Scott R. Hamann

Clinical Pharmacokinetics of Verapamil

SummaryVerapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels.Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism, with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound in in vitro studies.After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug.Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, ’standard’ dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil’s disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and β-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

The Pharmacology of Verapamil

The relative distribution of verapamil and its demethylated metabolite, norverapamil, was studied in rats at intervals after intraperitoneal injection of the parent drug (30 mg/kg). This route of drug

Pharmacokinetics of calcium-entry blockers

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.

Advances in cancer pain management.

Control of malignant pain and related symptoms is paramount to clinical success in caring for cancer patients. To achieve the best quality of life for patients and families, oncologists and palliative care clinicians must work together to understand problems related to psychologic, social, and spiritual pain. Pain is the primary problem targeted for control using the World Health Organization’s (WHO) analgesic ladder. This article focuses on increased knowledge of analgesic action that may enable expansion of the WHO analgesic ladder to fulfill the broader objectives of palliative medicine. We discuss clinical experience with several classes of drugs that are currently used to treat cancer pain: 1) nonsteroidal anti-inflammatory drugs, with emphasis on cyclooxygenase-2 inhibitors; 2) opioid analgesics, with specific emphasis on methadone and its newly recognized value in cancer pain; 3) ketamine, an antagonist at N-methyl-D-aspartate receptors; and 4) bisphosphonates, used for pain resulting from bone metastases. New concepts that compare molecular actions of morphine at excitatory opioid receptors, and methadone at nonopioid receptor systems, are presented to underscore the importance of balancing central nervous system excitatory (anti-analgesic) versus inhibitory (analgesic) influences.

Interactions of "ultra-low" doses of naltrexone and morphine in mature and young male and female rats.

Sex and age influence morphine analgesia in humans and animals. Mature rats show greater morphine analgesia in males than in females. Ultra-low doses of naltrexone enhance morphine analgesia. In mature rats (18-22 weeks), naltrexone (0.002-2.0 mg/kg)-morphine (2 mg/kg) cotreatment enhanced morphine analgesia in females, an effect inversely related to naltrexone dose. Conversely, in mature male rats, naltrexone tended to decrease morphine analgesia with increasing dose. In young rats (8-10 weeks), morphine analgesia was unrelated to sex and in both sexes the naltrexone-morphine interaction was negligible. These data show that dose, age, and sex alter the naltrexone-morphine interaction in rats.

Thermally evoked tail avoidance reflex: input-output relationships and their modulation.

Latency to onset and magnitude (angular displacement) of thermally evoked tail avoidance reflexes (TETAR) to graded thermal stimuli were measured in pentobarbital-treated and untreated rats. The latency to onset was inversely and the magnitude was directly proportional to the thermal stimulus intensity. Pentobarbital prolonged the latency to onset of the TETAR to low by not high stimulus intensities. Activation of (-)-nicotine sensitive brainstem hyperalgesic processes shortened the latency and increased the magnitude of the TETAR. The hyperalgesic actions of (-)-nicotine were most demonstrable at lower thermal stimulus intensities. These studies suggest that the TETAR is graded in intensity as the stimulus intensity is increased and that the response evoked by different intensities of stimulus probably involve common neurophysiologic mechanisms.

Evaluation of gentamicin pharmacokinetics during peritoneal dialysis

The pharmacokinetics of gentamicin were examined in two functionally anephric patients undergoing peritoneal dialysis (PD). Peritoneal dialysis effectively decreased the gentamicin half-life (t1/2 beta) by 73 and 78% while increasing total body clearance [QB(ml/min/kg] of gentamicin 4.3- and 3.4-fold. The appreciable variability in gentamicin pharmacokinetics among renal failure patients being peritoneally dialyzed may necessitate dosage adjustments based on rapid and accurate measurement of serum gentamicin concentrations.

Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord

Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective-like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.

Analgesic actions of dynorphin A(1–13) antiserum in the rat brain stem

This study was performed to evaluate the effects of dynorphin A(1-3) antiserum when microinjected into an active hyperalgesic region within the rat brain stem. When administered within the dorsal posterior mesencephalic tegmentum (DPMT) of intact conscious rats, dynorphin A(1-13) antiserum produced rapid onset and persistent prolongation of a low intensity thermally evoked tail avoidance response (LITETAR). These analgesic actions of the dynorphin A(1-13) antiserum appeared to be dose dependent. These studies support previous hypotheses about the existence of tonically active brain stem opioid hyperalgesic process. Further, the results provide indirect evidence for a potential role of brain stem dynorphin(s) in facilitating pain.

Effects of verapamil on the arrhythmogenic action of acetylstrophanthidin.

Although coadministration of verapamil and digoxin results in significant increases in plasma glycoside concentrations, evidence of digitalis toxicity appears to be infrequent with this combination. To evaluate the effect of verapamil on electrophysiologic toxicity from digitalis, 5 anesthetized dogs were instrumented for physiologic recording and given acetylstrophanthidin by intravenous infusion until evidence of toxicity appeared. Each animal was then treated with verapamil intravenously, with mean steady-state plasma levels of 177 +/- 30 ng/ml, and acetylstrophanthidin infusion repeated; after return of sinus rhythm, the verapamil infusion was increased (producing mean levels of 379 +/- 50 ng/ml) and acetylstrophanthidin given a third time. Prior to verapamil dosing, ventricular ectopy was the manifestation of glycoside toxicity; following the first verapamil infusion, only 20% of the dogs developed ectopy, the remainder having second- or third-degree atrioventricular (AV) block, or AV junctional tachycardia. With the higher verapamil dose, AV block or junctional tachycardia occurred in all animals during acetylstrophanthidin infusion. In addition, the dose of glycoside required to produce electrophysiologic toxicity was significantly increased by verapamil. Therefore, verapamil appears to exert a protective effect against the development of digitalis-induced arrhythmia, possibly by suppressing delayed afterpotential generation, and significantly increases the dose of digitalis required to produce AV block.