Pharmacokinetics of Sotalol and Propranolol - Assignment Example

 Pharmacology Introduction Sotalol is a non-selective beta- adreno receptor antagonist. It contains equal amounts of D (+) sotalol and L (-) sotalol. This drug does not have the toxic effects in the myocardium of the experimental animals (Frankl and Soloff, 1968). In dogs, sotalol was very effective in lowering the heart beat rate. The effect of propranolol was greater than sotalol in the untreated dogs (Allely and Ungar, 1985). Speaking of propranolol, it is a very potent and pure antagonist which blocks the beta1 and beta 2 receptors. It is a highly lipid soluble drug and it enters the brain easily (Rang et al., 2010). Propranolol was found to reduce the blood pressure, cardiac output, and others in the cats, when administered intravenously (Aderg et al., 1969). Enantiomers Sotalol is an important anti-arrhythmic, class II/III drug. It is an oral drug with equal amounts of two enantiomers: D- and L--sotalol. Both enantiomers have the potency to act as non-selective blockers. The L – enantiomer gives greater benefits by acting as beta- blockade for a long term period. L- Sotalol has 38% protein binding capacity and D-sotalol has 35% protein binding capacity (Chhabra, Aseri and Padmanabhan, 2013). D-sotalol has no beta blocking activity. The action potential of sotalol is due to the L-isomer and it also acts as alpha- blocker, while D-sotalol acts as anti-arrhythmic. D-sotalol has 30 to 60 times lower affinity than L-sotalol. On the other hand, in the case of Propranolol, there are two isomers: D and L – propranolol. D-propranolol binds to the proteins more extensively than L- propranolol. The L–isomer of propranolol is the biologically active form of drug. It is nearly absorbed orally and metabolized in the liver on its first passage. D-propranolol is inactive in beta-adrenoreceptor blocking activity. So, it was observed that isomerism leads to many therapeutic and adverse drug reactions (Chhabra, Aseri and Padmanabhan, 2013). D and L–propranolol have membrane stabilizing property and this racemic mixture reduces the heart rate and the force of contraction in treated animals. Pharmacokinetics: The pharmacokinetic parameters of sotalol were studied in dogs and rats. Dogs had a higher volume of distribution and the elimination of the drug was through renal excretion. In rats, high concentration of sotalol was observed in various tissues. (Tawara, 1977). The half life of the drug was longer than other beta adrenergic blockers in dogs. Beta blockade was observed without any change in the blood pressure in dogs (Ishizaki and Tawara, 1979). Propranolol is highly lipophilic and completely absorbed in the gastrointestinal tract. The bioavailability of the drug is more after food and when administered chronically. The distribution of the drug is very rapid. The pharmacokinetics studies have confirmed that they have a high binding affinity with the plasma. At the same time, the binding capability differs with the half – life of the drug. The plasma protein binding of propranolol may affect the rate of excretion and hepatic clearance in animals including dogs and rats (Evans, Nies and Shand, 1973). The half life of the drug is largely dependent on the liver blood flow. Studies of intravenous administration in rats showed that higher concentrations of propranolol produced a reduced binding affinity for propranolol. At high doses, the half-life of the drug and the volume of distribution were found to be high (Schnelle and Garrett, 1973). Table 1: Pharmacokinetics of Sotalol and Propranolol: Property Sotalol Propranolol Plasma level concentration 1-3.4 microgram/ml in dogs (Tawara, 1977) Plasma clearance 90% in dogs (Ishizaki and Tawara, 1979) 4.78 ± 0.96 microgram/ ml in rats ( Kulmatycki et al., 2001) Plasma clearance 100% ( Kulmatycki et al., 2001) 99.2% for monkeys, 96.6% for dogs and 92.2% for rats.(Evans, Nies and Shand, 1973) Elimination Renal clearance in dogs (Tawara, 1977) Renal clearance in rats ( Kulmatycki et al., 2001) Kidney and liver in dogs and rats.(Evans, Nies and Shand, 1973) Renal clearance 4.21 ± 0.31 ml/min/kg in dog Unchanged drug excretion in urine – 72 ± 12% in dogs (Ishizaki and Tawara, 1979) Unchanged drug excretion in rats ( Kulmatycki et al., 2001) was 66 ± 6% ml / kg/ minute for dogs (Christ et al., 1990) 50% of unchanged drug is excreted in urine in rats ( Smits et al., 1982) Bioavailability 90-100% in dogs.(Schnelle and Garrett, 1973) 4.15 ± 0.76 microgram/ ml for racemate S-sotalol in rats ( Kulmatycki et al., 2001) 25-30% in dogs (Christ et al., 1990) 25% in rats (Smits et al., 1982). Pharmacodynamics The half- life of the Sotalol in dogs was 4.3 ± 0.4 hours and this is longer than any other beta adrenergic blocker in dogs. The renal clearance of the drug was 4.21 ± 0.31 ml/ min/ kg in dogs. The total plasma clearance was around 90% and 72 ± 12 % of the drug was excreted unchanged in urine (Ishizaki and Tawara, 1979). Distribution and elimination of the drug follows first order kinetics and the drug is excreted through the kidney. The total absorption of the drug orally was around 75- 90%. Sotalol is eliminated by the urine as unchanged drug up to a concentration of 90 +/- 12% in urine (Schnelle and Garrett, 1973). On the other hand, propranolol was highly metabolized in the liver. The hepatic clearance of the drug from the whole body was around 65 – 103%. The drug is completely absorbed and hence it is not eliminated as unchanged drug from the body through urine (Breckenridge et al., 1973). In monkeys, propranolol was completely absorbed and the plasma concentrations were observed after 1 hour. The excretion of the drug was completely through urine in monkey, but in dogs and rats, 25% of the excretion was through the feces (Hayes and Cooper, 1971). When drug concentration was observed through HPLCS, the basic metabolites were present in the concentration of 35± 1% in dog, 59± 2% in rats, and 53± 5% in the hamster. Similarly the acidic metabolites were present in the dog, rat, and hamster urine at 32 ±3% , 4 ±1% and 5 ±1% respectively. An unknown fraction of propranolol metabolites were excreted in the urine of dogs (34 ± 2%), rats ( 37± 1%), and in hamsters ( 40 ± 8%) and these metabolites had a long half- life period in dog and rat (Bargar et al., 1983). The physicochemical properties of any drug includes lipophilicity, solubility, Ionization constants, melting point, and bioavailabiltiy, volume of distribution and half life of the drug. They are given in table 3 for sotalol and propranolol. Table 2: Pharmacodynamics of Sotalol and Propranolol: Property Sotalol Propranolol Absorption 75-90 % in dogs.(Schnelle and Garrett, 1973) 100% in dogs. (Breckenridge et al., 1973) 100% in rats (Hayes and Cooper, 1971) Excretion Kidney in dogs (Schnelle and Garrett, 1973) Kidney in rats (Kulmatycki et al., 2001) Kidney in dogs. (Breckenridge et al., 1973) Kidneys in rats (Hayes and Cooper, 1971) Distribution Follows first order kinetics in dogs (Schnelle and Garrett, 1973) First order kinetics in dogs (Breckenridge et al., 1973) First order kinetics in rats (Smits et al., 1982) Elimination 90 ± 12% through urine in dogs (Schnelle and Garrett, 1973) 65 – 103% through urine in dogs and rats. 25% through feces in dogs and rats (Hayes and Cooper, 1971) Antagonist Beta – adrenergic receptor Beta- adrenergic receptor. Competitive antagonism is exerted by isoprenaline (Doggrell, 1990) Antagonist effect It directly depends on the dose concentration (Lynch et al., 2008). It directly depends on the dose concentration (Doggrell, 1990) Agonist and antagonist action Blocking the beta- adrenergic receptor and increases the QT interval duration. Decrease in heart rate based on concentration of dose. Hypotension was observed in monkeys (Lynch et al., 2008). Blocking beta –adrenergic receptor activity and inhibiting the response to electrical stimulation – (-) propranolol is 100 times more potent than (+) propranolol. This study also blocked the activity of isoprenaline (Doggrell, 1990) Affinity They have high affinity (Lynch et al., 2008). They have high affinity (Doggrell, 1990) Potency D- sotalol has same potency as D-propranolol and were very effective in increasing the fibrillation threshold. It can also increase the action potential of cardiac contractility (Patterson and Lucchesi, 1984) D-propranolol has same potency as D-sotalol and was very effective in increasing the fibrillation threshold (Patterson and Lucchesi, 1984) Table 3: Physicochemical properties of Sotalol and Propranolol: Property Sotalol Propranolol Lipophilicity Hydrophilic (Brittain and Florey, 1992) Lipophilic (Silber and Riegelman, 1980) Solubility Soluble in water, ethanol, propylene glycol Slightly soluble in chloroform (Brittain and Florey, 1992) Soluble in water, ethanol and insoluble in non-polar solvents (Silber and Riegelman, 1980) Ionization constants Pka for amine – 9.8 pKa for sulfonamide – 8.3 (Brittain and Florey, 1992) pKa – 9.53 (Brittain , 2007) Melting point 204- 218 °C (Brittain and Florey, 1992) 196 °C (Silber and Riegelman, 1980) Volume of distribution 1.2 – 2.4 liters/ kg in dogs(Schnelle and Garrett, 1973) 0.80 ± 0.28 for rats (Kulmatycki et al., 2001) 4 liters / kg in dogs. (Evans, Nies and Shand, 1973) 8.5 liters / kg in rats (Bianchetti et al , 1980) Half life 4.3 ± 0.4 hr in dog (Ishizaki and Tawara, 1979) Intravenous – 6- 8 hours in dogs (Schnelle and Garrett, 1973) 1.43 ± 0.41or rats (Kulmatycki et al., 2001) 2-3 hours for dogs.(Evans, Nies and Shand, 1973) 63 minutes for rats (Bianchetti et al., 1980) References: Aderg, G., Dzedin, T., Lundholm, L., Olsson, L and Svedmyr, N. (1969) A Comparative Study of some Cardiovascular Effects of Sotalol (MJ1999) and Propranolol. Life Sciences. 8 (7). p.353-365. Alley, M. C and Ungar, A. (1985) Interactions of β- adrenoceptor Antagonists and Thyroid Hormones in the control of Heart Rate in the Dog. British Journal of Pharmacology. 86. p.393-398. Bargar, E. M. et al. (1983) Quantitative Metabolic rate of Propranolol in the Dog, Rat, and Hamster using Radiotracer, high performance Liquid Chromatography, and Gas Chromatography-mass Spectrometry Techniques. 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