LOCAL ANESTHETICS Local Anesthetics Historically the first local anesthetic discovered was the tropane alkaloid cocaine: Cocaine is still used in ocular.

LOCAL ANESTHETICS

Local Anesthetics Historically the first local anesthetic discovered was the tropane alkaloid cocaine: Cocaine is still used in ocular surgery (anesthetic) and nasal/sinus surgery to decrease post-operative bleeding due to its vasoconstrictive properties----- cocaine addicts Readily absorbed from the mucous membranes with good local activity - Rapidly hydrolyzed and inactivated due to the presence of two ester groups Addiction includes both physical and psychological addiction

Desirable Properties of Local Anesthetics 1) Reversible 1) Reversible 2) Non-irritating to the tissues 2) Non-irritating to the tissues 3) Rapid onset of acting 3) Rapid onset of acting 4) Long duration of acting 4) Long duration of acting 5) High therapeutic index 5) High therapeutic index 6) Effective topically and by injection 6) Effective topically and by injection 7) Proper physical properties (water solubility and stability in solution) 7) Proper physical properties (water solubility and stability in solution)

LOCAL ANESTHETICS CHEMISTRY It composed of hydrophilic domain Which either tertiary or secondary amine and hydrophobic domain it aromatic residue separated by alkyl chain The hydrophobic & hydrophilic domains linked with either ester or amide This bonds determine the pharmacology of L.A.

ANESTHETICS

Pharmacological Classes of Local anesthetic a- Amide 1- Lidocaine (lignocaine) Risk B & C 2- Prilocaine Risk B & C 3- Bupivacaine (Marcain) Risk C 4- Ropivacaine (Naropin) Risk C 5- Dibucaine Risk C 6- Mepivacaine ( Scandonest or Carbocaine) Risk C 7- Etidocaine (Dranest) Risk B

Pharmacological Classes of Local anesthetic B- Ester 1- Tetracaine (Amethocaine) Risk C 2- Benzocaine Risk C 3- Cocaine Risk C & X 4- Proparacaine (Fluoracaine) Risk C 5- Procaine Risk C 6- Chloroprocaine Risk C

Pharmacological Classes of Local anesthetic C- Miscellaneous 1- Dyclonine (ketone) Risk C 2- Pramoxine (ether )

MECHANISM OF ACTION * Block initiation & propagation of action potential * By preventing the voltage-Dependent increase in sodium conduction * Via physical plugging the transmembrane pore * The binding site is in the inner end of sodium channel

SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE 1. Diffusion of the base form across the across the nerve sheath and nerve membrane 2. Re-equilibration between the base and cationic forms in the axoplasm 3. Penetration of the cation into and attachment to a receptor site within the sodium channel. 4. Blockade of the sodium channel

SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE 5. Inhibition of sodium conduction 6. Decrease in the rate and degree of the depolarization phase of the action potential 7. Failure to achieve the threshold potential 8. Lack of development of a propagated action potential 9. Blockade of impulse conduction

CONDUCTION OF A NERVE IMPULSE

Ionized

Common features of Local Anesthetics Weak bases (pKa > 7.4) [poorly water soluble] Packaged as an acidic hydrochloride [pH 4-7 now soluble] In solution- non-ionized lipid soluble (free base) AND ionized water soluble (cation) Body buffers raise the pH, increase free base lipid soluble form crosses axonal membrane water soluble form blocks sodium channel

Important Clinical Properties of Local Anesthetics ONSET POTENCY DURATION OF ACTION

Important Clinical Properties of Local Anesthetics ONSET = pKa pKa = pH at which 50% of drug is ionized LA ’ s <50% exists in the lipid soluble nonionized form Only the nonionized form crosses into the nerve cell

ROLE of pH and pKa in LOCAL ANESTHETICS

Important Clinical Properties of Local Anesthetics Speed of Onset low pKa = fast onset Bupivacaine 8.1 Lidocaine 7.7 ? LA action in septic tissue –acid tissue -> é  ionized % of LA -> slow entry into membrane -> low concentration of LA for block

Important Clinical Properties of Local Anesthetics Anesthetic Potency Potency lipid solubility Higher solubility can use a lower concentration and reduce potential for toxicity [LA]

Important Clinical Properties of Local Anesthetics DURATION OF ACTION Duration protein binding Bupivacaine 95% Lidocaine 65% Procaine 6%

Important Clinical Properties of Local Anesthetics CLEARANCE ESTERS hydrolysis via pseudocholinesterase AMIDES metabolism via hepatic enzymes

Important Clinical Properties of Local Anesthetics Absorption of local at site LA ’ s cause some vasodilitation LA washout related to blood flow LA toxicity related to rate of absorption via blood flow

Important Clinical Properties of LA ’ s ADDITION of VASOCONSTRICTORS 1- Why it is combined with L.A. ? Vasoconstriction slows systemic absorption & increases duration 2- Epinephrine is commonly used in 1 in 200000 to 80000 (5ug-12.5ug/ml ) Least effective with high lipid soluble LA’s (bupivacaine/etidocaine) Epi may produce distal and systemic effects

ADDITION of VASOCONSTRICTORS 3- The total dose should not exceed 200-500ug 4- Epi-Drugs interaction Tricyclic anti-depressant Sympatholytic drugs 5- Contraindications ? -not recommend for digits injection 6- Do you prefere Norepinephrine OR EPINEPHRINE?

Effect of pH on the efficacy of local anesthetics 1- The activity of local anesthetic is strongly pH dependent 2- L.A. need to penetrate the nerve sheath and axon to reach the binding site of sodium channel 3- In acidic media penetration is very poor 7- Inflammed & infected tissues are acidic

ADDITION of Sodium Bicarbonate NaHCO3 - é pH & nonionized base Speeds onset of block 1 mEq NaHCO3 per 10 ml Lido/Mepiv .1 mEq NaHCO3 per 10 ml Bupiv

Methods of administration of L.A. 1- Infilteration Lidocaine or Bupivacaine 2- Surface Lidocaine, tetracaine, benzocaine 3- Intravenous regional anesthesia mainly lidocaine, prilocaine 4- Nerve block lidocaine or bupivacaine 5- Spinal anesthesia mainly lidocaine, tetracaine 6- Epidural anesthesia mainly lidocaine, marcain

A. Surface or Topical Anesthesia 1. The oral cavity, pharynx, larynx and tracheobronchial tree provide examples of mucosal surfaces where local anesthetics are applied topically. 1. The oral cavity, pharynx, larynx and tracheobronchial tree provide examples of mucosal surfaces where local anesthetics are applied topically. 2. A great danger exists in these areas for overdosage since rapid absorption into the circulatory system may occur and exceed the rate of detoxification of the drug. 2. A great danger exists in these areas for overdosage since rapid absorption into the circulatory system may occur and exceed the rate of detoxification of the drug. 3. To avoid this danger use a fine spray with a low concentration of the drug and limit the volume of solution used. 3. To avoid this danger use a fine spray with a low concentration of the drug and limit the volume of solution used. 4. Most often used agents cocaine (4-10%), tetracaine (1-2%) and lidocaine (2-4%) 4. Most often used agents cocaine (4-10%), tetracaine (1-2%) and lidocaine (2-4%) B. Local Infiltration 1. Used for superficial surgery such as removal of moles, warts, sebaceous cysts, etc. Also for iv insertion. 1. Used for superficial surgery such as removal of moles, warts, sebaceous cysts, etc. Also for iv insertion. 2. Use the lowest concentration of drug which will block sensory perception. Large volumes are generally used. 2. Use the lowest concentration of drug which will block sensory perception. Large volumes are generally used. 3. Epinephrine approximately doubles duration of action. 3. Epinephrine approximately doubles duration of action. 4. Most frequently used agents include lidocaine 0.5-1% and Bupivacaine 0.5% 4. Most frequently used agents include lidocaine 0.5-1% and Bupivacaine 0.5%

C. Regional Nerve Block and Field Block 1. Field block : Similar to local infiltration, but the goal is to specifically interrupt nerve transmission proximal to the site to be anesthetized. 1. Field block : Similar to local infiltration, but the goal is to specifically interrupt nerve transmission proximal to the site to be anesthetized. 2. Nerve Block - The goal is to inject local anesthetic into or about individual nerves or nerve plexuses. Produces even greater areas distal of anesthesia with a smaller amount of drug 2. Nerve Block - The goal is to inject local anesthetic into or about individual nerves or nerve plexuses. Produces even greater areas distal of anesthesia with a smaller amount of drug 8. Agents include Procaine (0.5-2.0%); Lidocaine (1-2%); Mepivacaine (up to 7 mg/kg of 1-3%); Bupivacaine (0.25- 0.75% up to 3 mg/kg ); Tetracatine (up to 1.5 mg/kg of 0.1-0.2%). 8. Agents include Procaine (0.5-2.0%); Lidocaine (1-2%); Mepivacaine (up to 7 mg/kg of 1-3%); Bupivacaine (0.25- 0.75% up to 3 mg/kg ); Tetracatine (up to 1.5 mg/kg of 0.1-0.2%).

D. Intravenous Regional Anesthesia 1. Consists of iv injection of local anesthetic into vein of exsanquinated extremity with proximal tourniquet. 1. Consists of iv injection of local anesthetic into vein of exsanquinated extremity with proximal tourniquet. 2. Binding of drug occurs in tissues of extremity 2. Binding of drug occurs in tissues of extremity - with tourniquet down (after 15-30 min minimum up time) only 15-30% released into systemic circulation. - with tourniquet down (after 15-30 min minimum up time) only 15-30% released into systemic circulation. 3. More effective in upper extremity 3. More effective in upper extremity 4. Lidocaine (1.5 mg/kg of 0.5%) frequently used. 4. Lidocaine (1.5 mg/kg of 0.5%) frequently used.

E. Epidural Anesthesia (caudal anesthesia) 1. Epidural space terminates cephically at the foramen magnum. 1. Epidural space terminates cephically at the foramen magnum. 2. Epidural anesthesia consists of epidural injection into the lumbar, or less frequently, the thoracic area. 2. Epidural anesthesia consists of epidural injection into the lumbar, or less frequently, the thoracic area. 3. Two sites of action 3. Two sites of action (a) diffusion into subarachnoid space (b) diffusion into paravertebral area through intervertebral foramina to produce multiple paravertebral blocks foramina to produce multiple paravertebral blocks

Continue--. Epidural Anesthesia (caudal anesthesia) 4. Danger of inadvertent subdural and subarachnoid puncture. 4. Danger of inadvertent subdural and subarachnoid puncture. * Lidocaine & Bupivacaine for longer action are used. 5. Unlike spinal, no differential zone of sympathetic blockade. 5. Unlike spinal, no differential zone of sympathetic blockade. There is a zone of differential motor blockade 4-5 segments less than sensory block. There is a zone of differential motor blockade 4-5 segments less than sensory block. 6. Other dangers include anterior spinal artery syndrome, hematoma, infection, and adhesions. 6. Other dangers include anterior spinal artery syndrome, hematoma, infection, and adhesions. 10. Advantages include 10. Advantages include (a) blood pressure remains stable (b) in obstetrical cases, the mother retains motor control of the abdominal muscles and can assist in the delivery of the fetus

F. Spinal Anesthesia (subarachnoid block) 1. Injection of local anesthetic into the lumbar subarachnoid space 1. Injection of local anesthetic into the lumbar subarachnoid space ; usually at T2-T3 or T3-T4 interspace. 2. Distribution of the drug in the subarachnoid space determines the level of anesthesia. This is controlled by: 2. Distribution of the drug in the subarachnoid space determines the level of anesthesia. This is controlled by: a) Positioning of the patient a) Positioning of the patient b) Speed of injection b) Speed of injection c) Specific gravity of solution c) Specific gravity of solution d) Volume injected d) Volume injected 3. Nerve fibers affected in the following sequence: 3. Nerve fibers affected in the following sequence: autonomic  sensory  motor 4. Zones of differential anesthesia: sympathetic block segments higher than sensory - motor segments lower 4. Zones of differential anesthesia: sympathetic block segments higher than sensory - motor segments lower

Continue-- Spinal Anesthesia (subarachnoid block) 5. It causes sympathetic blockade. Most important changes are on venous side of circulation. 5. It causes sympathetic blockade. Most important changes are on venous side of circulation. 6. Cardiovascular effects: hypotension, bradycardia, ↓preload ↓afterload 6. Cardiovascular effects: hypotension, bradycardia, ↓preload ↓afterload 7. Respiratory complications: due to ischemic paralysis of medulla 7. Respiratory complications: due to ischemic paralysis of medulla and not usually phrenic paralysis 8. Other dangers: 8. Other dangers: * chemical transection of cord * chemical transection of cord * traumatic destruction of a spinal end artery * traumatic destruction of a spinal end artery * traumatic damage of a nerve root & chronic arachnoiditis * traumatic damage of a nerve root & chronic arachnoiditis * postural headache and infection. * postural headache and infection. 9. Agents frequently employed include: Tetracaine & Lidocaine 9. Agents frequently employed include: Tetracaine & Lidocaine

Pharmacology of L.A. They interfere with function of all organs in conduction occurs A- CNS Stimulate CNS leads to restlessness and may proceed by clonic convulsion Then CNS depression Respiratory failure is main cause of death Drowsiness is the most complain

Pharmacology of L.A. B- Cardiovascular Decrease mycardium excitability Conduction Decrease force of contraction Hypotension These effects occurred in high dose which cause CNS toxicities Arteriodilation Rarely occurs in infilteration

Pharmacology of L.A. C- Hypersensitivity Mostly occurred with ester type Allergic dermatitis asthmatic attack Amide almost free of hypersensitivity

Lidocaine 2% 1- DOSE *OVER 10 YRS: Not exceed 6.6 mg/kg or 300 mg per dental appointment 2- under 10 years 100-150 mg per dental appointment 3- Drug interaction -beta blockers -antiarrhythmia agents 4- Metabolism

Prilocaine 4% 1- DOSE: -Less than 10 yrs 40 mg per setting or less - greater than 10 yrs and adult 40-80 mg -Not exceed 400-600 mg in adult 1- Toxicities * Methemoglobinemia 2- under 10 years 100-150 mg per dental appointment

BUPIVACAINE 0.5% 1- DOSE: -Less than 10 yrs NOT ESTABLISHED - greater than 10 yrs and adult 9 mg -Not exceed 90 mg in adult per dental appointment 2- duration -Nerve block 5-7 hrs 3- Toxicities - much greater than lidocaine

MEPIVACAINE Amide Products: Longer duration of action 1- Indications: Peripheral, transvaginal, paracervical, caudal, epidural and infiltration nerve block, dental procedures 2- protein bound 78% 3- Warnings: * NOT recommended for obstetrical epidural anesthesia due to cardiac arrest and death * Reserve the 0.75% solution for surgical procedures where prolonged activity is needed—danger of inadvertent IV injection and cardiac arrest

ETIDOCAINE Amide Products: - Longer duration of action 1- Indications: peripheral, central or lumbar peridural nerve block; intra-abdominal/pelvic/lower limb/ceasarean section surgery; caudal or maxillary block 2- Onset of action 3-5 minutes 3- with a duration of action of 5-10 hours 4- surprisingly epinephrine addition does NOT increase the duration—why?----Partition coefficient is 7050X of procaine---94% protein bound

ROPIVACAINE Amide Products: - Longer duration of action 1- Indications: local or regional anesthesia for surgery, post-operative pain management and obstetrical procedures 2- Avoid rapid administration of large doses---use fractional or incremental administration 3- ideal for continuous infusion for epidurals during birth 4- Onset of action is 10-15 minutes 5- with a duration of action of 2-8 hours---safe to use this as an epidural product for up to 24 hours

TETRACAINE Ester Products: 1- Indications: Spinal anesthesia including high, median, low and saddle blocks including prolonged action of 2-3 hours 2- Slower onset of action than procaine but duration is 2-3 hours ------ can increase to 3-5 hours by including epinephrine 3- This drug should not be used in children due to a lack of safety data

COCAINE (1)- Mechanism of action A- Blocks sodium channel B- inhibit NE UPTAKE-1 (2) Direct vasoconstrictor action and potentiation sympathetic system (3) Extensive cardiovascular actions (4) Powerful CNS stimulant (5) Considered a narcotic with potentially for psychic dependence (6) Used for surface anesthesia in 1.0-10.0% solutions, occasionally with epinephrine (7) Metabolized by esterases and hepatic enzymatic degradation; t1/2 after oral or nasal administration, approximately 1 hour

LOCALLY ACTING AGENTS LOCAL HAEMOSTATIC AGENTS

LOCALLY ACTING AGENTS 1- Sympathomimetic Epinephrine with LA Epinephrine-imprignated cord to retract and control gingival haemorrhage 2- Astringents & STYPTICS -They react with proteins of oral cavity and make protective layer: Aluminum chloride (Sansilla) –Example of Styptics : Silver nitrate rod LOCAL HAEMOSTATIC AGENTS

Aluminum chloride retraction cord (HEMODENT 25%) Tannins: Pyralvex -it is an oral paint contains tannic acid and salicylic acid - It is used for mild peri-oral lesion & less effective in oral lesion 3- Mechanical haemostatics They forms matrices in which blood cells and fibrin can trapped They are more effective than astringent, styptics or sympathomimetics in controlling capillary oozing & surface bleeding LOCAL HAEMOSTATICS

1- Absorbable gelatin ( Gel Foam) * Advantages of absorbable gelatin -It does not interfere with the followings: Thrombin Epithelization Bone regeneration 2- Oxidized cellulose ( Oxycel &Novocel) It has high affinity to haemoglobin & it is form of gauze of cotton pellets It is more effective than Gelfoam It interfere with followings: - Epithelization & bone regeneration (not suitable for packing in bone fracture - Inactivates thrombin Types of mechanical haemostatics

3- Oxidized regenerated cellulose (Surgicel) Advantages - It does not interfere with epithelization -Therefore, it is suitable for surface dressing Disadvantages - It interferes with bone regeneration - Inactivates thrombin 3- Microfibrillar collagen hemostat (Avitene) It is in the form of powder & used to control bleeding after oral surgery * Advantages - It does not interfere with: * epithelization * bone regeneration * activity of thrombin Disadvantage: it is source of animals which may transfere diseases

HAEMOSTATIC SYSTEMS 1- Formation of fibrin via clotting factors 2- Fibrinolysis 3- Platelets aggregation 4- Blood vessels (PGE12) SYSTEMIC HAEMOSTATICS

VITAMIN K Role of vitamin K in clotting system - Vit K is necessarly for final stage of clotting factors synthesis such as prothrombin,factor vii, ix &x Premature Mature clotting factor Clotting factors Examples of systemic haemostatic agents

CAUSES OF VIT K DEFICIENCY 1- Obstructive jaundice 2- malabsorption 3- Reduced GIT flora -Rarely after broad spectrum antibiotics CLINICAL USES OF VITK 1-Reverse bleeding induced by oral anticoagulant 2- Inadequate vit k availability 3- new born baby

VIT K Preparations vit k1 (phytomenandione) konakion - it is lipid soluble and injected in new born baby -onset within 12 hours -Menadiol sodium phosphate (vitk3) it is water soluble onset 24 hrs prefered in malabsorption or obstructive jaundice It has tendency to induce hemolytic anemia

1- MECHANISM OF ACTION Prevents plasminogen not to attach to fibrin resulting in inhibition fibrinolysis inhibits the proteolytic activity of plasmin 2- Clinical uses Use as Mouthrinse 4.8% to prevent bleeding in hemophiliac & patient under warfarin due to dental extraction ORAL: 25 MG/KG FOR 2-8 DAY in haemophiliac Hereditary angioedema & menorrhagia Thrombolytic over dose TRANEXAMIC ACID

3- pregnancy Risk factor B to prevent bleeding in hemophiliac & patient under warfarin due to dental extraction 3- Adverse effects If taken orally -GIT Disturbances such as diarrhea -Hypotension -Thrombosis -Blurred vision requires regular eye examination --Regular liver function tests in long term oral use for hereditary angioedema TRANEXAMIC ACID

1- Mechanism of action Inhibits the activation of plasminogen to plasmin 2- Clinical uses Treatment of excessive bleeding from fibrinolysis 5-30 g/day in divided dose at 3-6 hrs interval AMINOCAPROIC ACID

3- pregnancy Risk factor C 4- Adverse effects Hypotension bradycardia Arrhythmia Myopathy GIT irritation AMINOCAPROIC ACID

It is inhibitor of plasmin (plasmin causes fibrin lysis) CLINICAL USES - Over dose of thrombolytic drugs such streptokinase - Hyperplasminia as a result of mobilization and dissection of malignant tumor SIDE EFFECTS -Hypersensitivity --localized thrombophlebitis APRPTONIN (Trasylol)

1- Mechanism of action CORRECT ABNORMAL PLATELETS ADHESION 2- Clinical uses Short term use in blood loss in menorrhagia(500mg tablets four times daily during menses Prophylaxis and treatment of periventricular haemorrhage in low birth weight infants (i.v. or i.m.) 3- Clinical uses - Rashes, Nausea and Headache ETHAMSYLATE OR ETAMSYLATE DICYNENE ®

1- Mechanism of action Enhance reabsorption of water in kidney Increase Von Willebrand factor & factor viii 2- Clinical uses Control bleeding in mild hemophilia & Von Willebrand disease during dental extraction Diabetes insipidus Nocturnal enuresis CAUTION : Avoid overhydration (it has ADH activity) DESMOPRESSIN ACETATE(Stimate ® )

3- pregnancy Risk factor B 4- Adverse effects Facial flushing Dizziness Nasal congestion hyponatremia Water intoxication DESMOPRESSIN ACETATE

1- Anti-hemophilic factor (Kogenate ® ) It is factor viii derived from recombinant DNA - CLINICAL USES - Control bleeding in hemophilia A - Life threatening haemorrhage 2- FACTOR VIIa (NovoSeven ® ) -It is recombinant DNA CLINICAL USES: * PATIENT WITH INHIBITORS TO FACTORS VIII & IX BLOOD PRODUCTS

3- FACTOR IX (Replenine ® ) - CLINICAL USES - it indicated in patient with factor ix deficiency (Hemophilia B) - CAUTION : Risk for thrombosis BLOOD PRODUCTS

1- Composition Two separate solutions a- fibrinogen b- thrombin & calcium It is completely reabsorb within 2 –4 weeks Some products contain -tranexamic acid or aprotonin 2- Effective in preventing bleeding in bleeding disorders FIBRIN GLUE (Beriplast)

Management of patient under warfarin 1- Minor surgery Use tranexamic mouth rinse without adjustment of anticoagulation if INR is less than 4 2- Major surgery Stop warfarin preoperative use low molecular weight heparin

Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic PathwayExtrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants

ANTI-COAGULANTS 1- Drugs inhibit vit k actions (oral anticoagulant) -By prevents maturation of the clotting factors - slow onset (3 days) 2- Drugs directly acting on the clotting factors - Rapid onset (Heparin) 3- Drugs inhibit platelets aggregation 4- Fibrinolytic drugs (dissolve clot)

ORAL ANTI-COAGULANTS WARFARIN (Coumadin ® ) 1- CLINICAL USES OF WARFARIN Prophylaxis and treatment of venous thrombosis such as : - Deep vein thrombosis (DVT) - Atrial fibrillation - prosthetic cardiac valves with antiplatelets - thromboembolic disorders such post MI or Stroke and embolism

ORAL ANTI-COAGULANTS WARFARIN (Coumadin ® ) 2- MOA OF WARFARIN Warfarin interferes with hepatic synthesis of vit K-dependent factors (ii, vii, ix, x) PREVENT RECYCLING OF VIT K by inhibiting reductase enzyme which convert epoxide vit K to vit K 3- ONSET OF WARFARIN -Within 36-72 hours

Mechanism of action Descarboxy ProthrombinProthrombin Reduced Vitamin KOxidized Vitamin K NADHNAD WARFARIN

ORAL ANTI-COAGULANTS WARFARIN (Coumadin ® ) 4- MONITORING ITS EFFICACY Prothrombin time expressed by : International Normalized Ratio (INR) determined daily initially then at longer intervals depends on the response INR 2-2.5 For prophylaxis of DVT, AF, Cardioversion, dilated cardiomyopathy, MI, Rheumatic valve disease INR 3.5 For recurrent DVT, pulmonary embolism and mechanical prosthetic heart valve

ORAL ANTI-COAGULANTS WARFARIN (Coumadin ® ) 4- ADVERSE EFFECTS OF WARFARIN The main is hemorrhage Skin necrosis in patient with protein c & s deficiency 5- PREGNANCY AVOID RISK FACTOR D REPLACED BY HEPARIN

ORAL ANTI-COAGULANTS WARFARIN (Coumadin ® ) 6- DRUG INTERACTION INCREASE EFFECTS: - NSAIDs - Sulfa drugs - cimetidine Decrease effects liver enzyme inducer such as: -phenobarbitone, rifampicin, phenytoin

HEPARIN 1- RAPID ONSET, inject only S.C. OR I.V. 2- CLINICAL USES Preventive and treatment of thromboembolic disorders such as DVT, MI, pulmonary emobolism patient undergoin general surgery (low dose) orthopedic surgery unstable angina & Pregnancy Extracorporeal circuits such as hemodialysis & cardiopulmonary bypass

HEPARIN 3- DOSES OF HEPARIN PROPHYLAXIS DOSE A- Post-operative & MI 5000 units s.c. every 8-12 hrs B- pre-surgery 5000 units 2 hours before surgery C- Pregnancy 5000 -10,000 units every 12 hours (REQUIRED APTT monitoring

HEPARIN 4- MECHANISM OF ACTION OF HEPARIN Heparin enhances the activity of anti-thrombin It inhibits factor X in small dose 5- MONITOR THE EFFICACY Prophylaxis dose does NOT require APTT (Activated partial thromboplastin) APTT should be in the ranges 1.5-2.5

Heparin mechanism of action Heparin Antithrombin III Thrombin

HEPARIN 6- ADVERSE EFFECTS Bleeding if APTT more than 3 or - impaired hepatic or renal functions Thrombocytopenia Osteoporosis (long term use) skin necrosis & hypersensitivity It may induce hyperkalemia by inhibition of aldosterone secretion 7- ANTIDOTE OF HEPARIN - Protamine sulfate 100mg neutralizes 100 unit

LOW MOELCULAR WEIGHT HEPARIN 1- EXAMPLES: Enoxaprin, Dalteparin & Ardeparin 2- Advantages A- Do not required APTT monitoring B- because it has little effects on antithrombin but it potent inhibition on factor Xa C- Long duration (once daily) الى هنا

HEPARINOID 1- EXAMPLES: DANAPAROID 2- MOA : inhibits Xa & IIa factors 3- Advantages A- Low incidence of thrombocytopenia * therefore it can be used in patient had history of thrombocytopenia due to heparin 4- Disadvantage : not effectively antagonized by protamine sulfate

ANTIPLATELETS AGGREGATION 1- EXAMPLES: Aspirin Clopidogrel Dipyridamole Ticlopidine Abciximab Eptifibatide Tirofiban

ANTIPLATELETS AGGREGATION 2- THEY DECREASE PLATELETS AGGREGATION and inhibit thrombus formation in the arterial circulation where anti-coagulants have little effects. 3- General Clinical uses cerebral vascular diseases such as Transient ischemic attack (TIA) Unstable angina Post MI Coronary artery bypass surgery & Angioplasty

ASPIRIN 1- CLINICAL USES OF ASPIRIN (small dose) Prophylaxis for MI ( 75mg - 81mg - 160-325 mg) Transient ischemic episode & stroke (600 mg twice daily) Following coronary bypass surgery percutaneous transluminal coronary angioplasty Eclampsia in small dose ? Unlabelled 2- MOA : Irreversibly inhibits COX (cyclooxygenase) leading to inhibit thrombane A2 in platelets

ASPIRIN 3- ADVERSE EFFECTS OF ASPIRIN GIT upset may develop ulcer May precipitate bronchial asthma in patient has histry of bronchial asthma Some patient develop subcutaneous hemorrhage (as spots) 4- contraindication * children under 12 years and breast feeding mother * active peptic ulcer * bleeding disorders 5- Caution: * asthma, pregnancy

CLOPIDOGREL (PLAVIX) 1- CLINICAL USES *Reduces atherosclerosis events such as MI, Stroke & peripheral artery diseases Prevent of thrombotic complications after coronary stenting Acute coronary syndrome such as unstable angina or non-Q-wave MI It can be used instead of aspirin if patient allergic to aspirin 2- MOA It blocks the ADP receptors in platelets which prevent fibrinogen binding to platelets leading to reduce platelets aggregation.

CLOPIDOGREL (PLAVIX) 3- ADVERSE EFFECTS Bleeding (GIT & Brain) & leukopenia GIT upset such as gastritis (less than aspirin) 4- CONTRAINDICATIONS Active bleeding avoid first few days after MI & 7 days after stroke Not recommend for angioplasty Stop it 7 days before surgery Liver impairment Breast feeding

TICLOPIDINE (TICLID) 1- CLINICAL USES It is reserved for patients who are intolerant to ASPIRIN Prophylaxis of major ischemic events in patient with a history of ischemic stroke Adjuvant therapy with aspirin following coronary stent to reduce stent thrombosis 2- MOA Similar to plavix

TICLOPIDINE (TICLID) 3- ADVERSE EFFECTS Bleeding Neutropenia, agranulocytosis & pancytopenia Thrombotic thrombocytopenic purpura Increases liver enzymes Jaundice hyperlipidemia

DIPYRIMADOLE (PERSANTIN) 1- CLINICAL USES: Maintains patency after surgical grafting include coronary artery bypass Used with Warfarin to decrease thrombosis in patient after artificial heart valve replacement Use with ASPIRIN to prevent thromboembolic disorders It can be given 2 days prior open heart surgery 2- MOA: Inhibits adenosine deaminase & phosphodiesterase leading to accumulation of: Adenosine, adenosine nucleotides These inhibit platelets aggregation cAMP this causes vasodilation

DIPYRIMADOLE (PERSANTIN) 3- ADVERSE EFFECTS Hypotension Headache Increased bleeding during or after surgery Worsening symptoms of coronary heart disease 4- CAUTIONS Rapidly worsening angina Aortic stenosis Recent MI CHF & Migraine

ABCIXIMAB(REOPRO) 1- CLINICAL USES Adjunct to percutaneous transluminal coronary angioplast Prevention of acute ischemic complications in patients at high risk for abrupt closure of treated coronary vessels Use with heparin in unstable angina 2- MOA It binds with platelets iib/iiia receptors preventing their aggregation

FIBRINOLYTIC DRUGS 1- EXAMPLES Alteplase (recombinant DNA tissues plasminogen activator) Reteplase Streptokinase tenecteplase

ALTEPLASE (ACTIVASE) 1- CLINICAL USES Management of acute MI & pulmonary embolism for lysis of thrombi 2- MOA * It initiates local fibrinolysis by binding to fibrin in clot and converts entrapped plasminogen to plasmin

ALTEPLASE (ACTIVASE) 3- adverse effects Multiple emboli Arrhythmia due to cardiac reperfusion bleeding

ANTICOAGULANT DRUGS TO TREAT THROMBOEMBOLISM Drug ClassPrototypeActionEffect Anticoagulant Parenteral HeparinInactivation of clotting Factors Prevent venous Thrombosis Anticoagulant Oral WarfarinDecrease synthesis of Clotting factors Prevent venous Thrombosis Antiplatelet drugs AspirinDecrease platelet aggregation Prevent arterial Thrombosis Thrombolytic Drugs StreptokinaseFibinolysis Breakdown of thrombi

ORAL PROTECTIVE AGENTS 1- CLINICAL USES :Protectives are used for non-specific mouth ulceration such as aphthus ulcer It is usually combines with local anesthetic and antiseptics such as [ORAL B ® ] composed of: -lidocaine, cetylpyridinium, menthol & cineole 2- examples of oral protectives Carmelose gelatin (ORABASE ® ) Choline salicylate dental gel (BOJELA ® ) Benzdamine (DIFFLAM ® )

ANTI-SEPTIC MOUTH RINSE 1- Chlorhexidine 2- Cetylpyridinium chloride & Triclosan 3- phenols 4- Hexitidine (oraldene mouth rinse) 5- Domiphen bromide (Bradoral lozenges)

CHLORHEXIDINE 0. 2% CORSODYL ® & Hexidine ® 1- PROPERTIES OF CHLORHEXIDINE * It is used in 0.2% as mouth rinse * It is the most effective mouth rinse It Reduces gingival pathogen The anti-microbial last several hours it is effective in gingivitis associated with bleeding & PUS it cause permanent stain of restorative But reversibly stains natural teeth & dorsum of the tongue

CHLORHEXIDINE 0. 2% CORSODYL ® & Hexidine ® 2- MOA It broad spectrum antiseptic its bacterial action exerts by disruption of bacterial membrane of both gram positive & negative bacteria 3- CLINICAL USES Oral hygeine especially if there heavy plaque Inhbition of plaque formation Gingival infection It may help in recurrent aphous ulcer

CHLORHEXIDINE 0. 2% CORSODYL ® & Hexidine ® 4- ADVERSE EFFECTS Reversible brown staining of natural teeth Irreversible brown staining of artificial teeth (restorative) Idiosyncratic Epithelial irritation of oral cavity Rarely parotid gland swelling Inflammation of salivary glands It may mask periodontitis

CETYLPYRIDINIUM CHLORIDE0.5% SCOPE ® 1-PROPERTIES It is surface active agent It is ineffective in present of bleeding, sputum & pus It is weak antibacterial 2- MOA It acts as detergent which help removal of bacteria & Disrupts the membrane of bacteria

PHENOLS CHLORASEPTICS® It contains phenol Available as spray, mouth rinse & lozenges 2- ADVERSE EFECTS OF PHENOL Nephrotoxicity if exceeds the dose It inhibits polymerization of resin restoration It damage the cavity liner

Agents used in dental procedures 1- HYDROGEN PEROXIDE It is used for root canal irrigation Its action is mediated by releasing nascent oxygen which kills bacteria 2- SODIUM HYPOCHLORITE 5% It is used to irrigate root canal It is irritant to mucous membrane of oral cavity

Agents used in dental procedures 3- OBTUNDANTS A- DEFINTION OF OBTUNDANT Chemical precipitates cellular protein of nerve fiber Causing paralysis of nerve fiber which leads to diminish sensation of dentine B- IDEAL PROPERTIES OF OBTUNDANTS Acts without initial pain Does not stain teeth, dentine or enamel It penetrates quickly through the dentine but not too deep otherwise it may lead to inflammation of the pulp

Agents used in dental procedures C- MOA OF OBTUNDANT It precipitates cellular protein of nerve fiber Causing paralysis of nerve fiber which leads to diminish sensation of dentine D- CLINICAL USES Obtundants allow painless excavation

EXAMPLES OF OBTUNDANTS 1- Eugenol It causes initial stimulation followed by paralysis of nerve 2- Zinc chloride It stains teeth and has poor penetration 3- Absolute Alcohol It requires the oral cavity to be dry 4- Cresote

Agents used in dental procedures 4- MUMIFYING AGENT A- Definition of mumifying agents It is a chemical causes aseptic dryness and hardness of pulp tissues and root canal They have astringent and antiseptic properties All mumifying agents are obtundant but not all obtundants are mumifying agents B- CLINICAL USES * They applied when pulp or content of the root can NOT be removed

EXAMPLES OF MUMIFYING AGENTS 1- Iodinated cresol 2- beta-naphthol 1% in alcohol 3- iodoform 4- Ammonical silver nitrate (it stains teeth) 5- Forlmaldehyde

FLOURIDE PREPARATIONS 1- NATURAL SOURCE OF FLOURIDE Water (1PPM iseffective cincentration) Fish (20 PPM) Tea (100 PPM) 2- METABOLISM & ABSORPTION OF FLOURIDE Calcium and magnesium decrease flouride absorption Flouride concentrates in bone & teeth In children, the flouride concentrates in bone and teeth than elderly

FLOURIDE PREPARATIONS 3- MECHANISM OF ACTION OF FLOURIDE Flouride converts hydroxyapatite to FLOUROAPATITE which leads - Makes the apatite structure more stable which improve CRYSTALLINITY of the structure - FLOUROAPATITE is less soluble in acid - FLOURIDE inhibits bacteria enzymes

EXAMPLES FLOURIDE PREPARATIONS 1- ACIDULATED PHOSPHATE FLOURIDE (APF) It contains flouride between 10,000 to 20,000 PPM It is the preparation of choice for professional flouride application It benefits last 2-3 years after application on the teeth Contact time upon application is (1-4 minutes) depends on the type of preparation.

EXAMPLES FLOURIDE PREPARATIONS ACIDULATED PHOSPHATE FLOURIDE (APF) A- Advantages of APF Stable in solution Not irritant to gingiva Agent of choice for professional application B- Disadvantages of APF APF is acidic solution may affect CEMENTUM Not suitable for dentrifrices

EXAMPLES FLOURIDE PREPARATIONS 2- SODIUM FLOURIDE It is available in tablets such as Zymaflour® 1mg 0.25 MG (1/4 Tablet) per day required for 5-16 years old A- Advantages of sodium flouride Stable in solution Neutral solution (Ph 7.0) B- Disadvantages of sodium flouride It is NOT compatible with many abrasives in tooth-paste because: - it reacts with CALCIUM & PHOSPHATE - and becomes insoluble compound - Not absorb into circulation (not effective)

EXAMPLES FLOURIDE PREPARATIONS MOUTH RINSE CONTAINS SODIUM FLOURIDE It is more effective than MFP present in tooth-paste but combination of sodium flouride mouth rinse with dentrifrices are more effective than either product alone Mouth rinse containing FLOURIDE 100 PPM recommend to use it twice daily Mouth rinse containg 250 PPM used once daily mouth rinse contains 1000 ppm used once weekly or every other week ( هنا

EXAMPLES FLOURIDE PREPARATIONS 3- SODIUM MONOFLOUROPHOSPHATE (MFP) It is commonly used in tooth-paste A- Advantages of (MFP) Stable in various pH It is compatible with tooth-paste abrasives B- Disadvantages of (MFP) It is weak flouride source Efficacy is questionable

EXAMPLES FLOURIDE PREPARATIONS 4- STANNOUS FLOURIDE A- Advantages of STANNOUS FLOURIDE Both cation & anion are effective B- Disadvantages of STANNOUS FLOURIDE Unstable in solution Stain teeth bitter taste

TOXICITY OF FLOURIDE A- ACUTE TOXICITY It is common during applying APF IN CHILDREN Fatal dose 50-225 mg/kg Symptoms of toxicity - Nausea, vomiting - Abdominal pain - Sweating - Convulsion - Death

TOXICITY OF FLOURIDE B- CHRONIC TOXICITY It is occurs at concentration ranges between 2-8 ppm consumed in drinking water Flourosis occurs when the crown of permanent teeth are forming DEFINITION OF FLOUROSIS - Is hypoplastic defect resulting from disturbance in the function of AMELOBLAST (enamel) during teeth development Symptoms of chronic toxicity - endemic flourosis is associated with - mottled enamel & deformed teeth

DENTRIFERICES 1- It is a pharmaceutical preparations are used locally on the teeth & oral cavity to perform the followings: Clean Polish Prevent bacterial fermentation Prevent gingivitis Prevent dental caries

EXAMPLES OF DENTRIFERICES TOOTH PASTE POWDER LIQUID IN FORM OF SOLUTION

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 1- Abrasive It is am inert, insoluble and finely powdered Examples of abrasives - calcium pyrophosphate - dicalcium phosphate Main action of abrasive - it cleans and polish - removes stain and plaque

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 2- Flavouring agents They have the following properties: good odor mild antiseptic mild local anesthetic counter irritant Examples of flavouring agents - peppermint - cinnamon - clove oil - menthol

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 3- SWEETNER Examples of sweetner - Saccharin - aspartame - glycerin

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 4- HUMICTANT FUNCTIONS OF HUMICTANTS: - Keep moisture of the tooth-paste - prevents dryness of the tooth paste - it gives plasticity to the tooth-paste - it has demulcent action on the gum Examples of sweetner -GLYCERIN - SORBITOL

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 5- DETERGENT & FOAMING AGENTS FUNCTIONS OF HUMICTANTS: - they lower surface tension(emulsifying agents) - emulsify fatty materials - Promote good penetration and mixing of constituents of the tooth-paste - they assists in removal mucous deposit and debris - Help to dissolve plaque

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE EXAMPLES DETERGENT & FOAMING AGENTS Examples of detergent and foaming agents: - sodium lauryl-sulfate - magnesium lauryl-sulfo-acetate - monoglyceride - dioctyl-sodium-sulfo-succinate

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 6- THICKENING AGENTS FUNCTIONS - Improve & maintain the consistency of the paste - they prevent separation of the tooth-paste contents under extreme temperatures (high & low) Examples of thickening agents: - glycerin starch - carboxy-methyl-cellulose - sodium alginate - methyl-cellulose

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 7- PRESERVATIVES FUNCTIONS - prevent bacterial, fungal growth which prevents fermentation of the tooth-paste Examples of preservatives: - methylparaben 0.15% - propylparaben 0.15%

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 8- FLOURIDE FUNCTIONS - It is anti-cariogenic agent and significantly reduces caries - it is commonly used sodium-mono-flouro- phosphate (MFP) because : * it is stable at various Ph * compatible with many abrasives

TOOTH-PASTE MAIN INGREDIENTS OF TOOTH PASTE 9- DESENSITIZING AGENTS Not present in most of tooth-paste examples of desensitizing agents - Potassium nitrate - Potassium oxalate

GLUCOCORTICOIDS Adrenal steroids are synthesised from zona fasciculata of adrenal cortex as needed It is stimulated by ACTH which is release from pituitary gland ACTH is regulated by CRF in hypothalamus Glucocorticoids is synthesised from chlosterol Stress also stimulate glucocorticoids

Adrenal Gland

Glucocorticoids

Glucocorticoids bind with specific receptors in the cytoplasms The complex binds with DNA which leads to: * prevent transcription such as - COX-2 - Block Vit D3 –mediated induction of osteocalcin * or induce particular gene - Such as LIPOCORTIN-1 & Tyrosine hydroxylase MECHANISM OF ACTION

GRE Direct effects come from receptor binding transcription protei n Altered cellular function HSP70 HSP90 IP HSP70 HSP90 IP GRE CBG albumin

Example of indirect inhibition of gene induction TNF-  TNFR NF-  B B  I  B  I  B  I  B  B Cytokines GLUCORTICOIDS GCR GC GCR COX-2 NOS-2

(PAF) Phospholipase A 2

Pharmacological action of glucocorticoids 1- General effects on metabolism - Water, edlectrolyte balance and organ systems 2- Negative feedback on Pituitary & Hypothalamus 3- Anti-inflammatory and immunosuppressive

GENERAL METABOLIC & SYSTEMIC EFFECTS 1- Carbohydrate and protein metabolism 2- Decrease glucose utilization 3- increase gluconeogenesis which may induce hyperglycemia 4- Decrease in protein synthesis breakdown 5- It has permissive effects on the lipolytic response to catecholamines

GENERAL METABOLIC & SYSTEMIC EFFECTS 6- Redistribute fat in large dose 7- It has some mineralocorticoids activities 8- Increase calcium secretion & decrease its absorption 9- Reduce function of osteoblast 10- and Increase the activity of osteoclast (Digest bone) * by hypocalcemia-induced parathyroid hormone secretion * These lead to osteoporosis

NEGATIVE FEEDBACK EFFECTS 1- Both endogenous and exogenous glucocorticoids have a negative feedback on CRF & ACTH 2- The inhibitory effects of endogenous glucocorticoids due to exogenous steroids is prolonged (months) 3- lipocortin-1 play negative feedback on hypothalamus and pituitary 3- and leads to atrophy of adrenal cortex

Atrophy due to negative feedback inhibition of ACTH Adrenal d ( - ) ( + ) Cortisol ACTH CRF neuron 3rd vent immune system ( - ) ( + ) IL-1 IL-2 IL-6 TNF-  administered glucocorticoid

Anti-Inflammatory 1- Inhibit production of prostaglandins due to decrease the expression of COX-2 2- inhibit early and late manifestation of inflammation 3- Which leads to prevent chronic inflammation 4- Decrease fibroblast which leads to inhibition of chronic inflammation (less fibrosis) and wound healing and repair

Continue anti-inflammatory effects 5- Inhbits Phospholipase A2 by inducing lipocortin which leads to: Decrease production of PAF Arachidonic acid which is the precursor for: * Production of prostaglandins * Leukotrienes (slow reacting substance of anaphylaxis

Continue anti-inflammatory effects 6- Decrease histamine release 7- decrease production of nitric oxide 8- Decrease production of PAF 9- Decrease the production of GM-CSF which is essential for production of: -platelets -Monocyte, neutrophil & eosinophil -RBCs

* Drug binds only to certain targets Supress initiation generation of immune response It is non-selective ** Supress cellular immunity ** and Humeral * It induces apoptosis of lymphocyte IMMUNOSUPPRESSIVE EFFECTS

Adverse effects occur after prolonged used or large dose 1- Supress response to infection or injury 2- Impair wound healing 3-Slight incidence of peptic ulcer 4- Cushing’syndrome 5- Osteoporosis 6- Hyperglycemia ADVERSE EFFECTS OF GLUCOCORTICOIDS

7- Muscle wasting 8- Inhibit growth in children 9- Euphoria & Psychosis 10- decrease blood supply to bone leading to necrosis the head of the femur inhalation ADVERSE EFFECTS OF GLUCOCORTICOIDS

11- cataract 12- glaucoma 13- increase in intracranial pressure 14- disorder of menestrual cycle 15- oral thrush especially when taken by inhalation 16- Adrenal insufficiency * It may take two months or more up to 18 months ADVERSE EFFECTS OF GLUCOCORTICOIDS

1- It should based on the severity of diseases 2- Dosage, frequency, duration & preparation influence the response and adverse reactions 3- Administered locally when possible inorder to minimize the adverse effects & efficacy 4- The pharmacological dose should be tapered in order to avoid adrenal crisis GUIDELINES FOR GLUCOCORTICOID THERAPY

1- Replacement therapy (Addison’disease 2- Asthma 3-Topically in various inflammatory condition -skin, eye, nose 4- Post neurosurgery &head and spinal injury 5- Autoimmune diseases -Inflammatory bowel disease - haemolytic anemia CLINICAL USES OF GLUCOCORTICOIDS

6- Anti-cancer with other cytotoxic agents 7- Autoimmune diseases 8- Inflammatory diseases - haemolytic anemia - organ transplant with other immunosuppressants 9- Anti-emetic in conjunction with other anti- emetic CLINICAL USES OF GLUCOCORTICOIDS

10- Temporary relief of sympton associated with Oral inflammation and ulcerative lesion such as A- Recurrent aphthus stomatitis Triamcinolone acetonide (Kenalog orabase) B- Erosive lichen planus -- Dexamethasone C- Major aphthae - Kenalog orabase GLUCOCORTICOIDS USES IN DENTAL PRACTICE

CLASSIFICATION OF GLUCOCORTICOIDS DURATION OF ACTIONPregnancy RiskPotency Short (8-12hrs) - Hydrocortisone - Cortisone CDCD 1 0.8 Intermediate (18-36) - Methylprednisolone - Prednisolone - Prednisone - Triamcinolone CCBCCCBC 54455445

CLASSIFICATION OF GLUCOCORTICOIDS Duration of actionPregnancy RiskPotency Long acting (36-54) - Betamethasone - Dexamethasone CCCC 25 25-30

INHALER GLUCOCORTICOIDS DRUG Pregnancy Risk Potency Compare to dexamethasone=1 Fluticasone C 1200 Budesonide (Pulmicort, Rhinocort) C 980 Beclomethasone (Beconase, Beclovent) C 600 Triamcinolone 330

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LOCAL ANESTHETICS Local Anesthetics Historically the first local anesthetic discovered was the tropane alkaloid cocaine: Cocaine is still used in ocular.

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LOCAL ANESTHETICS Local Anesthetics Historically the first local anesthetic discovered was the tropane alkaloid cocaine: Cocaine is still used in ocular.

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Presentation on theme: "LOCAL ANESTHETICS Local Anesthetics Historically the first local anesthetic discovered was the tropane alkaloid cocaine: Cocaine is still used in ocular."— Presentation transcript:

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