-dideoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse transcriptase inhibitor (NARTI) sold under the trade name Hivid.

The recommended dosage is 0.750 mg (one tablet) every 8 hours, as part of a combination regimen.

Zalcitabine appears less potent than some other nucleoside RTIs, has an inconvenient three-times daily frequency and is associated with serious adverse events. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV), and even removed from pharmacies entirely in some countries.[citation needed]

History

Zalcitabine was first synthetized in the sixties by Jerome Horwitz [1] [2] and subsequently developed as an anti-HIV agent by Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan at the National Cancer Institute (NCI). Like didanosine, it was then licensed because the NCI may not market or sell drugs. The National Institutes of Health (NIH) thus licensed it to Hoffman LaRoche.

Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV infection and AIDS. It was approved on Jun 19, 1992 as a monotherapy and again in 1996 for use in combination with Zidovudine (AZT). Using combinations of NRTIs was in practice prior to the second FDA approval and the triple drug combinations with dual NRTIs and a protease inhibitor (PI) were not far off by this time.

The sale and distribution of zalcitabine has been discontinued since December 31, 2006.[3]

Mechanism of action

Zalcitabine is an analog of pyrimidine. It is a derivative of the naturally existing deoxycytidine, made by replacing the hydroxyl group in position 3' with a hydrogen.

It is phosphorylated in T cells and other HIV target cells into its active triphosphate form, ddCTP. This active metabolite works as a substrate for HIV reverse transcriptase, and also by incorporation into the viral DNA, hence terminating the chain elongation due to the missing hydroxyl group. Since zalcitabine is a reverse transcriptase inhibitor it possess activity only against retroviruses.

Pharmacokinetics

Zalcitabine has a very high oral absorption rate of over 80%. It is predominantly eliminated by the renal route, with a half-life of 2 hours.[4]

Drug interactions

Lamivudine (3TC) significantly inhibits the intracellular phosphorylation of zalcitabine to the active form, and accordingly the drugs should not be administered together.[4]

Additionally, zalcitabine should not be used with other drugs that can cause peripheral neuropathy, such as didanosine and stavudine.[4]

Adverse events

The most common adverse events at the beginning of treatment are nausea and headache. More serious adverse events are peripheral neuropathy, which can occur in up to 33% of patients with advanced disease, oral ulcers, oesophageal ulcers and, rarely, pancreatitis.[4]

Resistance

Resistance to zalcitabine develops infrequently compared with other nRTIs, and generally only occurs at a low level.[5] The most common mutation observed in vivo is T69D, which does not appear to give rise to cross-resistance to other nRTIs; mutations at positions 65, 74, 75, 184 and 215 in the pol gene are observed more rarely.[4][5]

Lopinavir

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Lopinavir

Systematic (IUPAC) name

(2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-

diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide

Identifiers

CAS number 192725-17-0

ATC code J05 AE06

PubChem 92727

DrugBank EXPT00388

Chemical data

Formula C37H48N4O5 

Mol. mass 628.810 g/mol

SMILESeMolecules &

PubChem

Pharmacokinetic data

Bioavailability Unknown

Protein binding 98-99%

Metabolism Hepatic

Half life 5 to 6 hours

Excretion Mostly fecal

Therapeutic considerations

Pregnancy cat.C (U.S.)

Legal status℞-only (U.S.), POM

(UK)

Routes Oral

Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. It is marketed by Abbott as Kaletra (high-income countries) and Aluvia (low-income countries), both of which represent a co-formulation with a sub-therapeutic dose of ritonavir, as a component of combination therapy to treat HIV/AIDS. The Kaletra formulation has also been used successfully as monotherapy in some studies.[1]

As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.[2] It is available as capsules, tablets and oral solution.

Contents

[hide] 1 History 2 Pharmacology 3 Adverse effects 4 Access 5 References

6 External links

[edit] History

Lopinavir was developed by Abbott in an attempt to improve on the HIV resistance and serum protein-binding properties of the company's earlier protease inhibitor, ritonavir.[3] Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of cytochrome P450 3A4.[3] Abbott therefore pursued a strategy of co-administering lopinavir with sub-therapeutic doses of ritonavir, and lopinavir is only marketed as a co-formulation with ritonavir. It is the first multi-drug capsule to contain a drug not available individually.

Lopinavir/ritonavir was approved by the US FDA on 15 September 2000, and in Europe in April 2001. Its patent will expire in the US on June 26, 2016.

Abbott Laboratories was one of the earliest users of the Advanced Photon Source, a national synchrotron-radiation light source at Argonne National Laboratory. One of the early research projects undertaken at the Advanced Photon Source was the Human Immunodeficiency Virus. Using X-ray crystallography, researchers found the points of attack of the HIV protease inhibitors – agents that block the breakdown of proteins. Protease inhibitors stop HIV from making new copies of itself by blocking the last step in the process, when the virus attempts to replicate - and out of that discovery came the drug Kaletra.[4]

[edit] Pharmacology

Lopinavir is highly bound to plasma proteins (98-99%).[5]

There are contradictory reports regarding lopinavir penetration into the CSF. Anecdotal reports state that lopinavir cannot be detected in the CSF; however, a study of paired CSF-plasma samples from 26 patients receiving lopinavir/ritonavir found lopinavir CSF levels above the IC50 in 77% of samples.[6]

[edit] Adverse effects

The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%.[5] Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.[5]

Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.

As reported at the 2009-04-10 patients with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use Kaletra (lopinavir/ritonavir) with caution [7].

[edit] Access

As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January, 2007, to produce and/or import generic versions of lopinavir and ritonavir.[8] In response, Abbott Laboratories withdrew its registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for patents.[9] Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbott's medicines by the French NGO AIDES.[10]

Indinavir

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Indinavir

Systematic (IUPAC) name

(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4-{[(1S,2R)-2-hydroxy-2,3-dihydro-

1H-inden-1-yl]carbamoyl}butyl]-N-tert-butyl-4-(pyridin-3-

ylmethyl)piperazine-2-carboxamide

Identifiers

CAS number 150378-17-9

ATC code J05 AE02

PubChem 5362440

DrugBank APRD00069

Chemical data

Formula C36H47N5O4 

Mol. mass 613.79 g/mol

Pharmacokinetic data

Bioavailability  ?

Protein binding 60%

Metabolism Hepatic via

CYP3A4

Half life 1.8 (± 0.4) hours

Excretion  ?

Therapeutic considerations

Licence dataUS FDA:link

Pregnancy cat.C(US)

Legal status

Routes Oral

Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy (HAART) to treat HIV infection and AIDS.

[edit] History

The Food and Drug Administration (FDA) approved indinavir March 13, 1996, making it the eighth approved antiretroviral. Indinavir was much more powerful than any prior antiretroviral drug; using it with dual NRTIs set the standard for treatment of HIV/AIDS and raised the bar on design and introduction of subsequent antiretroviral drugs. Protease inhibitors changed the very nature of the AIDS epidemic from one of a terminal illness to a somewhat manageable one.

Increasingly, it is being replaced by newer drugs that are more convenient to take and less likely to promote resistant virus, such as lopinavir or atazanavir.

[edit] Administration

Unfortunately, indinavir wears off quickly after dosing and therefore requires dosing very precisely every eight hours in order to thwart HIV from forming drug resistant mutations including resistances to other protease inhibitors. It has restrictions on what sorts of food may be eaten concurrently.

[edit] Side effects

Side effects include

Kidney stones Metabolic abnormalities including hyperlipidemia (cholesterol or triglyceride

elevations) alterations in body shape known as lipodystrophy