Verapamil dosing

Currently, all marketed verapamil products are racemic mixtures of R and S enantiomers (7,8). The totd pharmacological activity of a verapamil dose is determined by the combined bioavailability of both individual enantiomers. The S enantiomer is preferentially metabolized after oral dosing, resulting in the R enantiomer being the more prevalent in the systemic circulation (8). The actual value of the enantiomeric ratio (R S) in the plasma, however, is determined by a combination of factors. Pharmacokinetic distinctions between the two enantiomers (e.g., volumes of... 

Patients who have an inadequate response to /S-blockade may respond to verapamil." Doses of verapamil up to 480 mg/day have beneficial effects on symptoms. There are several reasons why CCBs may be of benefit to patients with HCM. Increased calcium concentrations have been shown to play a role in prolonging the ventricular action potential, as well as the duration of isometric contraction and relaxation. Patients with HCM have a hyperdynamic ventricle in systole and delayed relaxation and decreased compliance during diastole. CCBs decrease the myocardial oxygen demand, resulting in an improved balance between oxygen supply and demand therefore, diastolic function may be improved. 

The interactions of cimetidine with diltiazem and nifedipine are established. Concurrent use need not be avoided but the increase in the calcium-channel blocker effects should be taken into account. It has been suggested that the dosage of diltiazem should be reduced by 30 to 50% " and that of nifedipine by 40 to 50%. " The interaction between verapamil and cimetidine is not well established, but monitor the effects until more is known. It has been suggested that the verapamil dose may need to be reduced by 50%. Monitoring is advised if isradipine is given with cimetidine and a reduction in isradipine dose may be required. ... 

Supraventricular tachycardia was inadequately controlled in a patient taking rifampicin 600 mg daily and isoniazid 300 mg daily, despite a verapamil dose of 480 mg every 6 hours. Substitution of the rifampicin hy ethambutol resulted in a fourfold rise in serum verapamil levels. A later study in 6 healthy subjects found that after taking rifampicin 600 mg daily for 2 weeks the oral bioavailability of verapamil was reduced from 26 to 2%, and the effects of verapamil on the ECG were abolished. Yet another study in elderly patients similarly found that rifampicin 600 mg daily markedly increased the clearance of verapamil 120 mg twice daily. The effects of verapamil on AV conduction were almost abolished. ... 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

The toxic mechanism of action of these various jellyfish venoms is complex. The cardiotoxic reaction seems to focus on calcium transport and is blocked by the prior or post administration of therapeutic doses of verapamil (7J). In neuronal tissue, Chrysaora venom induces large cationic selective channels which open and close spontaneously. These channels are permeable to Na , Li, K, and Cs but not and the channels are present in spite of the treatment with sodium and potassium inhibitors such as tetrodotoxin and tetraethylammonium (14). 

STE ACS class lla recommendation and NSTE ACS class I recommendation for patients with ongoing ischemia who are already taking adequate doses of nitrates and P-blockers or in patients with contraindications to or intolerance to P-blockers (diltiazem or verapamil for STE ACS and diltiazem, verapamil, or amlodipine for NSTE ACS). 

As described in the previous section, calcium channel blockers should not be administered to most patients with ACS. Their role is a second-line treatment for patients with certain contraindications to P-blockers and those with continued ischemia despite P-blocker and nitrate therapy. Administration of either amlodipine, diltiazem, or verapamil is preferred.2 Agent selection is based on heart rate and left ventricular dysfunction (diltiazem and verapamil are contraindicated in patients with bradycardia, heart block, or systolic heart failure). Dosing and contraindications are described in Table 5-2. 

Verapamil Inhibits AV nodal conduction by slowing AV nodal conduction and prolonging AV nodal refractoriness 1. 5-10 mg IV over 2-3 minutes 2. If necessary, an additional dose of 5-1 0 mg may be administered 30 minutes later 120-360 mg/day Inhibits digoxin elimination... 

Figure 2.2 Log flux-pH profiles at dosing concentrations (a) ketoprofen (acid, pKa 3.98), dose 75 mg (b) verapamil (base, pKa 9.07), dose 180 mg (c) piroxicam (ampholyte, pKa 5.07, 2.33), dose 20 mg. The permeability and the concentration of the uncharged species are denoted Po and Co, respectively. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

In solutions saturated (i.e., excess solid present) at some pH, the plot of log Co versus pH for an ionizable molecule is extraordinarily simple in form it is a combination of straight segments, joined at points of discontinuity indicating the boundary between the saturated state and the state of complete dissolution. The pH of these junction points is dependent on the dose used in the calculation, and the maximum value of log Co is always equal to log. Sb in a saturated solution. [26] Figure 2.2 illustrates this idea using ketoprofen as an example of an acid, verapamil as a base, and piroxicam as an ampholyte. In the three cases, the assumed concentrations in the calculation were set to the respective doses [26], For an acid, log Co (dashed curve in Fig. 2.2a) is a horizontal line (log Co = log So) in the saturated solution (at low pH), and decreases with a slope of —1 in the pH domain where the solute is dissolved completely. For a base (Fig. 2.2b) the plot of log Co versus pH is also a horizontal line at high pH in a saturated solution and is a line with a slope of +1 for pH values less than the pH of the onset of precipitation. 

This system is the only osmotic system developed commercially at this time that is suitable for the oral administration of insoluble drugs to humans. It has been utilized in the development of several other drugs including isradipine, doxazosin, diltiazem, contraceptive steroids, glipizide, and verapamil [48-53], The system has also been utilized to codeliver the free bases of compounds normally administered as water-soluble salts such as pseudoephedrine and bromo-pheniramine [54], The latter system includes both a loading dose and a controlled release dose and is intended for applications in the over-the-counter market. 

A direct in vivo assessment was carried out with the single-pass perfusion approach in the human jejunum by using the Loc-I-Gut technique with R/S-verapamil (log D6 5 2.7, octanol/water pH 7.4 MW 455 Da) as the model compound for CYP 3A4 and P-gp-mediated local intestinal kinetics [2, 34, 35, 122] (see Figs. 7.7 and 7.9). The Peff for both enantiomers at each of the concentrations (4.0, 40, 120, and 400 mg L-1) was 2.5 x 10 4, 4.7 x 105.5 x 104 and 6.7 x 104 cm s-1, respectively (Fig. 7.15) [34, 35], A luminal concentration of 400 mg L 1 is expected to be achieved in the upper part of the small intestine after oral administration of a 100-mg dose of verapamil in an immediate-release dosage form [1, 34, 35], The three other perfusate concentrations represent fractions of the dose when 30%, 10%, and 1%, respectively are left to be absorbed [34, 35], The increased in vivo jejunal Peff of R/S-vcrapamil, along with its increased luminal perfusate concentration, is in accordance with a saturable efflux mechanism mediated by... 

It was determined that 9.5% of an oral 80-mg dose of verapamil was absorbed in a 70-kg test subject. However, because of extensive bio transformation during its first pass through the portal circulation, the bio availability of verapamil was only 25%. Assuming a liver blood flow of 1500 mLAmin, the hepatic clearance of verapamil in this situation was... 

Maintenance dose 0.125-0.25 mg PO/IV qd low potassium or magnesium levels potentiate toxicity reduce dose in renal failure toxicity indicated by nausea, headache, visual disturbances (yellow-green halos), ventricular arrhythmias. Quinidine, verapamil, and amiodarone elevate digoxin level. 

Clinically, the drug has been studied (for the most part) in poorly controlled trials with few precautions against subjective bias [272- ]. Two careful doubleblind assessments have however been reported, one [275] measuring reduction of weekly consumption of glyceryl trinitrate. The other [276], by far the most informative published to date, demonstrates the drug s ability to increase the amount of exercise necessary to provoke anginal attacks,as well as its effectiveness in reducing the need for nitrate consumption. Qinically, this study failed to show any difference between propranolol and verapamil (in appropriate doses) and, in... 

Lower initial doses may be warranted in patients who may have an increased response to verapamil (eg, elderly people, those of small stature, impaired hepatic function). Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of verapamil are evident within the first week of therapy. 

Angina Usual initial dose is 80 to 120 mg 3 times/day 40 mg 3 times/day may be warranted if patients may have increased response to verapamil (eg, decreased hepatic function, elderly). Base upward titration of safety and efficacy evaluated about 8 hours after dosing. Increase dosage daily (eg, unstable angina) or weekly until optimum clinical response is obtained. 

Major metabolite cardiovascular activity is approximately 20% that of verapamil, following cessation of multiple dosing. 

Hypertrophic cardiomyopathy (IHSS) Serious adverse effects were seen in 120 patients with IHSS (especially with pulmonary artery wedge pressure more than 20 mm Hg and left ventricular outflow obstruction) who received oral verapamil at doses up to 720 mg/day. Sinus bradycardia occurred in 11%, second-degree AV block in 4% and sinus arrest in 2%. 

Concomitant use of calcium channel blockers (atenolol) Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with preexisting conduction abnormalities or left ventricular dysfunction are particularly susceptible. Recent acute Ml (sotalol) Sotalol can be used safely and effectively in the long-term treatment of life-threatening ventricular arrhythmias following an Ml. However, experience in the use of sotalol to treat cardiac arrhythmias in the early phase of recovery from acute Ml is limited and at least at high initial doses is not reassuring. 

For patients receiving weak CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole), reduce the starting dose to 25 mg once daily. 

Concomitant amiodarone or verapamil (immediate-release only) - In patients taking amiodarone or verapamil concomitantly with lovastatin, the dose should not exceed 40 mg/day. 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

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