PHYSICOCHEMICAL GROUPINGS OF DRUGS

PHYSICOCHEMICAL GROUPINGS OF DRUGS

It is the physicochemical properties, rather than pharmacological actions of drugs, that determine how they are handled in the body. Five characteristic patterns of drug disposition will be described corresponding with five physicochemical groups.

GROUPING OF DRUGS BY PHYSICOCHEMICAL PROPERTIES

1.Water-soluble drugs 2. Intermediate drugs 3. Lipid soluble drugs 4.Acidic drugs [ pKa 2- 8] 5. Basic drugs [ pKa 6- 12 ] Gentamicin GROUPSEXAMPLES • Digoxin. Thiopentone; Phenytoin Inhalatational anaesthesia. • Salicylic acid. • Lignocaine.

There are two major properties of a drug which determines how it is handled by the body:- • THE DEGREE OF IONIZATION OF THE DRUG MOLECULES IN SOLUTION • THE LIPID SOLUBILITY OF THE UNIONIZED DRUG MOLECULE-

a)THE DEGREE OF IONIZATION OF THE DRUG MOLECULES IN SOLUTION- This is dependent on the pKa of the drug and the pH of the fluid in which the drug is dissolved. i.e. Many drugs can be ionized in aqueous solution. However, only the non-ionized species of such drugs is lipid soluble. The proportions of ionized and non-ionized species are determined by the pH of the medium and the ionization constant of the drug (the pKa = acid dissociation constant= the pH at which one half of the drug molecules are ionized). This relationship is expressed in the Henderson-Hasselbach equation

b)THE LIPID SOLUBILITY OF THE UNIONIZED DRUG MOLECULE- This is often expressed as the partition coefficient between organic solvents and water.

1.WATER SOLUBLE DRUGS EXAMPLES: • Highly ionized [ strong ] acids [ pKa less than 2 ] which are almost 100% ionized in all biological fluids. Drug conjugates e.g. sulphates, glucuronides, glycine conjugates; Sodium Cromoglycate. • Drugs with multiple polar groups-: • Polyhydric alcohols- Mannitol, Sorbitol.

Aminoglycoside antibiotics- Gentamicin, Streptomycin, Neomycin. Mucopolysaccharides- Heparin. Polypeptide antibiotics- Colistin Highly ionized [ strong ] bases [ pKa more than 12 ] which are almost100% ionized in all biological fluids. Quartenary Ammonium derivatives [R4N+ OH ]- Mono-onium compounds- Choline, Tubocurarine, Neostigmine, Pyridostigmine, Cetrimide. Bis-onium compounds- Pancuronium, Suxamethoniun.

CHARACTERISTIC FEATURES • All Water soluble drugs are handled by the body essentially alike, that is : - 1. Absorption from the G.I.T. is negligible and injection is usually necessary for systemic effects. 2. Distribution is restricted to the ECF. 3. The drugs do not penetrate into CSF or brain. 4. Binding to plasma proteins is not important, except for some strong acids.

5. Elimination is mainly by excretion of the unchanged drug in theurine. The drug usually enters the urine by ultra filtration but many anions and cations are also actively secreted into the urine and the bile. Non renal excretion is relatively unimportant for these drugs unless they have a high MW [ greater than 400 Da], when biliary excretion become important. THE DISPOSITION OF THE AMINOGLYCOSIDE ANTIBIOTIC GENTAMICIN; is representative of the group.

1.1 GENTAMICIN • A widely used antibiotic which is effective against Gram-negative bacteria, including E.coli and Klebsiella pneumoniae. • It is important to understand how it is handled in the body because it has toxic effects on the inner ear (vestibular and auditory function) and on the kidney;

Note The vestibular ( middle part of inner ear ) function is more impaired than auditory the amount of drug required to produce damage is only a little greater than the amount required to treat infection [ i.e. the drug has a low therapeutic index ].

CHEMISTRY • Gentamycin is a variable mixture of three very similar components giving an average MW of about 480 Da. • Each component consists of two substituted aminosugar molecules linked through an aminocyclitol. • There are several polar groups on the molecules [ chiefly –OH ] which make them readily soluble in water and insoluble in lipid or organic solvents.

ABSORPTION (a) The drug is not absorbed from the gut and must be given by injection if a systemic effect is required. (b) As with other drugs the rate of absorption from the site of injection is proportional to the local blood flow.

DISTRIBUTION • The water soluble antibiotic molecules cannot generally penetrate into mammalian cells. They are restricted to ECF. • The distribution volume is about 15 Litres in adult. • Penetration across tissue barriers (lipid membranes) into brain, CSF, inner ear fluid, fetal circulation and sputum is slow.

ELIMINATION • Excretion by the kidney is the major route and clearance (CL) closely approximates to the GFR or creatinine clearance (CLcr). (b) Since, in general, cells are not penetrated there is little opportunity for contact with intracellular enzymes and consequent biotransformation.

PERSISTENCE AND ACCUMULATION • The average plasma half-life is about 2 hours… • Thus 8 hours after a dose more than 90% [ 50 + 25 + 12.5 + 6.25 ] of that dose has been eliminated, the dose can therefore be repeated without accumulation.

PERSISTENCE AND ACCUMULATION Cont…. • Severe renal disease produces a very different state however. A reduction in CL causes a proportionate prolongation of plasma half-life. It is then essential to scale down dosage in order to avoid accumulation and toxicity.

PLASMA CONCENTRATION AND PATIENT RESPONSE • Concentration [C] of gentamicin 1 hour after dosage must exceed 5 mg/L, for therapeutic effect in septicaemia but can be as high as 12 mg/L without causing toxicity. (b) Trough concentration [just before the next dosage ] are more relevant to toxicity. However, with less than 2mg/L there is little risk, but with more than 4mg/L the risk is large.

PLASMA CONCENTRATION AND PATIENT RESPONSE (continue) If the trough concentration is large the tiny but slowly penetrated compartment of the inner ear fluid gradually fills up with the drug. (c) A mean concentration [ Css,av ] of 3 to 4 Mg/L represents a compromise that avoids inadequate peaks and excessive troughs.

DOSAGE REQUIREMENTS IN RENAL DISEASE: • The daily dosage rate to maintain a desired Cssav is linear function of creatinine clearance (CLcr). • It varies from about 20 mg/day [ 40 mg every 48 hours] in anuric patients (which allows estimation of non-renal clearance) to about 480 mg/day [ 160 every 8 hours ] in patients with normal kidney function. • Thus the daily dosage rate required to produce a given Cssav varies over a 24- fold range.

SUMMARY • Water soluble drugs either possess multiple polar groups or are strong acids or bases. • The disposition of gentamicin is typical of the group. It is not absorbed orally and must be given by injection. Its distribution is restricted to the ECF. It is eliminated by renal excretion. • Dosage of gentamicin must be reduced in renal failure and in children

2. DRUGS WITH INTERMEDIATE SOLUBILITY • Not all drugs have extreme physical properties. Many are intermediate between highly water soluble aminoglycoside antibiotic agents and the highly lipid soluble i/v anaesthetic agents. • Tetracycline is included but Digoxin has been selected as an important example.

CHARACTERISTIC FEATURES 1. Absorption from the gut is adequate for clinical use but is often not complete. 2. Distribution is not restricted to ECF; the drugs penetrates through cell membranes and into the intracellular water.

CHARACTERISTIC FEATURES (continue) 3.Protein binding has an influence on the distribution and elimination of the drug. 4. Elimination is predominantly by excretion of the unchanged drug in the urine, although a proportion of the drug suffers biotransformation

2.1 DIGOXIN • This drug has the invaluable effect of slowing ventricular rate in patients with atrial fibrillation and increasing the force of contraction in heart failure. • The toxic dose [ heart block; ectopic ventricular activity ] is very close to the therapeutic dose, so there is little safety margin.

CHEMISTRY • The relatively lipid soluble steroid nucleus carrying two OH groups is linked to a highly water-soluble trisaccharide [ three- digitoxose units] by a glycosidic bond. • This structure probably favours concentration at cell surfaces where the drug acts on Na+/K+ ATPase. (inhibits the Na+/K+-ATPase pump) • The glycoside (Mw 781 Da) dissolves more readily in Ethanol than in water or other organic solvents.

ABSORPTION • Digoxin is usually administered by mouth in tablet form. • The dissolution standard that tablets are expected to meet is 75% in solution within 1 hour. • It is absorbed quickly but not completely.

Absorption… • The fraction (F) absorbed or bioavailability is approximately 0.6 (mean) and rather variable (0.4-1.0) • Reduction in particle size in the formulation increases the rate of dissolution and improves bioavailability • A solution for i/m or i/v injection is available for a more rapid response but at the cost of increased liability of acute toxicity.

DISTRIBUTION • Digoxin is distributed throughout body water. • It is bound to protein in plasma [ fb= about 0.3 ] and probably in tissues.

When distribution is complete most of the dose is located in skeletal muscle. Digoxin does not enter fat. V is much greater than body weight [ about 5L/Kg ] because of the high binding capacity of skeletal muscle. The distribution is best described by a two-compartment model.

ELIMINATION • The total CL is greater than for the aminoglycosides but the t1/2 is much longer (1-2 days) because of the large volume. EXCRETION • The renal CL is approximately equal to CLcr: both glomerular filtration and tubular secretion contribute. 70% of the drug is excreted unchanged in the urine

ELIMINATION (continue) METABOLISM • The non-renal CL is about one-half of the renal CL in normal subjects. • -Sugar molecules are spilt off and the steroid nucleus is further hydroxylated in the liver.

PERSISTENCE AND ACCUMULATION • about one-third of the dose is excreted per day. • Digoxin therefore accumulates until the total amount of the drug in the body is about 3 times the single daily dose.

PERSISTENCE AND ACCUMULATION (continue) • This process is 90 % complete in about one week [ 3- 4 x t1/2 ]. • Once the steady state has been attained the total amount of digoxin in the body fluctuates relatively little during the dosage interval. (contrast to gentamicin)

PLASMA CONCENTRATION AND PATIENT RESPONSE • The concentration/ time curve is biphasic because absorption is more rapid than distribution. • The brief high peak may be associated with nausea via an action on the CTZ(Chemosensitive trigger zone) but not with cardiac toxicity.

The cardiac response parallels the hypothetically concentration in a deeper tissue comparment. Css,av is probably the most relevant concentration, which is approximated by C at 6 hours. A concentration of 1-2 g/L is usually adequate to control the ventricular rate in atrial fibrillation. However a concentration above 2 g/L is associated with an increased frequency of ventricular ectopic beats. The therapeutic index approaches unity

DOSAGE REQUIREMENTS IN DISEASE • The rapid attainment of a high therapeutic concentration (~2g/L) would require i/v injection of 2 x V g or 10 g/Kg. • V is approximately halved, however in the elderly and in those with severe renal impairment. Both these states are associated with a relatively low skeletal muscle mass.

DOSAGE REQUIREMENTS IN DISEASE (continue) • Daily dosage requirement for Css,av of 1-2 g/L in the adult varies from 62.5 g in the anuric (one paediatric/geriatric tablet) to 500g in patients with normal kidney function. • Dosage requirement approximately parallels CLcr

SUMMARY • Digoxin is typical of a drug with intermediate solubility. It is partially absorbed from the gut. Its distribution volume is large. Its elimination is by renal and hepatic mechanisms. • Digoxin has a long half-life due to a very large distribution volume, consequent on extensive binding in skeletal muscle

3. LIPID SOLUBLE DRUGS • A large group of drugs including many drugs that act on the CNS. • They have in common a high lipid ( or organic solvent) /water partition coefficient.

The group includes: 1. Weakly acidic drugs ( pKa greater than 8)-Phenytoin and other anticonvulsants. 2. Virtually neutral drugs -Thiopentone and other i/v anaesthetic agents, many sedatives and inhalational anaesthetics, glycerly trinitrate, steroids ( Ethinyloestradiol, Norethisterone, Dexamethasone).

CHARACTERISTIC FEATURES • Absorption from the gut is usually rapid and complete unless chemical inactivation occurs. • Initial distribution of the drug is very rapid. Characteristically the drugs enter tissues, including the brain, at a rate that is limited by the flow of blood, not by the rate of diffusion through the cell membranes.

CHARACTERISTIC FEATURES (continue) • A large proportion of the drug is bound to plasma proteins and to intracellular proteins and lipids. The concentration of drug molecules free in the body water may be very small indeed.

The concentration of drug in the glomerular filtrate is also very small and the drug molecules are so lipid soluble that they are re-absorbed from the renal tubule as quickly as the filtered water. Thus the unchanged drug is not effectively excreted in the urine Some of the drugs in this group, that have a high vapour pressure, are excreted unchanged in the expired air.

Drugs of this group are oxidized in the liver, and to a lesser extent in other tissues, to more polar metabolites; which may be alcohols or phenols. (phase I) Water-soluble metabolites resembles Gentamicin in their elimination. Many are conjugated with sulphate, glycine or glucuronic acid prior to excretion. (phase II)

3.1 THIOPENTONE • Is a short acting barbiturate administered i/v for production of complete general anaesthesia of short duration of action or for induction of sustained anaesthesia.

CHEMISTRY • Thiopentone (MW 242 Da) is a highly lipid-soluble compound due the presence of barbituric acid and an alkyl chain. • Although it has a pKa of 7.6 and is therefore a very weak acid ( it is used as the sodium salt), its predominant physicochemical property is its lipid solubility.

DISTRIBUTION • Is approximately 70% bound to serum albumin by ‘hydrophobic bonds’. • The binding of barbiturates increases with lipid solubility • A single i/v dose of thiopentone can produce almost instantaneous anaesthesia that only lasts for approximately 5 minutes. • Large doses cause respiratory arrest.

PHYSICOCHEMICAL GROUPINGS OF DRUGS