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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 C08CA01
PubChem 2162
DrugBank APRD00520
ChemSpider 2077
Chemical data
Formula C20H25ClN2O5
Mol. mass 408.879 g/mol
eMolecules &
SMILES
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 status POM(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 sheet
2. ^ 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
3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate
Identifiers
ATC code C08CA02
PubChem 3333
DrugBank APRD00374
Chemical data
Formula C18H19Cl2NO4
SMILES eMolecules & PubChem
Bioavailability >95% [1]
Metabolism Hepatic
Half life ??
Excretion Renal
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
Nicardipine
2-[benzyl(methyl)amino]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate
Identifiers
ATC code C08CA04
PubChem 4474
DrugBank APRD00088
Chemical data
Formula C26H29N3O6
Physical data
Melt. point 6 °C (43 °F)
Bioavailability ?
Protein binding >95%
Metabolism ?
Half life 8.6 hours
Excretion ?
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
Nifedipine
3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-
dicarboxylate
Identifiers
ATC code C08CA05
PubChem 4485
DrugBank APRD00590
ChemSpider 4330
Chemical data
Formula C17H18N2O6
Physical data
Melt. point 173 °C (343 °F)
Bioavailability 45-56%
Protein binding 92-98%
Metabolism Gastrointestinal, Hepatic
Half life 2 hours
Excretion Renal: >50%, Biliary: 5-15%
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

Nisoldipine
isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Identifiers
ATC code C08CA07
PubChem 4499
DrugBank APRD00635
Chemical data
Formula C20H24N2O6
Bioavailability ?
Protein binding 99%
Metabolism ?
Half life 7-12 hours
Excretion ?
Legal status ℞-only(US)
Verapamil

Verapamil
(RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-dimethoxyphenyl)ethyl]-
(methyl)amino]-2-isopropylpentanenitrile
Identifiers
CAS number 52-53-9
ATC code C08DA01
PubChem 2520
DrugBank APRD00335
ChemSpider 2425
Chemical data
Formula C27H38N2O4
Bioavailability 35.1%
Metabolism Hepatic
Half life 2.8-7.4 hours
Excretion Renal: 11%
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

Diltiazem
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
ATC code C08DB01
PubChem 39186
DrugBank APRD00473
ChemSpider 35850
Chemical data
Formula C22H26N2O4S
Bioavailability 40%
Metabolism Hepatic
Half life 3-4.5 hours
Excretion Renal
Biliary
Lactic (in lactiferous females)
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/10774785
9. ^ 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

Amrinone
5-amino-3,4'-bipyridin-6(1H)-one
Identifiers
ATC code C01CE01
PubChem 3698
Chemical data
Formula C10H9N3O
Bioavailability n/a
Protein binding 10 to 49%
Metabolism Hepatic
Excretion Renal (63%) and fecal (18%)
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/qr73200
0-03-01.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
1-benzhydryl-4-cinnamyl-piperazine
Identifiers
CAS number 298-57-7
ATC code N07CA02
PubChem 2761
DrugBank APRD00332
Chemical data
Formula C26H28N2
Bioavailability ?
Metabolism ?
Half life 3..4h
Excretion ?
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
5-(1,4-diazepane-1-sulfonyl)isoquinoline
Identifiers
ATC code C04AX32
PubChem 3547
Chemical data
Formula C14H17N3O2S
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
Pregabalin
(S)-3-(aminomethyl)-5-methylhexanoic acid
Identifiers
ATC code N03AX16
PubChem 5486971
DrugBank APRD01198
ChemSpider 4589156
Chemical data
Formula C8H17NO2
Mol. mass 159.23 g.mol-1
Bioavailability ≥90%
Protein binding Nil
Metabolism Negligible
Half life 5–6.5 hours
Excretion Renal
Licence data US Daily Med:link
Pregnancy cat. B3 (Au), C (U.S.)
Legal status S4 (Au), POM (UK), Schedule V (U.S.)
Routes Oral(main), IV, Insufflation
(what is this?) (verify)
Pregabalin (INN) (pronounced /prɨˈɡæbəlɨn/) 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]

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 fine
7. ^ 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 Guide
12. ^ 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
Risedronic acid
(1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonic acid
Identifiers
ATC code M05BA07
PubChem 5245
DrugBank APRD00410
Chemical data
Formula C7H11NO7P2
Bioavailability 0.63%
Protein binding ~24%
Metabolism None
Half life 1.5 hours
Excretion Renal and fecal
Pregnancy cat. B3(AU) C(US)
Legal status POM(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
Bosentan
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-
yl)pyrimidin-4-yl]benzene-1-sulfonamide
Identifiers
ATC code C02KX01
PubChem 104865
DrugBank APRD00829
Chemical data
Formula C27H29N5O6S
eMolecules &
SMILES
PubChem
Bioavailability 50%
Protein binding >98%
Metabolism Hepatic
Half life 5 hours
Excretion ?
Pregnancy cat. X
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
Methyldopa
(S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid
Identifiers
CAS number 555-30-6
ATC code C02AB01
PubChem 4138
DrugBank APRD01106
Chemical data
Formula C10H13NO4
Bioavailability approximately 50%
Metabolism Hepatic
Half life 105 minutes
Excretion Renal for metabolites
Pregnancy cat. a drug of choice in PIH
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.
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 nightmares
o Apathy and/or anhedonia, as well as dysphoria
o Anxiety, especially of the social anxiety variant
o Decreased alertness, awareness, and wakefulness
o Impaired attention, focus, and concentration
o Decreased desire, drive, and motivation
o Fatigue or lethargy and/or malaise or lassitude
o Sedation or drowsiness and/or somnolence or sleepiness
o Agitation or restlessness
o Cognitive and memory impairment
o Derealization and/or depersonalization, as well as mild psychosis
o Sexual dysfunction including impaired libido, desire, and drive
• Physiological
o Dizziness, lightheadedness, or vertigo
o Miosis or pupil constriction
o Xerostomia or dry mouth
o Gastrointestinal disturbances such as diarrhea and/or constipation
o Headache or migraine
o 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 paralysis
o Sexual dysfunction consisting of impaired erectile dysfunction and/or
anorgasmia
o 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 rate
o 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 damage
o Pancreatitis or inflammation of the pancreas
o 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
Tizanidine
5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine
Identifiers
ATC code M03BX02
PubChem 5487
DrugBank APRD00128
ChemSpider 5287
Chemical data
Formula C9H8ClN5S
Mol. mass 253.712
4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-8-thia-7,9-
Synonyms
diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-amine
Bioavailability ?
Protein binding 30%
Metabolism CYP 1A2
Half life 2.54 hours
Excretion ?
Pregnancy cat. ?
Legal status Rx-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
N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine
Identifiers
ATC code C02AC06
PubChem 68712
Chemical data
Formula C10H16N2O
Bioavailability ?
Protein binding 7%
Metabolism Minimal
Half life 8 hours
Excretion Renal, unchanged
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.
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.

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
Celiprolol
(RS)-N'-{3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl}-N,N-
diethylurea
Identifiers
ATC code C07AB08
PubChem 2663
Chemical data
Formula C20H33N3O4
Metabolism ?
Half life 5 hours
Excretion ?
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
(RS)-1-[2-(allyloxy)phenoxy]-3-(isopropylamino)propan-2-ol
Formula C15H23NO3
Mol. mass 265.348
Metabolism Hepatic
Half life 1-2hours
Excretion Renal
Lactic (In lactiferous
females)
Pregnancy cat. C(AU)
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
Propranolol
(RS)-1-(isopropylamino)-3-(1-naphthyloxy)propan-2-ol
Identifiers
CAS number 525-66-6
ATC code C07AA05
PubChem 4946
DrugBank APRD00194
ChemSpider 4777
Chemical data
Formula C16H21NO2
Bioavailability 26%
Metabolism hepatic (extensive)
Half life 4-5 hours
Excretion renal <1%
Licence data US FDA:link
Legal status Prescription 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]

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]
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
• β2-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 doses
o 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
Timolol
(S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-
yl)oxy]propan-2-ol
Identifiers
ATC code C07AA06
PubChem 5478
DrugBank APRD00229
Chemical data
Formula C13H24N4O3S
Bioavailability 60%
Metabolism Hepatic: 80%
Half life 2.5-5 hours
Excretion Renal
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
Pindolol
(RS)-1-(1H-indol-4-yloxy)-3-(isopropylamino)propan-2-ol
Identifiers
ATC code C07AA03
PubChem 4828
DrugBank APRD00678
Chemical data
Formula C14H20N2O2
Bioavailability 50% to 95%
Metabolism Hepatic
Half life 3–4 hours
Excretion Renal
Pregnancy cat. C(AU) B(US)
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.
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)
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
Rasagiline
(R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1-amine
Identifiers
ATC code N04BD02
PubChem 3052776
Chemical data
Formula C12H13N
Bioavailability 36%
Protein binding 88 – 94%
Metabolism Hepatic (CYP1A2-mediated)
Half life 3 hours
Excretion Renal and fecal
Licence data EU EMEA:link, US FDA:link
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
Selegiline
(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 N04BD01 QN06AX90
PubChem 26757
DrugBank APRD00525
ChemSpider 24930
Chemical data
Formula C13H17N
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
Pregnancy cat. C (US)
Legal status prescription 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

Didanosine
9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3H-purin-6-one
Identifiers
ATC code J05AF02
PubChem 50599
DrugBank APRD00240
Chemical data
Formula C10H12N4O3
Bioavailability 30 to 54%
Protein binding Less than 5%
Metabolism ?
Half life 1.5 hours
Excretion Renal
Pregnancy cat. B2(AU) B(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.
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.

• 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]

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

Zalcitabine
4-amino-1-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-
2-one
Identifiers
ATC code J05AF03
PubChem 24066
DrugBank APRD00562
Chemical data
Formula C9H13N3O3
Bioavailability >80%
Protein binding <4%
Metabolism Hepatic
Half life 2 hours
Excretion Renal (circa 80%)
Pregnancy cat. D(AU) C(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

Lopinavir
(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
ATC code J05AE06
PubChem 92727
DrugBank EXPT00388
Chemical data
Formula C37H48N4O5
eMolecules &
SMILES
PubChem
Bioavailability Unknown
Protein binding 98-99%
Metabolism Hepatic
Excretion Mostly fecal
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]

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

Indinavir
(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
ATC code J05AE02
PubChem 5362440
DrugBank APRD00069
Chemical data
Formula C36H47N5O4
Bioavailability ?
Protein binding 60%
Metabolism Hepatic via
CYP3A4
Half life 1.8 (± 0.4) hours
Excretion ?
Licence data US FDA:link
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

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Amlodipine

Systematic (IUPAC) name

Routes Oral (tablets)

Amlodipine (as besylate, mesylate or maleate) is a long-acting calcium channel blocker

Amlodipine is marketed as Dailyvasc in the Philippines by Xeno Pharmaceuticals, and

• Very often: peripheral edema (feet and ankles) - in 1 of 10 users

The efficacy and tolerability of a fixed-dose combination of amlodipine 5mg and

[edit] Drug metabolism and excretion

[edit] Patent loss

[edit] See also

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Felodipine is a calcium channel blocker (calcium antagonist), a drug used to control

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Nicardipine is a dihydropyridine calcium-channel blocking agent used for the treatment

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

Nifedipine (brand name Adalat, Nifedical, and Procardia) is a dihydropyridine calcium

Extended release formulations of nifedipine should be taken on an empty stomach, and

Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed

Jump to: navigation, search

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Mechanism and uses

In cardiac pharmacology, calcium channel blockers are considered class IV

[edit] Uses in cell biology

Potential Use in the Treatment of Malaria

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Diltiazem is a member of the group of drugs known as benzothiazepines, which are a

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

[edit] Brand names

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

Negative dromotropic effect. By slowing conduction through the AV (atrioventricular)

[edit] Nontherapeutic effects and toxicities

• Stable angina (exercise-induced) . Diltiazem increases coronary blood flow and

Supraventricular tachycardias. Diltiazem appears to be as effective as verapamil in

Atrial fibrillation[6] or atrial flutter.

Hypertension. Because of its vasodilatory effects, diltiazem is useful for treating

[edit] Contraindications and precautions

SA node or AV conduction disturbances. Use of diltiazem should be avoided in patients

Wolff-Parkinson-White syndrome. Diltiazem may paradoxically increase ventricular rate

Diltiazem is relatively contraindicated in the presence of sick sinus syndrome,

[edit] Drug interactions

Inhibition of hepatic enzymes. Diltiazem and verapamil inhibit hepatic cytochromes

[edit] Potential future indications

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Amrinone (INN) or inamrinone (USAN, changed in 2000 to prevent confusion with

[edit] Side effects

[edit] Pediatric dosage

Cinnarizine could be also viewed as a nootropic drug because of its vasorelaxating

• Barrett RJ, Zolov B (December 1960). "A clinical evaluation of cinnarizine

Fasudil Hydrochloride (INN) is a potent Rho-kinase inhibitor and vasodilator[1]. Since it

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Pregabalin (INN) (pronounced /prɨˈɡæbəlɨn/) is an anticonvulsant drug used for

[edit] Adverse effects

• Very common (>10% of patients): dizziness, drowsiness

Absorption: Pregabalin is rapidly absorbed when administered on an empty stomach,

Metabolism: Pregabalin undergoes negligible metabolism in humans.[13] Approximately

Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal

[edit] Drug interactions

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Risedronic acid (INN) or risedronate sodium (USAN, trade name Actonel) is a

In common with other bisphosphonate drugs, risedronate appears to be associated with

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