Plasma quinine concentrations

Fig. 5. Observed hearing threshold shift (dB) at 1, 2 and 4 kHz versus measured unbound (upper panel) and total plasma quinine concentration in a subject who received a computer-controlled quinine infusion. The reduced sigmoid Fmax model has been applied and is shown as the solid line. Note that the y axis is hy definition a log scale. (From Karlsson KK, Beminger E, Gustafsson LL, Al-van G. Pronounced quinine-induced cochlear hearing loss. A mechanistic study in one volunteer at multiple stable plasma concentrations. J Audiol Med 1995 4 12-24, with permission.)...

Fig. 5 Mean plasma quinine concentrations following dosing with 50 mg of the dihydrochloride salt in the Pulsincap after treatment with codeine or lactulose. Error bar shows standard deviation.

Quinine given orally is well absorbed the half-life is 11 hours. Clearance is predominantly by hepatic metabolism urinary clearance accounts for only 20%. Information on pharmacokinetics in healthy volunteers can be misleading, since plasma quinine concentrations are higher in the presence of malaria infection than in healthy subjects given the same dose (SEDA-13, 814). The dosage regimen therefore needs to be adapted to the severity of the illness and amended as improvement occurs. 

An 8-year-old child given an incorrect dose of quinine had ventricular tachycardia and status epilepticus after 48 hours the plasma quinine concentration was 20 pg/ml (SEDA-18, 288), compared with the target range of 1.9-4.9 pg/ml. 

Repeated oral administration of activated charcoal reduces plasma quinine concentrations and mitigates toxicity (34). 

The pharmacological effect is exerted by unbound drug molecules. Thus, if only total drug concentrations (e.g. in plasma) are analysed, one should consider whether these measurements are reflective of the concentrations at the site of action. If the unbound drug fraction is more relevant than the total concentration, e.g. because of saturable protein binding, it should be used as the independent variable in the PK-PD model. Figure 5 shows the consistency of the PK-PD relationship between total, as well as unbound quinine concentration and hearing impairment in man. 

Clinical signs and symptoms of hypoglycemia are reported occasionally most cases are subclinical, but severe cases have been described (SEDA-13, 815). A study of the effect of quinidine on glucose homeostasis in Thai patients with malaria showed a near doubling of plasma insulin concentrations and a corresponding fall in serum glucose concentrations. An additional factor may have been impaired nutritional status and the effects of parenteral quinine in severely ill patients not taking food (SEDA-13, 815 SEDA-14, 240 SEDA-18, 288). 

Pedersen KE, Lysgaard Madsen J, Khtgaard NA, Kjaer K, Hvidt S. Effect of quinine on plasma digoxin concentration and renal digoxin clearance. Acta Med Scand 1985 218(2) 229-32. 

The use of quinine to treat cerebral malaria, and to a lesser extent severe malaria, has always been considered more risky than treatment of common cases of malaria. The changes in the pharmacokinetics of quinine caused by the malaria provide an explanation the standard dose of 10 mg/kg is usually well tolerated in patients with uncomplicated malaria but causes markedly higher plasma serum concentrations in patients with cerebral malaria. Total quinine clearance and total apparent volume of distribution are significantly lower in severe malaria, and after recovery, the pharmacokinetics return to normal. Probably the first loading dose should be as generally advised, but with a reduction in subsequent doses until the general condition has improved. Monitoring of plasma or red cell concentrations of quinine would of course be ideal, but this luxury is rarely available (SEDA-13, 816). 

Fig. 6. Counterclockwise hysteresis appearing between hearing threshold shift and quinine plasma concentration in a subject who received two identical oral doses (dotted and solid lines) and an infusion (dashed line) of quinine. (From Paintaud G, Alvan G, Beminger E et al. The concentration-effect relationship of quinine-induced hearing impairment. Clin Pharmacol Ther 1994 55 317-23, with permission from MOSBY Inc.)...

Karlsson KK, Berninger E, Gustafsson EE, Alvan G. Pronounced quinine-induced cochlear hearing loss. A mechanistic study in one volunteer at multiple stable plasma concentrations. J Audiol Med 1995 4 12-24. 

Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-... 

Figure 7 Change in the biliary and renal clearance of digoxin caused by quinidine or quinine treatment. After a steady state concentration of quinine or quinidine was achieved by multiple oral administrations, the plasma concentration and biliary and urinary excretion of digoxin after oral administration were measured in healthy volunteers. The steady state concentrations of quinine and quinidine were 7.0 2.5 and 4.5 0.5 pM, respectively. Source From Ref. 291.

BETA-BLOCKERS QUININE Risk oft plasma concentrations and effects of labetalol, metoprolol and propranolol t systemic effects of timolol eye drops Quinine inhibits CYP2D6, which metabolizes these beta-blockers Monitor BP at least weekly until stable... 

DIGOXIN QUININE Plasma concentrations of digoxin may t when co-administered with quinine Uncertain, but seems to be due to -I non-renal (possibly biliary) excretion of digoxin Monitor digoxin levels watch for digoxin toxicity... 

Quinine was originally extracted from the bark of the Cinchona tree (Peruvian bark or Jesuits bark) and was used to treat ague, that is fever, usually due to malaria. It fell out of fashion with the advent of other antimalarial drugs, but has once again become the drug of first choice for malaria originating in areas with multiresistant Plasmodium falciparum. To be effective, quinine plasma concentrations greater than the minimal inhibitory concentration must be achieved and maintained. 

Adverse effects of quinine are common at plasma concentrations over 10 pg/ml. The dose often recommended, 10 mg/kg intravenously over 10-20 minutes, may be too high in patients with cerebral malaria (SEDA-14, 240). In the USA, intravenous quinine has been discontinued in favor of quinidine (SEDA-17, 329). In some areas, a high rate of recrudescence is seen after short-term treatment with quinine. The addition of specific antibiotics may improve the cure rate. 

Drugs for which measurement is useful include carbon monoxide, digoxin. ethanol, iron, lithium, paracetamol, paraquat, phenobarbitone, phenytoin. quinine, salicylate and theophylline. The main reason for drug analyses is to assess the prognosis. The concentration in a blood or plasma specimen gives a good... 

Quinine and quinidine block potassium channels, both calcium independent ones and calcium-activated ones in several types of membranes [498,499, 500]. Quinine also has less specific effects on other ion channels — chloride as well as cations [501]. Blocking of potassium channels has a secondary effect of stimulating synthesis of phosphatidylserine and affecting other processes that are controlled by potassium concentration [289, 502, 503]. The bisbenzylisoquinoline alkaloid dauricine seems to act similarly to quinidine [504]. Some effects of quinine and quinidine, rather than showing actions on specific ion channels may come from more general effects on membrane structure. Quinidine does decrease the fluidity of liver plasma membrane [505] and it does interact with lipid bilayers [506]. 

Quinine rarely causes cardiovascular complications unless target plasma concentrations are exceeded. QTc prolongation is mild and does not appear to be affected by concurrent mefloquine treatment. However, severe hypotension is predictable when quinine is administered too rapidly intravenously. Acute overdosage also may cause serious and even fatal cardiac dysrhythmias. Quinidine is even more cardiotoxic than quinine. Cardiac monitoring of patients on intravenous quinidine is advisable where possible. 

Concentrated solutions of quinine may cause abscesses when injected intramuscularly or thrombophlebitis when infused intravenously. GI absorption of quinine can be delayed by antacids containing aluminum. Quinine and quinidine can elevate plasma levels of digoxin. Likewise, the alkaloid may raise plasma levels of warfarin. The action of quinine at neuromuscular junctions will enhance the effect of neuromuscular blocking agents and oppose the action of acetylcholinesterase inhibitors. Prochlorperazine can amplify quinine s cardiotoxicity, as can halo-fantrine. The clearance of quinine is decreased by cimetidine and increased by acidification of the urine and by rifampin. 

Despite the completeness and rapidity of absorption just mentioned, there are great variations in the concentrations of the various alkaloids found in plasma after a standard oral dose. The data of Hiatt (69) on human volunteers demonstrates this dramatically (cf. summary in Fig. 2). These observations show that at a dosage of 10 mg. per kilogram the peak level of cinchonine in plasma is only one-fourth that of quinidine, one-fifth that of cinchonidine, and one-eighth that of quinine. Similar differences in plasma levels have been found in other species. 

The distribution of quinine and other cinchona alkaloids in blood and tissues following oral or intravenous administration of these drugs has been studied by many workers in a variety of animal species. It is generally agreed by all workers that peak concentrations of the drugs in plasma are reached within 2 to 4 hours of oral dosage and decline rapidly thereafter. At relatively low or therapeutic doses of the alkaloids, there is httle localization of any of the compounds in the erythrocytes (70). For example, plasma contains 6 to 12 times as much quinine as erythrocytes. At toxic doses, however, these distribution ratios are badly distorted until at lethal doses there are essentially equal concentrations of quinine in cells and plasma (70). 

Distribution of the cinchona alkaloids in tissues other than blood seems to vary both with the tissue and with the animal species. Relatively speaking, there is little concentration of the alkaloids in the muscle or nervous tissues of any species, levels in these tissues often being less than those in plasma. In animals such as the chicken and dog (71-73) the levels of the alkaloids in liver, spleen, kidney, intestinal mucosa, and lung were often 10 to 40 times the concentrations in plasma. However, in the monkey (70) concentrations of quinine in these tissues were rarely more than 5 times the level of the drug in plasma. These direct observations in the monkey are in accord with indirect findings in man (20). 

Fig. 2. Comparison of the concentrations of quinine, quinidine, cinchonine, and cinchonidine in the plasma of human subjects following ingestion of 10 mg. per kg. doses of these drugs.

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