PMC 432 Medicinal Chemistry of Local and General Anaesthetics.pptx

PMC 432: Medicinal Chemistry of Local and General Anaesthetics Pharm. Onyeka Obidiegwu 09/05/2024 1  LOCAL ANESTHETICS Introduction  Local anesthetics (L.A.) are agents that reversibly block...

PMC 432: Medicinal Chemistry of Local and General Anaesthetics Pharm. Onyeka Obidiegwu 09/05/2024 1  LOCAL ANESTHETICS Introduction  Local anesthetics (L.A.) are agents that reversibly block the generation and conduction of impulses along the axon.  They are agents which are applied locally and they block the transmission of impulses in the peripheral pain conducting nerve endings.  They are generally used in surgery, dentistry and ophthalmology to achieve either a partial or complete but necessary reversible block of impulses in peripheral nerves or nerve endings.  Like general anesthetics (G.A.), they are not used to alleviate the symptoms of any illness but are used by surgeons to carry out the surgical procedures on a patient without any resistance.  However, unlike G.A., the anesthesia produced by L.A. is without loss of consciousness. 09/05/2024 2  Mechanism of action of Local Anesthetics (LA) L.A. act by decreasing the excitability of nerve cells. The excitability of nerve cells is associated with movement of sodium ions across the nerve membrane. L.A. act by blocking the sodium channels whereas G.A. act through non-specific interaction with lipid layers which result in changes in membrane excitability through various mechanisms. 09/05/2024 3  Classification of Local Anaesthetics Based on their chemical grouping, there are three major classes of local anesthetics viz. Ester type, e.g. cocaine, benzocaine and procaine.  These are short acting and hydrolyzed by esterases. Amide type, e.g. dibucaine, lidocaine.  These are long acting and hydrolyzed by amidases. Miscellaneous compounds, e.g. chlorbutanol, amethone. 09/05/2024 4  Esther Group (Type I) They consist of a hydrophilic amino group linked through an ester connecting group to a lipophilic aromatic moiety. This consist of – The cocaine group – The benzocaine group 09/05/2024 5  The Cocaine Group COCAINE Nomenclature 1R, 2R, 3S, 5S)-2-Methylcarboxyl-tropane-3-yl-benzoate Sources and properties Cocaine is a euphoric-stimulant, alkaloid that occurs in Erythroxylon coca (and other species) leaves. Also obtained by semi-synthesis from ecgonine obtained from natural sources. Occurs as levo rotatory, colourless, crystals. 09/05/2024 6  SAR in cocaine Tropane moeity is necessary for activity Removal of the benzoyl group leads to loss of activity, hence important for activity Removal of carboxymethoxyl group has no adverse effect on activity Hydrolysis of carboxymethoxy group and benzoate group leading to ecgonine results in loss of activity 09/05/2024 7  The benzocaine esters 1. Benzocaine Chemical Name: Ethyl 4-aminobenzoate It has feeble or weak anaesthetic properties, comparatively non- irritant and non-toxic. Used mainly in dusting powders It undergoes hydrolysis to yield p-aminobenzoic acid 09/05/2024 8  Synthesis of benzocaine 09/05/2024 9  2. Procaine Chemical Name: 2-Diethylaminoethyl 4- aminobenzoate It also undergoes hydrolysis to yield p-aminobenzoic acid and as such should not be used with sulpha drugs (drugs containing sulphonamide) of which it is a competitive antagonist. Synthesis of Procaine 09/05/2024 10  Other Examples of Ester group 3. Tetracaine Chemical Name: 2-Diethylaminoethyl 4-butylaminobenzoate 4. Amylocaine 5. Butacone 09/05/2024 11  General Structure Activity Relationship in Ester type Local Anaesthetics The anaesthesiophoric moiety may be represented simply by the following structures Three criteria has been fulfilled for a compound to show high degree of activity – a. The ester must contain nitrogen, in the alcohol, the acid or both – b. The acid must be aromatic – c. The alcohol is usually aliphatic, either open chain or alicyclic 09/05/2024 12  SAR of ester type (contd.) For I, Benzoic acid and p-aminobenzoic acid proved the best: (a) Introduction of methylene group (-CH2-), e.g. in phenylacetic acid, led to decrease in activity; (b) the carboxyl group (COO-) must be conjugated with an aryl group to have activity; (c) the esters of p-amino acid are more effective than esters of benzoic acid or p-hydroxyl benzoic acid; (d) an alkyl group on the aromatic amino nitrogen increases anesthetic activity and toxicity (e) the best position for the amino group for activity is on the para position of aromatic nucleus. 09/05/2024 13  SAR of ester type (contd.) For the II chain, n=3, is best , followed by n=2, while n=1, makes the ester very irritant. For the III, aliphatic amino nitrogen is best as this produces water-soluble compounds; one or both of the hydrogen atoms are substituted; increase in size of alkyl group increases activity up to a maximum of C3 or C4 (R 1 and R2 may not be of the same substitution). 09/05/2024 14  Amide type They consist of a hydrophilic amino group linked through an amide (type II) connecting group to a lipophilic aromatic moiety. Drugs in this class are generally more stable and more resistant to hydrolysis. Thus, they have longer duration of action. Example Lignocaine (or Lidocaine or xylocaine) 2-(Diethylamino) N-(2,6-dimethyl)-acetanilide Properties It is probably the most important local anesthetic. It is extremely stable to hydrolysis because of two methyl groups ortho to amide function which causes steric hinderance. Undergoes first –pass effect and is given parenterally. 09/05/2024 15  SAR in Lignocaine) (lidocaine) Isomers of lignocaine with only one alkyl group ortho to amide function have much shorter duration of action. It is not necessary that both the substituents ortho to the amide function should be alkyl group. Butacaine in which one of the ortho methyl groups has been replaced with chloro, was found to be less toxic and more active than procaine. 09/05/2024 16  Synthesis of lignocaine 2- 2,6- chloroacetyl dimethy chloride l aniline 2-(Diethylamino) N-(2,6-dimethyl)- acetanilide 09/05/2024 17  Miscellaneous compounds Examples include dyclonine, pramoxine diperodon, chlorbutanol, Amethone Benzyl alcohol Clove oil Eugenol oil 09/05/2024 18  GENERAL ANAESTHETICS These are drugs which produce controllable reversible depression of the functional activity of CNS, causing loss of sensation and consciousness. Stages of General anesthesia Analgesia (Stage 1): This stage lasts from onset of drowsiness to loss of eyelash reflex (ie blinking when the eyelash is stroked). In this stage, variable levels of amnesia and analgesia are seen. The patient is taken as unconscious at the end of this stage 1. Excitement (Stage 11): This stage is characterized by agitation and delirium. Here, heart rate and respiration may be irregular. The patient should be moved through this undesirable stage quickly. Induction agents are designed to achieve this Surgical Anesthesia (stage III) This is the target depth for surgical procedures. Here a particular stimulus will not elicit a somatic reflex or deleterious autonomic response. Impending Death (Stage iv): This stage extends from onset of apnea to failure of circulation and respiration and ends in death. 09/05/2024 19  Ideal Anesthetic combination/agent is designed to allow the patient to proceed quickly from stage I to III and avoid stage iv 09/05/2024 20  Classification of General Anaesthetics General Anaesthetic are classified into 1. Inhaled General Anesthetics (InhGA) – Also known as volatile or inhalation anaesthetic 2. Injectable General Anesthetic (InjGA) 09/05/2024 21  Characteristics of a good/Ideal IGA Inexpensive Potent (so much action to be achieved with minimum dose) Pleasant to inhale Minimal solubility in the blood and tissues Should be stable on the shelf and during administration Should be void of undesirable effects such as cardiotoxicity, hepatoxicity renal toxicity and neurotoxicity. The above factors must be considered when choosing an anesthetic for a particular patient.  MAC MAC: Minimum Alveolar Concentration: This is defined as the concn of the vapour in the lungs of an inhalable GA (InhGA) that is needed to prevent movement(motor response) in 50% subjects in response to surgical pain or stimulus It is used to compare the strengths or potency of anaesthetic vapours. The lower the MAC, the more potent the volatile anaesthetic  Properties of inhaled GA Table 22.1 Properties of the inhaled sthetics Anesthetic MAC (%) BLOOD-Gas Oil –Gas Nitrous Oxide 104 0.46 1.1 Halothane 0.75 2.4 137 Enflurane 1.68 1.9 98 Methoxyflurane 0.16 16.0 970 Isoflurane 1.15 1.43 90.8 Sevoflurane 2.10 0.65 50 Desflurane 7.3 0.42 18.7 Xenon 71 0.12 1.9  Meyer-Overton Hypothesis States that the MAC of a volatile substance is inversely proportional to its lipid solubility(oil:gas partition coefficient By this it is understood that MAC is inversely related to potency, ie higher MAC is low potency. The hypothesis correlates lipid solubility of an anaesthetic with potency and suggests that the onset of anaesthesia occurs when sufficient molecules of the anaestheitc agent have dissolved in cell’s lipid membranes, giving rise to anaesthesia  BLOOD – GAS PARTITION COEFFICIENT: This is defined as the ratio of the concentration of the drug in blood to concentration of the drug in the gas phase in the lungs at equilibrium. When a volatile anesthetic is inhaled into the lungs, it diffuses into the blood and on achieving equilibrium, it diffuses into the tissues. For quick onset of action, the drug should have a low solubility in the blood, such that saturation will be  Recovery is also fast for the drugs with a low blood- gas partition coefficient. This is because the drug will be eliminated quicker, if it has a low solubility in the blood, as it will pass quickly into the lungs for exhalation. In the same view, most inhaled anesthetic have similar solubilities in lean organs but their solubilities in fat vary as predicted by their oil-gas partition coefficients. When a patient is exposed to the volatile gas for prolonged procedure (e.g. greater than 5 hours), the solubility of the drug in the tissues will also affect the recovery period. Hence obese patients may have increased recovery times if an inhaled anesthetics with high-fat solubility is used for a prolonged period.  STABILITY FACTOR Previously used inhaled anesthetics had stability issues causing explosions and operating room fires. The incidence of this has been drastically minimized by halogenating the ethers and hydrocarbon anesthetics. Halogenation stabilizes the IGA. This is why today most IGA contain halogens. The IGA in use today are: - + N=N =O Nitrous Oxide Cyclopropa ne  METHOXYFLURANE Chemical Structure Cl F H H –C – C – O – C - H Cl F H Chemical Name: 2,2-dichloro-1,1- difluoro-1-methoxyethane  F Br F–C–C–H F Cl Halothane (Fluothane) Chemical Name: 2-bromo-2-chloro-1,1,1-trifluoro ethane F F F H–C–C–O–C- H Cl F F Enflurane : Chemical Structure: 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether or (RS)- 2-chloro-1-(difluoromethoxyl)-1,1,2-trifluoro-  F H H F–C–C–O–C-F F CF3 H Fluoromethylhexafluoroisopropyl ether Sevofluron 1,1,1,3,3,3-hexafluoro-2- e (fluoromethoxyl)propane This is a highly halogenated compound There has been reports of fire involving sevoflurane even when the recapture and recirculatary apparatus are in use. Incidences of operating room fires are known.  Halothane: Become popular as a nonflammable GA, replacing volatile inflammable ones like diethyl ether and cyclopropane Newer anaesthetic agents have largely replaced it except for some veterinary purposes and in third world countries because of lower cost  F H F F– C – C – O – C - H F Cl F Isoflurane F H F F– C – C – O – C - H F H F Desflurane  SAR There is no single pharmacophore for the inhaled anesthetics. However, the chemical structure is still related to the activity of the drug molecules. The first SAR studies conducted by Meyer and Overton in the 1880 showed a distinct positive correlation between anesthetic potency and solubility in olive oil. Many series of compound follow the simple relationship. The potency of alkane, cycloalkanes, aromatic hydrocarbon increase in direct proportion to the number of carbon atoms in the structure upto a limit beyond which there is decrease.  For n-alkanes, the optimal is 10. For cycloalkanes, the cut-off is 8, with cycloctane showing no activity at all. The reduced activity of the compound beyond their optimal could be explained in terms of problems of access to site of action either hindered by reduced vapour pressure or high blood solubility. It can also be as a result of inability to bind to the site of action and induce the conformational change required for  The cycloalkanes are more potent anaesthetics than the straight chain counterparts with the same number of carbons e.g. the MAC of cyclopropane in rats is about one-fift of the MAC of n-propane. Similarly, there is increase in potency with increase in carbon length in n- alkanol series. However, n-alkanol with a given number of carbons is more potent than the n-alkane with the same chain length.  Effect of Halogenation Halogenation decreases flammability of ether anesthetics, enhance their stability and increases their potency. Higher atomic mass halogen increased potency more than the lower atomic mass halogen. E.g. Replacement of fluorine in desflurane CF2HOCFHCF3 with chlorine to isoflurane – CF2HOCClHCF3 increased potency more than fourfold.  Effect of Halogenation Halogenated ether compounds cause less laryngospasm than unhalogenated compound. Halogenations also increases the tendency of the compound to cause cardiac arrhythmias and/or convulsions. For n-alkane series, fully saturating the alkane with fluorine abolished activity except when n= 1.  Effect of unsaturation The addition of double and /or triple bonds to small anesthetic molecules, having 6 carbon atom or less increases potency.  Mechanism of Action The mechanism of the inhaled Anesthetics is not clear. However, it seems likely that the individual anesthetic molecule act with different potencies on multiple receptors that lead to similar clinical states of anesthesia  Meyer-Overton Theory It was originally thought that the Unitary hypothesis, viz- that the lipid-soluble drug somehow disrupted the biological membrane and produced anesthesia. This hypothesis is an extension of the work of Meyer & Overton which showed that there was a strong correlation between the potency of anesthetic and its solubility in olive oil. However it has been argued that if lipid solubility were the only factor for anesthetic potency, the chiral enantiomers would have the  This is not the case, for stereoisomers of isoflurane do not have the same in vivo potency despite having the same effect on the lipid membrane. It is also known that all lipophilic chemicals are not anesthetic. Hence, Unitary theory of anesthesia does not adequately explain the mechanism of action of IGAs. Interaction with ion channels. IGAs interact with various ion channels to influence the electrical activity of the cells and their physiological response. They act on GABA receptors. IGAs enhance chloride ion conductance into the cell and thus hyperpolarize the cell membrane and prevent impulse transmission.  Nitrous Oxide Also called laughing gas in dentistry. It is popularly used in dentistry. It has a low potency, with MAC of 104% necessitating use of large mass during anesthesia if it has to be used alone. However, the patient in this case would have to breathe in pure N2O to the exclusion of oxygen. This can precipitate hypoxia & eventual death. It is a gas at room temperature, usually supplied as a liquid under pressure in metal cylinders. When used,  + Structure N=N- O Metabolism Undergoes little or no transformation in the body. Synthesis NH4NO3 → N2O + 2H2O Obtained by heating ammonium nitrate to a temperature a little above its melting point.  Halothane This is a non-flammable, non-pungent volatile, liquid halogenated ethane with a B.D of 50oC. It undergoes spontaneous oxidation when exposed to U.V light to yield HCl, HBr, Cl-, Br – and phosgene (COCL2). It is usually packaged in amber bottles with low concentration of thymal to prevent oxidation. It has a high potency (MAC=0.75%) a blood-gas partition coefficient of 2.4 and high adipose solubility. The trifluoroacetyl chloride metabolite is electrophilic and can form covalent bonds with proteins leading to immune responses and halothane hepatitis on further exposure. Halothane metabolism Drawing on pg 714 wilson  Enflurane This is a volatile liquid with a B.P of 56.5oC and blood/gas partition coefficient of 1.8 and MAC of 1.68%. About 2-8% of the drug is metabolized primarily as chlorofluoromethyl carbon. Difluoromethoxydifluoroacetate and fluoride ion have been reported as metabolite. Read up- Properties and uses of isoflurane, sevoflurane General Anaesthetic Injectables (GAI) Three drugs of choice that are used solely for their anesthetic effect propofol Ketamine etomidate  Propofol Chemical name: 2,6, disopropylphenol SYNTHESIS PROPOFOL  Uses: Propofol is an injectable sedative hypnotic used for the induction and maintenance of anesthesia or sedation for short surgical procedures. Properties: It is slightly soluble in water with octanol/water partition coefficient of 6,761:1. Usually formulated as an oil-in-water emulsion.  Metabolism of Propofol 09/05/2024 52  Structure of ketamine (+) -2-(o-Chlorophenyl)-2-methylaminocyclohexanone 09/05/2024 53 SYNTHESIS OF KETAMINE CL O NHCH3 O O NCH3 Br2 CH3N HCl H2 ,A q Br HO C C C l l l + Cl- C O NCH3 l Thermolysi s HO NHCH3 C