Local anesthetic

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Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

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  • general surgery (e.g. laparotomy- a surgical procedure involving a large incision through the abdominal wall to gain access into the abdominal cavity
  • A hernia is the protrusion of an organ through the wall of the cavity that normally contains it from withinA Caesarean section is a surgical procedure in which one or more incisions are made through a mother's abdomen and uterus to deliver babies
  • Venipuncture means the collection of blood from a vein
  • http://www.ncbi.nlm.nih.gov/pubmed/3723357
  • Esters are metabolized in the plasmaby the enzyme pseudocholinesterases,
  • is metabolized by the plasma by the enzyme pseudocholinesterase through hydrolysis into para-amino benzoic acid (PABA)Occasionally injection of PABA-derived local anaesthetics to allergic individuals may cause swelling of the oral mucosa (stomatitis) at the site of the injection. Rarely, more severe reactions such as generalisedurticaria (rash) or anaphylaxis may result. Allergic contact dermatitis is an itchy skin condition
  • Why isBupivacaine more resistant to metabolism than lidocaine even when both have same di-ortho methyl groups ???
  • What will happen if GA drugs like barbiturates is administered like LA ie as plexus, epidural, spinalblocks? Will there still be whole body effect?Similarly what if LA are administered on brain directly, will it only block pain or other GA effects are also seen?
  • Ref: LA axon thickness PDF
  • If there were no such plasma enzymes, won’t there be any metabolism of esters?
  • Local anesthetic

    1. 1. Local Anesthetic
    2. 2. • Local anesthetics are drugs used to reversibly depress CNS to prevent or relieve pain in specific regions of the body without loss of consciousness • Unlike General Anesthetics, they generally don’t block sense of touch, pressure or temperature or relax skeletal muscles
    3. 3. Uses • Dentistry • Podiatry (treatment of disorders of the foot, ankle, and leg) • ENT operations • Surgery of skin • Labor pain • Postoperative pain • Skin Trauma
    4. 4. How Nerve conduction occurs? • Nerve conduction is a both electrical and chemical component • The electrical component occurs within the axon. It involves membrane bound voltage gated ionic channels (responds to change in voltage across the membrane) • The chemical component occurs at synapse. It involves membrane bound ligand gated ionic channel (responds to binding of a NT)
    5. 5. Chemical transmission of stimuli occurring at synapse through NT binding to their receptors Electrical transmission of stimuli occurring through axon by movement of ion in and out
    6. 6. •When charges are separated by distance, potential difference is created •The inside of cell has more potassium and less Sodium and large anionic Protein (A-) that cannot cross the lipid membrane and is thus localized inside the cell •The outside of the cell has more Sodium and less potassium •This difference is maintained by Na/K pumps that pump in 2K+ ion in cell and pump out 3Na+ ion out. Thus one extra positive charge out •Overall, the inside of the cell has more negative charge and the outside has more positive charge •This gives the cell a resting potential of -70mV Concept of potential difference and its generation (-70mV) in resting cell
    7. 7. Events during an action potential An action potential is a temporary “all or nothing” changes in cell membrane potential
    8. 8. Steps in a action potential • (1) A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential. • (2) If the threshold of excitation (-55mV) is reached, all Na+ channels open and the membrane depolarizes. • (3) At the peak action potential (+30mV) K+ channels open and K+ begins to leave the cell. The membrane starts to repolarized. At the same time, all Na+ channels close. • (4) The membrane becomes hyperpolarized (-90mV) as K+ ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot initiate another action potential • (5) The K+ channels close and the Na+/K+ transporter restores the resting potential (-70mV).
    9. 9. Changes in the resting membrane potential Cell state Active receptors Potential Resting potential Na/K Atphase pump active -70mV Stimuli causes Depolarization beyond threshold potential (-55mV) Voltage gated Na+ channel open Na comes inside cell +30mV Repolarized state Voltage gated Na+ channel close Voltage gated K+ channel open K goes outside cell +30 to -70mV Hyperpolarized state Voltage gated K+ channel close slowly -90mV Resting potential Na/K Atphase pump active -70mV
    10. 10. Mechanism of Action • Local anesthetics work in general by binding to the voltage gated sodium channel receptors inside the cell and thereby inhibiting generation of action potentials in the axon. Thus they reduce the excitability of the neuron. • The presence of large anionic proteins inside the cell and Na/K ion pumps in the cell membrane , that pump2 K+ intracellular for every 3 Na+ it pumps extracellular, create a -70mV resting potential
    11. 11. Mechanism of Action (cont’d) • If a stimuli depolarizes the resting potential to reduce the membrane potential to less than -55 mV (ie it goes towards +30mV) then a series of events occur where membrane potential increases to +30mV and back to -70mV. • The first step of this entire process is opening of voltage gated sodium channel which allows influx of sodium ion to cause increase in membrane potential. LA act here to block the Na influx and thus prevent stimuli propagation through the axon
    12. 12. How LA primarily blocks pain? • Different neurons carry different stimulus such as pain • cold, warmth, touch and deep pressure. • The neurons differ in the thickness of the axon • Thin axons are most sensitive to drugs • Neurons carrying pain has the thinnest axon • Then comes cold, warmth, touch, deep pressure • Thus effect of LA also follow this order • Also nerve fiber are thinner than muscle fiber, thus they are blocked preferentially and thus no muscle relaxation occur with LA
    13. 13. Applications of LA There are different ways to use LA depending on site on application: • Topical • Infiltration • Plexus block • Epidural block • Subarachnoid (spinal) block
    14. 14. • A topical anesthetic is a local anesthetic that is used to numb the surface of a body part. They can be used to numb any area of the skin as well as the front of the eyeball, the inside of the nose, ear or throat, the anus and the genital area. Topical anesthetics are available in creams, ointments, aerosols, sprays, lotions, and jellies. Examples include benzocaine, lidocaine, oxybuprocaine,
    15. 15. • Topical anesthetics are used to relieve pain and itching caused by conditions such as sunburn or other minor burns, insect bites or stings, poison ivy, poison oak, poison sumac, and minor cuts and scratches. • In dentistry, topical anesthetics are used to numb oral tissue before injecting a dental local anesthetic to prevent pain due to the entry of the needle into the soft tissues of the oral cavity
    16. 16. Infiltration • It is the application of LA in intradermal or subcutaneous layers • Only the nerve fibers near the injected site is affected • The adequate dosage required depends on – the extent of the area to be anesthetized – on the expected duration of the surgical procedure. • Patients frequently experience pain immediately after infiltration injection of local anesthetic solutions. This response is due in part to the acidic nature of these solutions. • neutralization of LA solutions by addition of sodium bicarbonate reduces pain • Used for postoperative pain control at incision site and suturing
    17. 17. Plexus block • plexus or ganglion are a group of nerves that transmits pain caused to a specific organ or body region. Use of LA in these region causes analgesia in the organs or region associated with it • Brachial plexus blocks are employed for surgery of shoulder, arm, forearm, wrist and hand. • A celiac plexus block is performed for surgery of the abdomen
    18. 18. The spinal cord run through a tunnel formed by bones of vertebrae called spinal canal
    19. 19. The spinal cord is surrounded by a sac (sac means bag, pouch) containing a liquid called cerebrospinal fluid. This is the site of spinal block ie right into this sac Epidural block is given in region just outside of this sac within the spinal canal
    20. 20. Epidural block • Application of LA in the epidural space, ie just outside of the sac of cerebrospinal fluid, and thus blocking the transmission of pain signals from peripheral sensory neuron Uses • More effective and safe than N2O during labor pain • Management of back pain for hospitalized patient • As a supplement to general anesthesia so that use of opiod analgesics can be avoided • gynaecological surgery, orthopaedic (muscle n bone) surgery, vascular (artery n veins) surgery
    21. 21. Spinal block • Application of LA in the region containing cerebrospinal fluid ,which holds the spinal cord, thus blocking the transmission of pain signals from peripheral sensory neuron • Uses: Total Hip Replacement, Total Knee Replacement, Caesarean sections, Lower limb Vascular surgery • limited to procedures involving regions below the upper abdomen. • Use in higher levels may affect the ability to breathe by paralyzing the intercostal respiratory muscles and the disturb heart rate by paralyzing cardiac nerve fibres
    22. 22. Epidural vs Spinal Epidural Spinal Dose is high (10-20 ml) Dose is low (1.5-2 ml) Onset is slow (25-30 min) Onset is fast (5 min) does not cause as significant neuromuscular block Does cause as significant neuromuscular block Multiple dosing possible Single dose only Can be given at various point along the Backbone Can only be given at specific point along the Backbone to avoid damaging the spinal cord
    23. 23. Block vs Infiltration • A block is placement of the local anesthetic adjacent to a major nerve or a major branch of the nerve that stops sensation from that point to the terminal end of the nerve. Everything "down stream" from where the block was placed will be numb. Infiltration is placement of local anesthetic near (or in) the area you want anesthetized. Mostly it affects the terminal branches of the nerves. Typically, an infiltration will only affect that area and not beyond. (thus it is the most localized LA!)
    24. 24. Local anesthetics used in eye only Ophthalmic anesthetics are topical agents that act locally to block pain signals at the nerve endings in the eyes. They are available as eye drops, ointment and gels. Uses • Perform a applanation tonometry.(Tonometry determines the intraocular pressure) • Perform a Schirmer's test. ( Schirmer's test determines whether the eye produces enough tears to keep it moist) • Remove small foreign objects from the uppermost layer of the cornea or conjunctiva Drugs used are Tetracaine 0.5% and Proparacaine 0.5%
    25. 25. Eutectic mixture of LA • A topical anesthetic made from equal parts of lidocaine and prilocaine which separately are solid but together take a liquid form with melting point of 18oC • This property where a mixture of substances having a melting point lower than that of any of its components is called Eutectic mixture • Manufactured as a 5% oil in water emulsion containing 2.5% each of lidocaine/prilocaine • It is applied as a cream on unbroken skin, then covered with an occlusive dressing, to kill pain prior to – venipuncture, intramuscular injections, intravenous cannulation,
    26. 26. Advantages over other topical LA a) the local anesthetic bases are present in their permeable uncharged forms; b) water is used as the vehicle which is a poor solvent for these drugs. This causes drug to rapidly saturated water (at low concentrations) and then move on to act on the skin c) Simply use of an oily vehicle would effect distribution coefficients of the active substances between the skin and the formulation d) the droplets consist of dissolvable drug and act as reservoirs to obtain steady-state release; and e) the fluid state of the excess drug provides a higher dissolution rate than from a solid state.
    27. 27. Local anesthetics and vasoconstrictors • LA are removed from site of application due to absorption into blood • Vasoconstrictors increase the duration of local anesthesia by constricting the blood vessels, so that less blood flow and consequently less absorption into blood occurs. Thus it allows LA to work for an extended duration, as well as reducing hemorrhage. Examples include: • Prilocaine hydrochloride and epinephrine • Lidocaine, bupivacaine, and epinephrine (recommended final concentrations of 0.5%, 0.25% and 1:200, respectively)
    28. 28. The classification of local anesthetics Ester • Cocaine • Procaine • Tetracaine Amides • Lidocaine • Bupivicaine Ether • Pramoxine Ketones • Dyclonine
    29. 29. Structure Activity Relationship • Most drugs are salts of weak acids or weak bases • But how to know by just looking at structure if a drug is acidic or basic?
    30. 30. Use of pKa? • Pka can’t tell the difference of acid/base • It only tells how strong an acid or base is but doesn’t tell if it’s an acid or base Paracetamol Pka is 9.5 but it is an acid It is weaker acid than acetic acid those Pka is 4.5 Diazepam Pka is 3.4 but it is a base It is weaker base than NH3 those pKa is 10
    31. 31. The key is to look for the specific functional groups • Acidic drugs contain one of these groups • ALL Basic drugs contain Nitrogen as amine groups, (all except quaternary amine) or double bonded to C (C=N) NH2 H3C H N CH3H3C H3C N CH3 CH3 primary amine Secondary amine tertiary amine H3C N CH3 CH3 quanternary amine CH3 All basic to the same degree Not basic OH H2N O R H3C O R AmideAldehyde /ketonePhenol R COOH carboxylica acid R
    32. 32. SAR of LA
    33. 33. • All local anesthetics have an amine on one end to an aromatic ring on the other • The amine end is hydrophilic, and the aromatic end is lipophilic. • The two groups are connected by mostly an ester or an amide group and less commonly by ether or ketones • Thus two main classes of local anesthetics exist: Amides and Esters • Esters have an ester link between the amine chain and the aromatic end. • Amides have an amide link between the amine chain and the aromatic end • They have pka in range of 7.5 to 9.5
    34. 34. • Esters and amino amides differ in metabolism, stability and adverse effects • Esters are metabolized in the plasma but Amides are metabolized in the liver. • Esters are unstable in solution, but amides are very stable in solution. • Esters are much more likely than amides to cause allergic reactions
    35. 35. Lipophilic group • Lipophilicity is important to penetrate the lipid layer and reach the binding site on the inside of the cell • Presence of electron withdrawing group in ortho or para (not meta) position decreases Lipophilicity but still increases activity for only ester group O C O H2 C C H2 N C2H5 C2H5 H2N O C O H2 C C H2 N C2H5 C2H5 Procaine is more potent if it has a e- donating amine group in the aromatic ring Procaine Note: Other e donating groups in decreasing order are –OH > -NH2 > - Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere) Less potent than procaine
    36. 36. • This increase in activity (valid for ester only) is due to possibility of Zwitterionic form which enhances activity due to formation of quanternary amine which is important for binding O C O H2 C C H2 N C2H5 C2H5 H2N Procaine O- C O H2 C C H2 N C2H5 C2H5 H2N+ Zw itterioninc form
    37. 37. What n when is ortho, para ,meta? No substituion No ortho, para ,m eta CH3 Single substituion Again, no ortho, m eta, para CH3 CH3 CH3 CH3 CH3 CH3 H3C H3C Only in bi-substituted there is ortho, m eta and para O rtho M eta CH3 CH3 Para
    38. 38. • Presence of e- withdrawing halogens in ortho position only can decrease duration of action by making the ester more Likely for a nucleophilic attack O C O H2 C C H2 N C2H5 C2H5 H2N Procaine O C O H2 C C H 2 N C2H5 C2H5 H2N Chlorine in ortho group makes the carbonyl carbon more positive and more likely to be attacked by nucleophiles that causes breakdown of compound. Nucleophiles contain a lone pair of electron. They attack atoms with positive charges. M ore positive the atom, the better the attack Cl longer acting shorter acting chloroprocaine
    39. 39. • For amide only, presence of di-ortho substituted group prevent breakdown of amide and thus increase it’s stability in both liquid formulation and the body enzymes CH3 CH3 NH C O CH2 N C2H5 C2H5 NH C O CH2 N C2H5 C2H5 CH3 groups m ake it difficult to hydrolyze. thus it is Stable in water and blood. Sufficient duration of action No protection against hydrolysis by disubstituted group. Thus unstable in water and blood. Not enough duration of action Note: instead of CH3, other groups such as OCH3 can also be used
    40. 40. Linker group • Linker group has short alkynene (-CH2-) chain containing few carbon atoms and various functional group such as Amides, Esters, Ether or Ketones • Increasing the length of alkylene chain increases the pKa which reduces potency because more drug get ionized outside the membrane and thus can’t penetrate into the binding site Note: -CH2- group is called methylene, -C2H4- is called ethylene -CH3 is called methyl, -C2H5 is called ethyl CH4 is methane, C2H6 is ethane
    41. 41. Hydrophillic group • Useful LA have a secondary or tertiary amine group • This is important because it is believed that when they enter the cell, they will accept a proton and form positively charged quanternary form which is needed for binding to voltage gated ion channels O C O H2 C C H2 N C2H5 C2H5 H2N O C O H2 C C H2 N C2H5 C2H5 H2N H charged Quanternary formis beleived to bind to receptor Procaine believed to bind to it’s receptor when the amine group is positively charge quanternary form
    42. 42. • However, Benzociane has no anime portion but is still an effective topical LA • Thus the use of Amine part could only be for proper water solubility and not directly related to proper binding O C O CH2 CH3 NH2 Benzocaine has no amine but is still effctive LA
    43. 43. PROCAINE • Procaine is a local anesthetic drug of the ester group • effective parental but are relatively weak when applied topically • slow onset (4-5 min), short duration, pKa=8.8 • Procaine has the advantage of constricting blood vessels* which reduces bleeding, unlike other local anesthetics like lidocaine • is metabolized by the plasma enzymes to form para-amino benzoic acid (PABA) which is causes allergic effect • MOA – blocks pain by depressing CNS by antagonizing votage gated Na+ channel thus inhibiting generation of action potential •This sud increase duration of action like with lidocaine and epinephrine but it can’t because esters are such functional groups that get naturally quickly hydrolyzed/metabolized than other functional groups such as amide, alcohol
    44. 44. Which is more lipophillic? Which can exist as enantiomers?
    45. 45. Lidocaine • Most commonly used potent amide type local anesthetic for both parenteral and topical use • has a rapid onset of action (Intravenous - 45 to 90 seconds). and more lipid solubility than procaine, pka = 7.8 • Di-ortho methyl groups make the amide group resistant to hydrolysis thus it has moderate duration of action (1-2 hrs) • Produces eutectic mixture with prilocaine • Class IB Antiarrhythmic function • MOA – blocks pain by depressing CNS by antagonizing votage gated Na+ channel thus inhibiting generation of action potential
    46. 46. Bupivacaine • A potent amide type local anesthetic used mostly parenterally • It has rapid onset of action and higher lipid solubility and lower hepatic degradation and thus longer duration of action (6-8 hrs) than the structurally similar lidocaine, pKa = 8.1 • It exists in racemic form. The R isomer has greater affinity for Voltage gated Na+ channels and is linked with cardiotoxicity • The S isomer, called levobupivacaine, is clinically used as it has lower cardiotoxicity and CNS toxicity • MOA – blocks pain by depressing CNS by antagonizing votage gated Na+ channel thus inhibiting generation of action potential
    47. 47. Procaine synthesis H2N C O O H HO CH2CH2N(C2H5)2 H2SO4 -HOH H2N C O O CH2CH2N(C2H5)2 HCl Procaine para- amino benzoic acid 2-D iethylamino-ethanol H2N C O O CH2CH2N(C2H5)2.HCl condensation Procaine hydrochloride
    48. 48. Lignocaine synthesis CH3 NH2 CH3 CH3 CH3 NHCO CH2ClCl.CO CH 2Cl Chloroacetyl chloride 2,6-D im ethyl-phenylam ine D iethyl am ine CH3 CH3 NHCO CH2N(C2H5)2 -H Cl N H (C2H 5)2 Lignocaine H Cl CH3 CH3 NHCO CH2N(C2H5)2.HCl Lignocaine Hydrochloride
    49. 49. Review General Anesthetic Local Anesthetic Blocks pain in entire body Blocks pain in specific region on body Blocks sensation of temperature, touch and pressure Selective to blocking pain only. Muscle relaxation occurs Muscle relaxation not caused Drug intended to penetrate brain Drug not intended to penetrate brain but act on local nerves branches Receptor is ligand gated chlorine channel and Binding site is outside of cell membrane Receptor is voltage gated Sodium channel and Binding site is inside of cell membrane
    50. 50. Chemical transmission of stimuli occurring at synapse through NT binding to their receptors Electrical transmission of stimuli occurring through axon by movement of ion in and out
    51. 51. Q) Why LA only blocks pain? Ans: Sensitivity to LA depends on thickness of axon. Thinner neuron are easily effected. Neuron function Thickness (uM) Sensitivity to LA motor 12-20 + Touch , pressure 5-12 ++ Temperature 2-5 +++ Pain 0.4-1.2 ++++
    52. 52. MOA: blocks Voltage gated Sodium channel --> Prevent generation of action potential --> blocks neuronal transmission of stimuli (especially pain)
    53. 53. • What is a stimuli? A thing or event that evokes a specific functional reaction in an organ or tissue
    54. 54. Applications of LA same drug can be used • Topical - skin, eye or any body cavity (vagina, nose, ear, interior surfaces) • Infiltration – maximum localized LA, acts on finer nerve branches • Plexus block – blocks a major nerve branch and its associated region – Brachial plexus blocks are employed for surgery of shoulder, arm, forearm, wrist and hand. – A celiac plexus block is performed for surgery of the abdomen
    55. 55. Block vs Infiltration
    56. 56. shoulder arm forearm hand thumb fingers Spinal cord Left armRight arm •Block used in major nerve branch •Infiltration in minor/local nerve branch
    57. 57. Site of Epidural and Spinal block
    58. 58. Epidural vs Spinal Epidural Spinal Dose is high (10-20 ml) Dose is low (1.5-2 ml) Onset is slow (25-30 min) Onset is fast (5 min) does not cause as significant neuromuscular block Does cause as significant neuromuscular block Multiple dosing possible Single dose only Can be given at various point along the Backbone Can only be given at specific point along the Backbone to avoid damaging the spinal cord •Epidural block is widely used in labor pain •Spinal block used in Caesarean sections
    59. 59. SAR of LA •Hydrophillic part imp for penetration inside the cell to reach binding site •Hydrophillic amine group binds to receptor in charged Quanternary form
    60. 60. Ester Amide relatively unstable than amides Relatively More stable than esters, Metabolism by plasma enzymes Metabolism by liver Allergic effect due to metabolic production of PABA (para amino benzoic acid) No allergic effect of metabolic product Presence of diortho methyl groups (or methoxy) Increases stability of amides Presence of amine in aromatic ring increases Potency due to charge on nitrogen due to Possibility of Zwitterionic form
    61. 61. O C O H2 C C H2 N C2H5 C2H5 H2N O C O H2 C C H2 N C2H5 C2H5 Procaine is more potent if it has a e- donating amine group in the aromatic ring Procaine Note: Other e donating groups in decreasing order are –OH > -NH2 > - Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere) Less potent than procaine
    62. 62. • All LA have Pka between 7.5 – 9.5 • Anything beyond this range and there will be more ionization at pH 7 of the blood. • More ionization blocks the penetration of drug through the lipid membrane and they can’t reach their biding site which in inside of cell
    63. 63. CH3 CH3 NH C O CH2 N(C2H5)2 CH3 CH3 NH C O CH2 CH2 CH3 CH3 NH C O CH2 CH2 CH2 N(C2H5)2 N(C2H5)2 pKa = 7.8 pKa = 9.0 pKa = 9.5 A ll LA are basic drugs because they contain am ine group A s pKa increases, the drugs becom e m ore basic and thus m ore ionized in the blood In ionized form , they can't cross the lipid m em brane and reach their binding site increasing pKa = increased ionized form= decreased potency Effect of increasing linker length in lidocaine Increasing CH2 group = increased pKa (increased basicity) = increased ionized form = decreased potency
    64. 64. CH3 CH3 NH C O CH2 N CH3 CH3 NH C O CH2 N C2H5 C2H5 C2H5 C2H5 H
    65. 65. Factors effecting Duration of action as by the SAR Phenobarbital Thiopental Sodium Branched R group Short ethyl chain Total carbon = 2 (not counting aromatic) Long chain of R group Total C = 7 Additional improvements to Thiopental Sodium tofurther decrease duration of action •N methylation (potency also inc) •Unsaturated R group
    66. 66. Thank you • This is a “photo” of a protein (tertiary Structure ) • It has 347 amino acids
    67. 67. Same protein but shown in helix( red ) and sheets (blue) And loops
    68. 68. Same protein but now there is a drug binding to it
    69. 69. This is the binding site of that drug
    70. 70. Only showing amino acids of the binding site Remember: proteins are made of amino acids
    71. 71. This is what the drug is doing in the binding site--> making chemical bonds with it

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