Important Preparations in Pharmacology - Lab Report Example

Pharmacology al Affiliation Pharmacology Introduction Sotalol relates to a non-selective beta- adreno receptor antagonist. It contains equal amounts of D (+) sotalol and L (-) sotalol. It is indispensable to note that sotalol drug does not have the toxic effects in the myocardium of the experimental animals (Frankl and Soloff, 1968). However, in dogs sotalol remains pharmacologically effective in lowering the heart beat rate. Nevertheless, the inherent effect of propranolol remains greater than sotalol amongst untreated dogs (Allely and Ungar, 1985). Propranolol relates to a significally potent and pure antagonist that blocks the beta-1 and beta- 2 receptors. Propranolol exists as a highly lipid soluble drug and normally enters the brain easily (Rang et al., 2010). Experiments established that propranolol can reduce blood pressure, cardiac output, and others diseases amongst cats especially when administered intravenously (Aderg et al., 1969). Enantiomers of Sotalol Sotalol is an important anti-arrhythmic, class II/III drug. Sotalol acts as an oral drug with equal amounts of two enantiomers including 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. In addition, the L- Sotalol has 38% protein binding capacity while D-sotalol has 35% protein binding capacity (Chhabra, Aseri and Padmanabhan, 2013). Notably, D-sotalol has no beta blocking activity. The action potential of sotalol results from L-isomer activity that also acts as alpha- blocker, while D-sotalol acts as anti-arrhythmic. However, D-sotalol has 30 to 60 times lower affinity than L-sotalol. Enantiomers of Propranolol Propranolol have two isomers including D and L – propranolol. D-propranolol binds to proteins more extensively than L- propranolol. However, L–isomer of propranolol acts as the biologically active form of drug. L–isomer of propranolol is nearly absorbed orally and metabolized in the liver on its first passage. On the contrary, D-propranolol is inactive in beta-adrenoreceptor blocking activity. Therefore, experiments established 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 heart rate and related force of contraction amongst treated animals. Table 3: Physicochemical properties of Sotalol and Propranolol Property Sotalol Propranolol Lipophilicity Hydrophilic (Brittain and Florey, 1992) Lipophilic (Silber and Riegelman, 1980) Solubility 1) Soluble in water, ethanol, propylene glycol 2) Slightly soluble in chloroform (Brittain and Florey, 1992) 1) Soluble in water and ethanol (polar solvents) 2) Insoluble in non-polar solvents (Silber and Riegelman, 1980) Ionization constants 1) pKa for amine – 9.8 2) 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) 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 values of Sotalol and Propranolol Property Sotalol Propranolol Plasma level concentration 1) 1-3.4 microgram/ml in dogs (Tawara, 1977) 2) Plasma clearance of 90% in dogs (Ishizaki and Tawara, 1979) 3) 4.78 ± 0.96 microgram/ ml in rats ( Kulmatycki et al., 2001) 4) Plasma clearance 100% ( Kulmatycki et al., 2001) 1) 99.2% for monkeys 2) 96.6% for dogs 3) 92.2% for rats.(Evans, Nies and Shand, 1973) Elimination 1) Renal clearance in dogs (Tawara, 1977) 2) Renal clearance in rats ( Kulmatycki et al., 2001) 1) Kidney and liver in dogs and rats.(Evans, Nies and Shand, 1973) Renal clearance 1) 4.21 ± 0.31 ml/min/kg in dog 2) Unchanged drug excretion in urine – 72 ± 12% in dogs (Ishizaki and Tawara, 1979) 3) Unchanged drug excretion in rats ( Kulmatycki et al., 2001) 1) Existed as 66 ± 6% ml / kg/ minute for dogs (Christ et al., 1990) 2) 50% of unchanged drug is excreted in urine in rats (Smits et al., 1982) Bioavailability 1) 90-100% in dogs.(Schnelle and Garrett, 1973) 2) 4.15 ± 0.76 microgram/ ml for racemate S-sotalol in rats ( Kulmatycki et al., 2001) 1) 25-30% in dogs (Christ et al., 1990) 2) 25% in rats (Smits et al., 1982). Volume of distribution 1) 1.2 – 2.4 liters/ kg in dogs(Schnelle and Garrett, 1973) 2) 0.80 ± 0.28 for rats (Kulmatycki et al., 2001) 1) 4 liters / kg in dogs. (Evans, Nies and Shand, 1973) 2) 8.5 liters / kg in rats (Bianchetti et al , 1980) Half life 1) 4.3 ± 0.4 hr in dog (Ishizaki and Tawara, 1979) 2) Intravenous – 6- 8 hours in dogs (Schnelle and Garrett, 1973) 3) 1.43 ± 0.41or rats (Kulmatycki et al., 2001) 1) 2-3 hours for dogs.(Evans, Nies and Shand, 1973) 2) 63 minutes for rats (Bianchetti et al., 1980) 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%. According to Schnelle and Garrett, 1973 sotalol remains eliminated by urine as unchanged drug up to a concentration of 90 +/- 12% in urine (Schnelle and Garrett, 1973). On the contrary, the liver highly metabolized propranolol. 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, meting point, and bioavailabiltiy, volume of distribution and half life of the drug. The pharmacodynamics exists as given in table 3 for sotalol and propranolol. Table 2: Pharmacokinetics (ADME) of Sotalol and Propranolol Property Sotalol Propranolol Absorption 1) 75-90 % in dogs.(Schnelle and Garrett, 1973) 1) 100% in dogs. (Breckenridge et al., 1973) 2) 100% in rats (Hayes and Cooper, 1971) Excretion 1) Kidney in dogs (Schnelle and Garrett, 1973) 2) Kidney in rats (Kulmatycki et al., 2001) 1) Kidney in dogs. (Breckenridge et al., 1973) 2) Kidneys in rats (Hayes and Cooper, 1971) Distribution Follows first order kinetics in dogs (Schnelle and Garrett, 1973) 1) First order kinetics in dogs (Breckenridge et al., 1973) 2) First order kinetics in rats (Smits et al., 1982) Elimination 1) 90 ± 12% through urine in dogs (Schnelle and Garrett, 1973) 1) 65 – 103% through urine in dogs and rats. 2) 25% through feces in dogs and rats (Hayes and Cooper, 1971) 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. Drug metabolism and disposition: the biological fate of chemicals. 11(3).p.266-72. Bianchetti, G. et al. (1980) Kinetics of Distribution of Di-propranolol in various organs and Discrete Brain areas of the Rat. Journal of Pharmacology and Experimental Therapeutics. 214(3). p.682- 687. Breckenridge, A. et al. (1973) Hepatic clearance of Propranolol in Dogs. British journal of Pharmacology. 48 (1). p.336-337. Brittain, H.G. (2007) Profiles of Drug substances, Excipients and related Methodology: Critical compilation of pKa values for Pharmaceutical substances. Waltham: Academic Press. Brittain, H.G. and Florey, K. (1992) Profiles of Drug Substances, Excipients and related Methodology, Waltham: Academic Press. Chhabra, N., Aseri, M. L. and Padmanabhan, D. (2013) A review of Drug Isomerism and its Significance. International Journal of Applied and Basic Medical Research. 3 (1). p.16 – 18. Christ, D.D. et al. (1990). Pharmacokinetics and metabolism of the pharmacologically active 4-hydroxylated Metabolite of Propranolol in the Dog. Drug Metabolism and Disposition: the Biological fate of chemicals. 18(1). p.1-4. Evans, G. H., Nies, A. S and Shand, D. G. (1973). The Disposition of Propranolol: Decreased half-life and volume of Distribution as a result of Plasma Binding in Man, Monkey, Dog and Rat. Journal of Pharmacology and Experimental Therapeutics. 186(1). p.114-122. Frankl, W. S and Soloff, L.A. (1968). Sotalol: a new, safe beta Adrenergic Receptor Blocking Agent. American Journal of Cardiology. 22(2). p.266-72. Hayes, A. and Cooper, R.G. (1971). Studies on the Absorption, Distribution and Excretion of Propranolol in Rat, Dog and Monkey. The Journal of Pharmacology and Experimental Therapeutics. 176 (2). p.302-311. Ishizaki, T and Tawara, K. (1979). Relationship between Pharmacokinetics and Pharmacodynamics of the beta adrenergic blocking drug Sotalol in Dogs. The Journal of Pharmacology and Experimental Therapeutics. 211(2). p.331- 337. Kulmatycki, K.M et al. (2001). Drug-disease Interactions: Reduced Beta- adrenergic and Potassium Channel antagonist Activities of Sotalol in the presence of Acute and Chronic Inflammatory Conditions in the Rat. British Journal of Pharmacology. 133(2). p.286-294. Rang, H. P. et al. (2010) Rang & Dales Pharmacology, 7E. Amsterdam: Elsevier. Schnelle, K. and Garrett, E.R. (1973) Pharmacokinetics of the beta- adrenergic blocker Sotalol in Dogs. Journal of Pharmaceutical sciences. 62(3). p.362-375. Silber, B and Riegelman, S. (1980). Stereospecific assay for (-)- and (+)- Propranolol in Human and Dog Plasma. The Journal of Pharmacology and Experimental Therapeutics. 215(3). p.643 – 8. Smits, J.F.M. et al. (1982). Antihypertensive effect of Propranolol in conscious spontaneously Hypertensive Rats: Central Hemodynamics, Plasma volume, and Renal function during Beta-blockade with Propranolol. Journal of Cardiovascular Pharmacology. 4(6). p.903 – 914. Tawara, K. (1977). Studies on the Pharmacokinetics and effects of beta-adrenergic Blocking agents, Sotalol. The Hokkaido Journal of Medical Science. 52(3).p. 245-259. Read More