J. Vanakoski

Heat Exposure and Drugs A Review of the Effects of Hyperthermia on Pharmacokinetics

Acute heat loading is encountered in several everyday situations, during physical exercise or work in a hot climate are just 2 examples. Special forms of heat exposure include different types of steam baths and saunas. External heating induces changes in haemodynamics, body fluid volume and blood flow distribution, which in turn may affect the pharmacokinetics of a drug and the therapeutic response. Documentation of the effects of heat exposure on the pharmacokinetics of drugs in humans is very limited, but based on the documentation some general conclusions can be drawn.The effects of external heating on absorption and elimination of those orally administered drugs which have been studied (e.g. midazolam, ephedrine, propranolol and tetracycline), have been minor. Systemic absorption of transdermally and subcutaneously administered drugs [insulin, nitroglycerin (glyceryl trinitrate) and nicotine] is in most cases enhanced by external heating, leading to higher plasma drug concentrations.In general, pharmacokinetic interactions between heat exposure and drug therapy are rare and limited to special situations, in which local blood flow (for example, over the skin) is enhanced many-fold because of hyperthermia. When pharmacodynamics are concerned, in most cases the probability of interactions is low, but in the treatment of malignant tumours hyperthermia may potentiate cytotoxic effects of drugs without enhancement of myelosuppressive effects.

Grapefruit juice does not enhance the effects of midazolam and triazolam in man

Objectives: Since grapefruit juice (Gra) inhibits hepatic P450 (CYP3A4), we studied its potential to enhance the effects of midazolam (Mid) and triazolam (Trz), which are metabolized by the CYP3A4 isoenzyme.Methods:In Study I parallel groups of healthy students were given orally Mid 10 mg with water or grapefruit juice (GraMid), two placebo groups receiving water or Gra. The effects of Mid were measured by psychomotor tests and by self-rating on visual analogue scales before and 30 and 90 min after intake. Study II was similar, but the post-treatment tests were at 45 and 90 min, and the active drugs used were 0.250 mg Trz, GraTrz, and Mid 10 mg. In the crossover Study III, 6 subjects took Mid 10 mg alone and with Gra (GraMid) and 750 mg erythromycin (EryMid). Performance tests were made and blood was sampled before and 30, 60 and 90 min after intake. Midazolam and its active metabolite α-OH-midazolam were assayed by gas chromatography (GC) and radioreceptor assay (RRA).Results:In Study I, both Mid and GraMid impaired digit symbol substitution (DSS), letter cancellation (LC) and flicker fusion (CFF) at 90 min. GraMid had more effect (P < 0.05) than Mid on the DSS performance. Mid caused drowsiness at 30 and 90 min. Both Mid and GraMid caused clumsiness and a feeling of impaired performance at 90 min. In Study II, the active drugs impaired objective test performances (DSS, LC, CFF) at 90 min, without having a clear subjective effect. In Study III, Mid, EryMid and GraMid impaired performance in the DSS, LC and CFF tests. EryMid proved stronger than Mid and GraMid on DSS and LC tests at 30 min. Mean values of plasma midazolam (and α-OH-midazolam) at 30, 60, 90 and 120 min after Mid 10 mg were 68 (19), 61 (19), 43 (14) and 42 (12) μg⋅l−1. The corresponding values after EryMid were 164 (14), 137 (13), 104(10) and 89(10) μg ⋅l−1, and after GraMid 60 (12), 69 (16), 61 (15) and 57 (14) μg⋅l−1.Conclusions:The grapefruit juice used did have any particular interaction with oral doses of 10 mg midazolam and 0.25 mg triazolam in healthy young subjects.

Exercise alters the pharmacokinetics of midazolam

Six healthy volunteers received 15 mg midazolam, 50 mg ephedrine, or placebo orally before a 50‐minute aerobic treadmill exercise and in a control session. Plasma drug concentrations for pharmacokinetic calculations were estimated from samples drawn up to 24 hours after drug intake. Heart rate, blood pressure, critical flicker fusion test, Maddox wing test, and visual analog scales relating to mood and feelings of tiredness were included in the sessions as pharmacodynamic measures. These tests were made at 35, 55, and 75 minutes and at 2, 2½, 3½, and 5 hours after drug intake. Exercise impaired the absorption of midazolam and counteracted the midazolam‐induced decrement in flicker fusion threshold. Whether the effect on flicker fusion was caused mainly by the pharmacokinetic changes or by a general alerting effect of exercise cannot be verified by this experiment. The kinetics of ephedrine was not affected by exercise, but exercise enhanced the tachycardic response to ephedrine and abolished its pressor effect.

Exposure to high ambient temperature increases absorption and plasma concentrations of transdermal nicotine

Absorption and plasma concentrations of transdermally delivered drugs may be increased during heat exposure. We studied the effects of short‐term heat exposure in a sauna bath on the pharmacokinetics of transdermal nicotine, 25 mg/16 hr, in 12 healthy smokers in an open, randomized crossover study that consisted of a control session and a sauna bathing session. In the sauna session the subjects stayed seated in a sauna bath (mean temperature 82° C (180° F); mean relative humidity 28%) for three 10‐minute periods separated by two 5‐minute breaks. Sauna bathing significantly (p < 0.01 versus control) increased peak plasma concentration, area under the plasma concentration‐time curve from 0 to 1 hour, the amount of nicotine absorbed, and the mean plasma nicotine concentrations during heat exposure. No significant difference in nicotine area under the plasma concentration‐time curve from 0 to 3 hours was observed. In addition, the combined effects of transdermal nicotine and sauna bathing on hemodynamics, some psychomotor skills, and subjective symptoms were evaluated. We concluded that absorption and plasma concentrations of transdermally delivered nicotine may be increased during exposure to high ambient temperature, probably because of enhanced skin blood flow. However, no adverse symptoms were recorded.

Effects of a sauna on the pharmacokinetics and pharmacodynamics of midazolam and ephedrine in healthy young women

SummaryThe effect of a sauna on the pharmacokinetics and pharmacodynamics of single doses of ephedrine 50 mg and midazolam 15 mg have been studied in 6 young healthy women in a placebo-controlled, double-blind study.The sauna (3 × 10 min; temperature 80–100°C; relative humidity 30–50%) modified the pharmacokinetics of both drugs: it retarded the absorption of midazolam estimated as Ka values, and it reduced the mean plasma midazolam concentrations at 2 h; ephedrine, was absorbed more rapidly and the maximum plasma concentration occurred earlier than in the control sessions.Changes in the pharmacodynamics due to the sauna were consistent with the pharmacokinetic findings: midazolam decreased flicker recognition and induced exophoria significantly less during the early sauna period than in the control session, whereas ephedrine made the volunteers subjectively more alert at that time. Later, at 2.5 and 3.5 h (1 h 20 min and 2 h 20 min after cessation of the sauna), and despite the equalisation of the plasma levels, midazolam caused significantly more exophoria after the sauna than in the control situation.This indicates an influence of a sauna on drug pharmacodynamics in the post-sauna adaptive phase. The results suggest that exposure to a sauna may alter both drug pharmacokinetics and pharmacodynamics.

Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects

Objectives: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D2- and D3-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible interaction with alcohol on human performance, amisulpride was studied for this potential.Methods:In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride 50 mg and 200 mg, without and with ethanol (0.8 g ⋅kg−1) taken 30 min later. Objective performance tests and self-ratings were done at baseline and 1.5, 3.5 and 6.5 h after drug intake. Memory (immediate and delayed recall) was tested 2 h after dosing. Breath ethanol and the plasma concentrations of amisulpride and prolactin were measured. Three-way ANOVA + Newman-Keul tests were used for statistical analyses; interactions were confirmed by factorial contrast ANOVA.Results:Mean blood ethanol was 0.94, 0.62 and 0.26 g ⋅l−1 at the three test times. It produced significant impairment in all performance tests (symbol digit substitution, simulated driving, body sway, flicker fusion, tapping, nystagmus), reduced both immediate and delayed recall in memory tests, and caused subjective clumsiness, muzziness and mental slowness, mainly between 1.5 to 4.5 h after dosing. Amisulpride, 50 and 200 mg elevated plasma prolactin but had minimal or no effect on performance, attention and memory. The decreases in immediate free recall after the 50 mg dose and in delayed free recall after the 200 mg dose were slight. Amisulpride neither modified blood ethanol concentrations nor enhanced the detrimental effect of ethanol on skilled and cognitive performance; it slightly antagonised ethanol in the digit copying test. Ethanol did not modify the effect of amisulpride on plasma prolactin, and the plasma concentrations of amisulpride were little changed by ethanol.Conclusions:Amisulpride in single oral doses of 50 and 200 mg did not interact significantly with the effects of high, moderate or low concentrations of ethanol on human skilled and cognitive performance. The drugs did interact pharmacokinetically.

Suriclone enhances the actions of chlorpromazine on human psychomotor performance but not on memory or plasma prolactin in healthy subjects

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a “Global test”, flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects.Compared to placebo, SU minimally affected “global” performance, although it slowed reactions and tended to impair digit substitution. ZO impaired “global” performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair “global” performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired “global” performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests.CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition.No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam +100 mg remoxipride.

Azithromycin does not alter the effects of oral midazolam on human performance

Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500mg+250mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam.In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin + midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min. The combination differed from midazolam 15 mg in producing less drowsiness and mental slowness. In Study II, mean plasma midazolam concentrations (μg·1-1) after erythromycin + midazolam 10 mg were 0 (baseline), 168 (30 min) and 113 (90 min), which were higher than the values (0, 79 and 41) after placebo + midazolam. The corresponding concentrations (μg·1-1) after azithromycin + midazolam (0, 85 and 46) were similar to those found after placebo + midazolam. Erythromycin but not azithromycin enhanced the objective and subjective effects of midazolam. Our results suggest that as azithromycin, unlike erythromycin, does not interfere with midazolam metabolism, it also does not enhance the effects of midazolam.

Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers.

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo. propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85–100°C, relative humidity 25–35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng·ml−1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0–5h (119 vs 71 μg·h·l-1) of propranolol from 0 to 5 hours tmax, t1/2β and AUC0–24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase. The results suggest that a sauna may increase the plasma propranolol concentration, but that did not notably affect the blood pressure or heart rate in healthy, young volunteers during the post-sauna phase.

Effects of heat exposure in a finnish sauna on the pharmacokinetics and metabolism of midazolam

Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg−1) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration.Results:After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam Cmax was increased and its t1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing.Conclusions:Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam.