Chapter | 1 | General principles of pharmacology Dave Lambert, Christopher Hebbes the patient. Drug-related factors include the nature of the Basic principles drug itself, chemical structure, size, lipid and water solubility, ionisation and charge. Patient-related factors influencing drug uptake and subsequent effects include regional blood A drug is a molecule or particle that produces a therapeutic flow, barriers to uptake such as membranes, the presence effect by modifying how a biological system responds to a of specific transport or acceptor molecules and the presence physical or chemical stimulus. This effect can occur locally of other modifying drugs or hormones. at the site of administration or after absorption and delivery to a more distant site of action through carriers or mass transit. Most drugs undergo passive or active transport Chemical structure across membranes as part of this process. Drugs may be organic or inorganic and of peptide or non-peptide origin. Organic molecules consist of functional groups organised Organic molecules have a carbon skeleton, with functional around a carbon skeleton. These structures may adopt classification dependent on the associated functional groups different conformations allowing specific and non-specific (giving rise to compounds such as esters and amines). interactions with receptors and binding with proteins and Inorganic molecules arise from non–carbon-based structures. other molecules within the body. The physical organisation Examples of inorganic substances used as drugs include salts of the drug’s molecules, functional groups and charge of lithium and magnesium. Chemical structure and other determines further interactions between groups on the same characteristics influence the effects of drugs on the body or other molecules. The exposure of charges and hydrophobic (pharmacodynamics) and the handling of the drug by the or hydrophilic groups may influence a drug’s ability to cross body (pharmacokinetics). membranes, reach a site of action or be excreted. The activity of a drug is determined by its ability to interact with its target; these interactions may be selective Isomerism or non-selective. The former describes interaction with a single type of receptor (e.g. atenolol is cardioselective as it Isomers are molecules sharing the same chemical formula has greater effects on the β1 myocardial adrenoceptors than but with a differing physical arrangement of atoms. Different the β2 bronchial adrenoceptors). Selective drug interactions forms (enantiomers) may interact with other molecules in with receptors and enzymes occur because a specific region a variable way and this, therefore affects function. There are on the ligand fits a complementary region on the effector several different classes of isomer (Fig. 1.1). molecule. This lock and key mechanism is critical to the Structural isomerism describes the organisation of func- functioning of some drugs. Some interactions occur without tional groups within an organic molecule, where either the the recognition of a molecular structure or motif. These carbon skeleton, functional group or position of functional non-specific interactions are known as physicochemical groups along a chain differs. Isoflurane and enflurane share effects and include neutralisation of stomach acid by antacids, the formula C3H2ClF5O but have differences in solubility, or molecular adsorption onto activated charcoal. metabolism, potency (as defined by the minimum alveolar The interaction and transportation of drugs within the concentration, or MAC) and other characteristics. The body is determined by factors specific to both the drug and different positions of the highlighted F and Cl atoms in 2 General principles of pharmacology Chapter | 1 | ISOMERS Structural isomers Stereoisomers Identical chemical formula but different Identical formula and structure spatial organisation Different spatial organisation Structural isomers Diastereomers Optical Enflurane and Isoflurane share the same Contain more than one Contain one chiral centre chemical formula but have a different chiral centre - not mirror images arrangement of functional groups (note the circled elements) Geometric isomers R/S Enantiomers F F F Require restricted rotation about a double O O bond, describes orientation of functional H C C O C H Enflurane R R groups as cis (same) or trans (opposite). R R Cl F F N N H3C H H3C CH3 F Cl F C C C C H CH3 H H Cl Cl F C C O C F Isoflurane Trans Cis S-Ketamine R-Ketamine F H H Ketamine exists as a racemic mixture of R- Tautomers Atracurium contains four chiral centres, and and S- forms. The S- form is more potent Exhibit dynamic isomerism based on exists as a mixture of 10 stereoisomers. and results in fewer adverse effects environmental conditions (such as pH) The Cis form results in less histamine release and theoretically improved L/D Enantiomers pH>6 pH<6 haemodynamic stability H3C H3C CH CH H3C H3C 3 3 N N O O N N + CH H C + N N H3C N 3 3 N CH O O O O 3 CH2 CH NH N O 2 2 O H C O H C Cl Cl O O 3 3 F F O O CH3 CH CH3 Ring closed Ring open 3 H3C CH CH Cis-atracurium 3 3 Lipophilic Hydrophilic L-Bupivacaine D-Bupivacaine Midazolam demonstrates tautomerism with Bupivacaine is available in racemic or the an open (hydrophilic) form, switching to a enantiopure L- form (levobupivacaine), closed lipophilic form at physiological pH which has less cardiotoxicity Fig. 1.1 Classification of isomers with examples from anaesthetic practice. Fig. 1.1 distinguish these different isomers. Because of the geometric mirror images of each other. The alternative R/S molecular size, spatial conformation and charges contained classification organises compounds according to the atomic within these functional groups, the different configurations number of groups of atoms attached directly to the chiral can affect end function and particularly interaction with centre. When viewed with the lowest priority (lowest atomic receptors and target molecules. number) facing away, the priority of the other groups Stereoisomerism refers to molecules with identical chemical can decrease clockwise (R form) or anticlockwise (S form). and molecular structures but a different spatial organisation These correspond to ‘right-handed’ (rectus) or ‘left-handed’ of groups around a chiral atom (usually carbon). Chiral (sinister) forms. Note that the laevo/dextro (or +/−) and R/S atoms are present in all stereoisomers and have bonds entirely properties of a drug are independent. occupied by dissimilar functional groups. Stereoisomers are The different configurations are known as enantiomers. subclassified by the direction in which they rotate plane Naturally occurring compounds (including some drugs) polarised light (optical isomerism) and/or by the spatial contain R and S forms in equal proportions – a racemic arrangement of atomic groups around the chiral centre. mixture. However, as enantiomers may have different proper- When polarised light is travelling towards the viewer, it can ties (including receptor binding, activity and effects) it may be rotated clockwise (termed dextrorotatory (d) or +) or be advantageous to use an enantiopure drug formulation anticlockwise (laevorotatory (l) or −). The dextro (+) and that contains a single enantiomer. Examples include S(+) laevo (−) enantiomers of a compound are non-superimposable ketamine and levobupivacaine, as discussed later. 3 Section | 1 | Basic sciences Molecules containing more than one chiral centre are hydrolysis of adenosine triphosphate (ATP) or movement described as diastereomers, which may form geometric isomers, of other molecules, and the latter occurs by diffusion with based on the orientation of functional groups around a no net utilisation of energy. Facilitated diffusion utilises non-rotational carbon-carbon double bond. Fig. 1.1 shows carrier proteins within the cell membranes to increase dif- the example of cis- and trans-geometric isomers. Atracurium fusion along a concentration gradient. contains four chiral centres, resulting in 10 stereoisomers The rate of passive diffusion is determined by the nature present in solution. The enantiopure form, cisatracurium, of the drug, barriers or membranes, concentration gradient causes less histamine release than the non-pure form, theo- and temperature. The presence of any transporter molecules retically conferring greater haemodynamic stability. or ion channels enhance diffusion. The rate of diffusion Tautomerism describes dynamic structural isomerism, is inversely proportional to the square of the molecular where drug structure may change according to the surround- weight (Graham’s law). The relationship between rate of ing environment. For example, midazolam has an open, diffusion and concentration gradient, membrane perme- water-soluble ring structure in storage at pH 3 but undergoes ability, thickness and surface area is described by Fick’s law. a conformational change at body pH of 7.4 to become a Drug solubility, by virtue of size, charge, and the presence completed ring structure, which is lipid soluble and passes of hydrophilic or lipophilic groups, also determines ease through the blood–brain barrier. of movement across membranes. Active transport describes the expenditure of energy to Ketamine facilitate the movement of molecules, for example via symports, antiports or cotransporters, either at the expense Ketamine is a phencyclidine derivative used for analgesia of other molecules or ATP. Bacteria may develop antibiotic and sedation. It has a chiral centre, forming R