Pharmacology Notes

Pharmacology

1. Introduction to pharmacology

A drug is defined as a chemical substance of known structure which when administered to a living organism produces a biological effect.

Pharmacology is the study of the effect of drugs on living systems.

Pharmacokinetics is what the body does to the drug. Pharmacodynamics is what the drug does to the body.

2. Pharmacokinetics – drug uptake and elimination

Drug absorption and distribution is divided into four stages that can be remembered using the acronym ‘ADME’. These are:

• Absorption from the site of administration

• Distribution within the body

• Metabolism

• Excretion

Drugs can be administered via either enteral or parenteral routes.

1. Enteral administration

Enteral administration is directly into the gastrointestinal tract. Enteral routes therefore include sublingual, oral or rectal administration.

Absorption of the drug then occurs along the length of the gastro-intestinal tract. In general, drugs that are absorbed rapidly have a low degree of ionisation, high lipid/water partition in the non-ionised form, relatively low molecular weight (less than 1000) and a biological affinity with transporters or for facilitated diffusion. The physiochemical properties of a drug determine whether the drug is absorbed in acidified (the stomach) or neutral/alkaline (intestine) compartments. Many drugs are weak acids or weak bases. Therefore the overall pH of the environment will affect how much of the drug is in the ionised versus neutral form, as follows:

HA H+ + A-

BH B- + H+

Ions require specific channels or transporters to cross cell membranes, whereas neutral compounds are able to diffuse across the membrane.

Drugs administered orally undergo first pass metabolism in the liver. After absorption from the gastro-intestinal tract, the liver is the first organ the drug will reach via the hepatic portal vein. In the liver, the drug will undergo oxidation and conjugation. This will make the compound water soluble. Many drugs are inactivated and excreted in this way. In general, drugs undergo a first catabolic phase of oxidation, reduction or hydrolysis to form a drug derivative. The drug derivative then undergoes a second anabolic stage of synthetic conjugation to produce the water soluble drug.

More specifically, this can be shown as:

Parent drugs or metabolites may recycle several times before entering the systemic circulation. This occurs as the drugs follow bile salts and are excreted back into the gastro-intestinal tract to be reabsorbed and metabolised by the liver.

In this way, drugs may be very long lasting, e.g. some antibiotics.

Liver enzymes act in the smooth endoplasmic reticulum of the hepatocytes.

Liver enzymes act in the smooth endoplasmic reticulum of the hepatocytes. The majority of CYP enzymes are found in the liver, but some are also present in the cell wall of the intestine. Mammalian CYPs are membrane bound to the endoplasmic reticulum. CYP 3A4, CYP 2D6 and CYP 2C9 are the main enzymes involved in the metabolism of drugs in humans.

Metabolites produced by drug metabolism in the liver can have several kinds of activity. Detoxification refers to routes that produce inactive drug metabolites. Metabolites may exhibit similar activity to the parent drug, often with a different potency or duration of action to the parent drug. The metabolite can also have different activity to the parent drug, or a toxic metabolite may be produced.

2. Parenteral administration

Parenteral routes include topical, intradermal, subcutaneous, intramuscular, intravascular and inhalation administration. The main advantage of parenteral administration is the bypassing of first pass metabolism.

Topical administration can involve administering a drug to the skin or to the eye via drops. The effects are local, slow and sustained.

Intradermal administration involves administering drug in between dermis and epidermis skin layers. The drug is slowly absorbed via this route.

Subcutaneous administration involves administering drug below the skin layer. The drug is absorbed faster, but the fat layer may trap lipid soluble compounds. Massaging of the administration site increases blood flow and so drug absorption.

Intramuscular administration produces very fast drug absorption. Physical activity or massage of the administration site increases absorption.

Intravascular administration is mostly used when the concentration of the drug in the body must be accurately controlled, for example is the drug has a narrow margin of safety between therapeutic and toxic index. The disadvantage of this type of administration is that the injected drug cannot be recalled. Slow administration is required to avoid side effects.

Inhalation administration of drugs can be via gas or aerosols. This route of administration causes rapid systemic effects but is dependent on the tidal volume and, if an aerosol, the size of the aerosol particle as smaller particles are more likely to reach alveolar ducts and sacs whereas larger particles will otherwise get stacked in bronchi.

3. Drug excretion and elimination

The main routes of drug elimination are via the kidneys, the hepatobiliary system and the lungs for volatile compounds such as general anaesthetics. Secondary routes of elimination include in the milk of lactating animals or in the sweat.

Renal excretion is affected by filtration, secretion and reabsorption of compounds. Net renal filtration is therefore the sum of filtration and secretion minus reabsorption. Filtration is influenced by glomerular filtration rate and by plasma protein binding, and can be calculated by GFR x drug plasma free fraction. If renal excretion is greater than filtration, secretion of the drug must be taking place. If renal excretion is less than filtration excretion, then net reabsorption of the drug must be taking place.

The pH of the urine has a strong influence on the renal excretion of drugs. As many drugs are weak acids or weak bases, the pH of the urine will affect...

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