The Nature of Drugs

The Nature of Drugs

• Drugs in common use: inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates
• Some found in plants or animals, but others are synthetic
• Alkaloids are drugs found in nature, having a basic pH in solution
• Drugs can vary in size from molecular weight (MW) 7 (lithium) to over MW 50,000 (thrombolytic enzymes, antibodies, other proteins)
• Most drugs have MWs between 100 and 1000
• Drugs smaller than MW 100 are rarely selective
• Drugs much larger than MW 1000 are often poorly absorbed
• Drugs bind to receptors with a variety of chemical bonds
• Very strong covalent bonds result in irreversible action
• Somewhat weaker electrostatic bonds exist between a cation and an anion
• Much weaker interactions: hydrogen, van der Waals, and hydrophobic bonds

Physicochemical Classification of Drugs

• Physicochemical properties determine how drugs are handled in the body
• Two major properties: the degree of ionization of the drug molecule in solution and the lipid solubility of unionized drug molecules
• Ionization depends on the pka of the drug and the pH of the fluid
• Lipid solubility is measured at the lipid/water partition coefficient
• There are five groups of drugs classification based on physicochemical properties
• Water-soluble drugs
• Intermediate soluble drugs
• Lipid-soluble drugs
• Acidic drugs (pka 2-7.4)
• Basic drugs (pka 6-12)

Water-Soluble Drugs

• Absorption from the GIT is negligible; injection usually needed
• Distribution is restricted to the ECF
• Binding to plasma protein isn't important, except for strong acids
• The drugs don't penetrate the CSF or brain
• Elimination is mainly by excretion of the unchanged drug in the urine
• Non-renal excretion is unimportant unless MW is greater than 400 Da
• Dosage of water-soluble drugs with a narrow therapeutic index must be reduced in renal failure
• Aminoglycoside antibiotics and gentamicin are representative

Drugs with Intermediate Solubility

• Many are an intermediate between the highly water-soluble aminoglycoside antibiotic agents & the highly lipid-soluble i/v anaesthetic agents
• Tetracycline is included but digoxin is an important example
• Absorption from the GIT is adequate for clinical use but is often incomplete
• Distribution is not restricted to ECF; the drug penetrates cell membranes and into the ICF
• Protein binding influences distribution & elimination
• Elimination is predominantly by excretion of the unchanged drugs in the urine, however, a proportion of the drug undergo metabolism.

Lipid-Soluble Drugs

• This group of drugs is large and includes many drugs that act on the CNS
• They have in common a high lipid/water partition coefficient
• Weakly acidic drugs (pka > 8)-phenytoin and other anticonvulsants
• Virtually neutral drugs – thiopentone and other i/v anaesthetic agents, sedative & inhalation anaesthetics, steroids
• Absorption from the gut is usually rapid and complete unless chemical inactivation occurs
• Initial distribution of the drug is very rapid
• The drug enters tissues, including the brain, at a rate limited by blood flow
• A large proportion of the drug is bound to plasma proteins and to intracellular proteins & lipids
• The concentration of free drug molecules in the body water may be very small indeed
• The concentration of the drug in the glomerular filtrate is very small and the drug molecules are so lipid soluble that they are re-absorbed from the renal tubule
• The unchanged drug is not effectively excreted in urine
• Some of the drugs in this group that have a high vapor 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: alcohols or phenols
• Water-soluble metabolites resemble gentamicin in their elimination
• Many are conjugated with sulphate, glycine or glucuronic acid prior to excretion

Acidic Drugs

• Acidic drugs, with diverse pharmacological actions, have similar modes of absorption, distribution & elimination
• Examples: NSAIDs, aspirin, naproxen, oral anticoagulant agents (warfarin), penicillin antibiotic agent (pen G, ampicillin), sulphonamide antibacterial drugs (sulphamethoxazole), oral hypoglycemic drugs (tolbutamide), diuretic agents (bendrofluazide), barbiturates (phenobarbitone), uricosuric agents (probenecid, sulfinpyrazone)
• All these drugs are donors of H+
• Many acidic drugs are mainly present as the uncharged acid
• The undissociated acid (HA) is more lipid-soluble
• The ionized form doesn't penetrate the cell membrane
• Acidic drugs are largely present in ionized form in plasma
• Plasma clearance varies inversely with the extent of re-absorption from the renal tubule
• High urine pH means no re-absorption & large plasma clearance
• Urine pH should be controlled when measuring excretion rates of acidic compounds
• Alkaline diuretics are useful in poisoning by salicylate or phenobarbitone

Basic Drugs

• Have pka 6-12 with diverse pharmacological actions but similar modes of absorption, distribution, & elimination
• Examples: opioid analgesic agents (morphine), local anaesthetic agents (lignocain), Antidysrhythmic drugs (liginocain), agonist at nicotinic acetylcholine receptor (nicotine), antagonist at muscarinic acetylcholine receptor (atropine), inhibitor of acetylcholinesterase (physostigmine), sympathomimetic amines (noradrenaline), antagonist at adrenoceptor (propranolol), antipsychotic agents (chlorpromazine), tricyclic antidepressant drugs (imipramine), anxiolytic agents (diazepam), antagonist at histamine receptors (chlorphenilamine, cimetidine), antiparasitic drug (chlorquine, piperazine), smooth muscle relaxant agents (theophylline), calcium channel blocker (verapamil, nifedipine)
• All these drugs are acceptors of H+
• Exist almost entirely as non-lipid-soluble cations (BH+) at pH 3; conditions do not favor absorption from the stomach
• In plasma less base is bound to protein than acids and alpha 1-acid glycoprotein is involved rather than albumin.
• Concentration of total drug in urine greatly increases when urine pH is reduced from 8 to 5
• Plasma concentration t1/2 is shortened when excretion is a major factor in elimination (amphetamine) and the urine is made acidic
• Urine pH should be controlled when measuring excretion rate of basic compounds
• Acid diuresis is useful in poisoning by amphetamine