Smith And Aitkenhead S Textbook Of Anaesthesia-PDF Free Download

Smith and Aitkenhead s Textbook of Anaesthesia
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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, H3C H3C CH3 CH3. N N O O, N N H3C CH3 H3C CH3 N N, N O O N, O O.
CH2 CH2 NH2, N O O H3C O H3C, Cl Cl O O, F F, O O. CH3 CH H3C CH3, 3, Ring closed Ring open CH3 CH3. Cis atracurium, 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. facilitate the movement of molecules for example via. Ketamine 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 and S enan resistance by actively extruding antibiotic molecules from. tiomers that exhibit and optical stereo isomerism their cells via such mechanisms . see Fig 1 1 , In its usual formulation as a racemic mixture of the.
R and S forms ketamine produces dissociative amnesia. Ionisation and equilibria, and analgesia but with significant tachycardia hypertension An acid is a proton donor and a base is a proton acceptor . and hallucinations The S enantiomer is more potent many drugs are weak acids or bases partially dissociat . with a greater affinity at its target N methyl D aspartate ing to exist in equilibria between ionised and unionised. NMDA receptor requiring a lower dose for equivalent forms Strong acids and bases are substances that dissociate. effect compared with the racemic mixture this results in completely . fewer adverse effects and a more rapid recovery The relative proportions of ionised and union . ised forms for a given drug may be derived from the. Henderson Hasselbalch equation Eq 1 1 and depend, Bupivacaine on the environmental pH and the pKa the pH at which. Bupivacaine is a local anaesthetic containing a chiral centre a given drug exists as equal proportions of its ionised and. and adopts dextro and laevo forms The enantiopure l form unionised forms The pKa is determined by the chemical. is less cardio and neurotoxic and has an equivalent potency nature of a drug and is independent of whether it is acidic. to the racemic mixture therefore levobupivacaine is often or basic . preferred to reduce the potential for toxicity Only the unionised forms of a drug or molecule. Stereoselectivity describes the differences in response at a are highly lipid soluble and can cross cell membranes. given receptor for the different enantiomers such as the easily so the environmental pH determines the action of. response discussed for S ketamine The opioid and NMDA many drugs . receptors also exhibit stereoselectivity The Henderson Hasselbalch equation see Eq 1 1 can. be rearranged to derive the relative proportion of ionised. and unionised forms of a drug given a known pKa and pH . Transport of drugs, Most drugs must pass from their site of administration to proton acceptor . pH pKa log10 Eq 1 1 , their site of action effect site before metabolism and proton donor . elimination usually via the kidneys or liver This occurs by. local diffusion across plasma membranes and subsequently For a weakly acidic drug dissociating to H and A . mass transport in the blood through dissolution or carriage substituting these into Eq 1 1 Eq 1 2 and rearranging. by transport proteins gives the relative proportions of the ionised A and union . Transmembrane movement is either active or passive ised form HA Eq 1 2C Similarly for a base accepting a. The former is undertaken by transporter proteins with the proton to form BH the same principles apply . 4, General principles of pharmacology Chapter 1 , proton acceptor .
pH pKa log10 , proton donor , For an acidic substance For a basic substance. HA H A Eq 1 2 A B H BH Eq 1 2 A , , Eq 1 2 , A B . pH pKa log10 Eq 1 2B pH pKa log10 Eq 1 2B , HA BH . , A B , 10pH pKa Eq 1 2C 10pH pKa Eq 1 2C , HA BH . The equilibria given are dynamic and follow the law of 100. Thiopental, mass action depending on the prevailing H The pKa is.
thiopental , the negative logarithm to the base 10 of the dissociation 80. pKa, constant It is an intrinsic property of a drug or molecule. and is also the pH at which half of all molecules are ionised . Unionised, 60, pH 7 4, The ionised BH form of a weak base predominates at a. pH lower than its pKa whereas the converse is true for weak. acids The principles of this are shown in Fig 1 2 40. Local anaesthetics are weak bases i e proton acceptors . with pKa values of approximately 8 Therefore at physiological 20. pH 7 4 the environment is relatively acidic compared with. the drug and this renders local anaesthetics ionised The 0. addition of alkali favours the unionised form by mass effect 6 0 6 5 7 0 7 5 8 0 8 5 9 0 9 5 10 0. and aids passage of local anaesthetic molecules across the. neuronal membrane Once inside the neuronal tissue the. A pH, molecule then becomes charged inside the nerve and is. Alfentanil, trapped facilitating interaction with its target the sodium.
channel Acidic environments in infected tissue promote the Fentanyl. ionised form preventing entry into nerve tissues rendering 100. local anaesthetics less effective , alfentanil , Weak acids such as thiopental have the opposite relation 80. pKa, ship with the proportion of unionised molecules decreasing. Unionised, with increasing pH see Fig 1 2A , pH 7 4. 60, Urinary alkalinisation traps the ionised form of acidic. compounds in the renal tubules preventing reabsorption . 40, fentanyl , and is hence sometimes used in the management of poison .
pKa, ing e g by salicylic acid , 20, How do drugs act 0. 5 0 5 5 6 0 6 5 7 0 7 5 8 0 8 5 9 0 9 5 10 0, Drugs may act at one or more specific molecules such as B pH. a receptor enzyme or carrier or at non specific sites for Fig 1 2 Effect of pH on ionisation for weakly acidic A and. example acid neutralisation by sodium citrate basic B substances . Fig 1 3 and Table 1 1 summarise these intra and extracel . lular mechanisms of drug action , 5, Section 1 Basic sciences. End effect Second, messengers, Mechanism Receptor enzyme Extracellular environment. Ion channels, or carrier Binding and encapsulation.
Ligand of active molecules, e g deferoxamine , TRK linked receptors. Intracellular environment, Chelation, Phosphorylation Activating or. inhibiting enzymes, e g neostigmine , b a G protein coupled. Nuclear receptors g, Enzymes, Physiochemical interactions. Second messengers, e g antacids neutralise acids .
mRNA, cAMP cGMP Ca H HCO3 H2CO3 CO2 H2O, Protein synthesis Neutralisation. Fig 1 3 Major targets solid boxes and mechanisms dashed boxes of drug action intra or extracellular and resulting. biochemical changes and second messenger cascades Targets include channels carriers and receptors mRNA Messenger RNA . TRK tyrosine kinase linked receptors , The extracellular environment may be affected by facilitates the design of specific targeted drugs and opens. chelation enzymatic breakdown of components or the the possibility of reverse pharmacology the discovery of. neutralisation of substances Receptors are a mechanism for new ligands for a given receptor structure . transducing extracellular signals to produce an intracellular Receptors enable cells to adapt to environmental condi . response either via molecules on the cell surface or in tions outside in the case of membrane bound receptors . the nucleus or inside in the case of nuclear receptors Receptors may. initiate responses locally such as the opening or closure. of ligand gated ion channels or via secondary messenger. Receptor mediated effects systems Through activating second messengers events on. Most drugs act at specific receptors A receptor is a protein the cell surface may be amplified and cause intracellular. that produces an intracellular response when a ligand which changes . may be a drug or an endogenous molecule binds to it In The structure of the receptor is fundamental to its function. the unbound state receptors are functionally silent Increasing and production of a specific response to ligand binding The. 2 General principles of pharmacology Dave Lambert Christopher Hebbes the patient Drug related factors include the nature of the drug itself chemical structure size lipid and water solubility

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