Chapter 4 - Pharmacology Basics PDF

PHARMACOLOGY BASICS CHAPTER 4  LEARNING OBJECTIVES  Discuss the pharmacologic properties of LA drugs and vasoconstrictors  Explain why tissue inflammation affects the success of LA  Evaluate the relationship between pH and pKa and discuss the clinical relevance of both.  Discuss the pharmac...

PHARMACOLOGY BASICS CHAPTER 4  LEARNING OBJECTIVES  Discuss the pharmacologic properties of LA drugs and vasoconstrictors  Explain why tissue inflammation affects the success of LA  Evaluate the relationship between pH and pKa and discuss the clinical relevance of both.  Discuss the pharmacodynamics and pharmacokinetics of the local anesthetic drugs.  Evaluate the signs and symptoms of and discuss the effects of LA on the CNS  Discuss the effects of LA on the CVS  Discuss the biotransformation pathways of amides and esters and the concept of 2 elimination half-life. DEAL WITH THE FEAR  DEAL WITH THE FEAR FIRST THEN PAIN WILL BE A MINOR PROBLEM LA SOLUTIONS IN DENTISTRY Pharmacology of LA solutions in dentistry Local anesthetic drugs Vasoconstrictor drugs Mechanisms of action, biotransformation, and toxic effects of each drug  CONTRASTING DRUGS Local anesthetics, for the management of pain differ from most other drugs commonly used in medicine. Other Medications/Drugs Local Anesthetics (LAs) Cease to provide clinical action when Must enter circulatory system absorbed into the circulatory system in sufficiently high The presence of a LA in the concentrations before clinical circulatory systems means that the action is exerted drug will be transported to every part of the body and can potentially alter cell function LOCAL ANESTHESIA  Primary benefit of LA - pain sensations can be suppressed without significant central nervous system (CNS) depression.  Majority of dental procedures can be performed without exposing patients to the risks of general anesthesia. DESIRABLE PROPERTIES OF LA DRUGS Biocompatibility Safety and Efficacy  Effective in tissues and mucous  Non-irritable membranes  Non-toxic  Short onsets  Non-allergenic  No residual effects  Biotransformable  Reasonable durations  Completely reversible  Adequate potency  Sterilizable  Patients remain conscious PHARMACOLOGY OF LA AGENTS Drug classifications used in dentistry AMIDES ESTERS Articaine Cocaine Bupivacaine Procaine Lidocaine Tetracaine Mepivacaine Benzocaine Prilocaine Chloroprocaine Propoxycaine ▪ Chemically differentiated by their linkages (intermediate chains) ▪ Amide chain contain a nitrogen atom whereas the ester chain does not.  INJECTABLE DENTAL LOCAL ANESTHETIC DRUGS IN THE UNITED STATES The 5 injectable dental local anesthetic drugs in the US.  Articaine  Bupivacaine  Lidocaine  Mepivacaine  Prilocaine * Procaine (ester) – Not available in dental cartridges  DESIRABLE PROPERTIES OF LA DRUGS  All five available dental LAs in the United States have reasonably low systemic toxicities and adequate onsets and durations of action.  Topical anesthetics are available in both esters and amides  Only two amides are acceptable as both a topical and injectable agent in dentistry  Lidocaine  Prilocaine ROUTES OF DELIVERY There are two primary routes of delivery of dental local anesthetic drugs Topical Submucosal Injection More effective on mucosa than on skin Submucosal and subcutaneous due to ease of penetrations through thin injections produce a more profound mucosal barriers. Applied to intact skin, anesthesia than topical routes due they do not provide an anesthetic action, to direct placement of the drugs in but with the skin damaged, as in a proximity to the nerves. sunburn, they can bring relief of pain. LOCAL ANESTHETIC MOLECULES  Local anesthetic molecules consist of 3 components:  Lipophilic aromatic ring – improves the lipid solubility and facilitates the penetration of the anesthetic through the lipid membrane where the receptor sites are located. Greater the lipid solubility – greater the potency.  Intermediate hydrocarbon – determines if the molecule is an ester or amide. Predetermines biotransformation.  Hydrophilic terminal amine- determines how the local anesthetic exist as either lipid soluble or water soluble configurations.  Local anesthetics without a hydrophilic part are not suited for injection but are good topical anesthetics. CHEMICAL FORMULAS AMIDE AND ESTER LOCAL ANESTHETICS Chemical Components Secondary or tertiary amine (hydrophilic) end - facilitates effectiveness in tissues by allowing the agent to disperse in the extra and intracellular fluids. Also provides pathway of biotransformation. Aromatic (lipophilic) end - facilitates diffusion (through nerve membranes) PHARMACOLOGY OF LA AGENTS Hydrophilic end of LA molecule dissolves in water, then is delivered by injection. – Responsible for the solution remaining on either side of the nerve membrane. LA without a hydrophilic part are not suited for injection but are good topical anesthetics (ex: benzocaine) Lipophilic end of LA molecule is lipid soluble. The nerve membrane is a lipid bilayer. Responsible for the solution penetrating through the nerve membrane. The anesthetic molecule must pass through the membrane in order to be effective. LIPOPHILIC END 15 LOCAL ANESTHETICS  In the laboratory, LAs are basic compounds and are poorly soluble in water and unstable when exposure to air.  Local anesthetics used for injection are dispensed as an acid salt, most commonly hydrochloride salt, dissolved in sterile water or saline. Once dissolved in sterile water, LAs dissociate into two forms: Positively charged molecule (cation) (RNH+) Uncharged or neutral molecule (neutral base) (RN)  DISSOCIATION The cation is more stable in solution ▪ The behavior of both the neutral base and cation within the nerve membrane determines the potency, duration and overall efficacy of the LA drug.  PHARMACODYNAMICS THE ACTIONS OF A DRUG ON THE BODY TERMINOLOGY PHARMACODYNAMICS Pharmacodynamics refers to the actions of a drug on the body (local anesthesia)  For LAs includes action on peripheral nerves, the Central Nervous System (CNS), cardiovascular system(CVS), and other tissues. DISSOCIATION OF ANESTHETIC MOLECULES ▪ It is the pharmacological function of dissociation of anesthetic molecules in solution that determines the effects of the drug. MODE AND SITE OF ACTION OF LOCAL ANESTHETICS The nerve membrane is the site local anesthetics exert their pharmacologic actions. ▪ The primary effects of local anesthetics occur during the depolarization phase of the action potential. Local anesthetics interfere with the excitation process in a nerve by:  Altering the threshold potential (firing level)  Decreasing the rate of depolarization MECHANISM OF ACTION Membrane Expansion Theory states: ▪ The membrane structure narrows the diameters of ion channels, which limits the membrane’s permeability to sodium (becomes smaller than sodium ions). ▪ Evidence shows that membranes do expand and become more fluid when exposed to LA, however no direct evidence suggest that nerve conduction is entirely blocked by membrane expansion. MECHANISM OF ACTION Membrane Expansion Theory states: ▪ membrane structure narrows diameters of sodium channels (smaller than sodium ions) MECHANISM OF ACTION Specific Protein Receptor Theory (most favored today) states: ▪ The action of LADs on nerve membranes is the binding of local anesthetic molecules to structural proteins or specific protein receptor sites. ▪ Studies indicate that a specific receptor site for local anesthetics exists in the sodium channel on its internal axoplasmic surface. ▪ Once the LA gains access to the receptors, permeability to sodium(Na+) is decreased or eliminated. ▪ Temporarily transforms nerve membranes to non-excitable states. HOW LOCAL ANESTHETICS WORK The primary action of LA is to produce a conduction block is to decrease the permeability of ion channels to Na+.  The following sequence is the action of local anesthetics: 1. Displacement of calcium ions from the Na+ channel receptor site, which permits…. 2. Binding of the local anesthetic molecules to this receptor site, which produces… 3. Blockade of sodium channel, and a…. 4. Decrease in the sodium flux, which leads to…. 5. Depression of the rate of electrical depolarization 6. Failure to achieve the threshold potential level, along with…. 7. Lack of development of propagated action potentials, also called…. 27 8. Conduction blockade. DISSOCIATION LAs dissociate into two forms: Positively charged molecule (cation) (RNH+) Uncharged or neutral molecule (neutral base) (RN) LA Molecule cation base  IONIC BASIS OF LOCAL ANESTHESIA Ionic Basis Of Local Anesthesia  Base molecule (RN) is lipophilic, only base molecule passes through nerve membranes  Inside membrane RN combines with hydrogen ions to form hydrophilic cations (RNH+)  Only RNH+ binds to specific receptor sites in sodium channels to block nerve impulses  In order for anesthesia to develop, cations must displace calcium ions.  IONIC BASIS OF LOCAL ANESTHESIA  LA exists as salts.  For stability in solution, LAs are formulated with a pH that favors water- soluble cations.  Allows dispersal of the anesthetic within mucosal tissues; however, will not penetrate nerve membranes. Ionic Basis Of Local Anesthesia This Henderson-Hasselbalch equation describes the equilibrium between neutral base molecules and cations in local anesthetic drug solution. RN + H+ ← → RNH+ (disassociation) RN = neutral base molecule RNH+ = cationic molecule H+ = hydrogen ion Cations represent the predominant molecule in LA solutions because neutral base molecules are far less stable. EFFECTS OF PH  Once LA solution is injected into the tissue in a mostly cationic form, more neutral base molecules develop in response to normal tissue pH.  Once at the nerves membrane the RNH+ cation must convert to a lipophilic neutral base (RN) to pass through the membrane.  After penetration of the nerve sheath and entry into the axoplasm, re- equilibration takes place inside the nerve. The RN accepts a H+ and the RNH+ binds to the channel receptor site and are responsible for the conduction blockade. EFFECTS OF PH Effect of inflammation on local anesthetics ▪ Lower pH of extracellular environment ▪ Increases numbers of H+ ▪ Inhibits base molecule (RN) disassociation ▪ Results ▪ Insufficient numbers of RN to penetrate membrane ▪ Profound anesthesia difficult to achieve or to sustain EFFECTS OF PH EFFECTS OF PH  The pH of a local anesthetic and the pH of the tissue which it is injected, influences nerve-blocking action.  Inadequate anesthesia results when local anesthetics are injected into inflamed or infected areas.  Inflammatory process produces acidic products: the pH of normal tissue is 7.4; the pH of an inflamed area is 5 to 6.  Local anesthetics containing epinephrine or other vasopressors are acidified to inhibit oxidation of the vasopressor. EFFECT OF INFLAMMATION ON LOCAL ANESTHETICS Status of extracellular environment (tissues) at injection site in the presence of inflammation Onset RNH+ Depth Duration Inflammation PKA Two important questions: 1. What is pKa? 2. Why do we care about the pH of drugs and the tissue environment? WHAT IS PKA? OR DISSOCIATION CONSTANT ▪ In VERY simple terms, the pKa value of a drug is a pharmaceutical factor that affects a drugs affinity for H+. ▪ When a drug has a high pKa (affinity for H+) there is a tendency to bond to H+, therefore creating more RNH+ (which will not pass through nerve membranes). ▪ If the tissue is more acidic, more H+ ions are available and a low pH condition exists, more anesthetic solution is in the cationic form. PKA VALUE OF LA DRUGS Literal Terms: “pH at which the drug can dissociate” to: 50% cation (RNH+) and 50% base (RN)  At a pH of 7.4 drug splits 75% - 25%  At a pH of 7.0 drug splits 90% - 10%  EXPRESSION OF DISSOCIATION Remember once the drug has injected into the tissues, it dissociates. The RN (base) moves the drug through the membrane RNH+ RN + H+ cation base The RNH+ (cation) blocks the sodium channel  PKA AND PH Relevance of pKa and pH When pKa = pH, there is an equal distribution of cations (RNH+) and uncharged base molecules (RN) in solution. In the presence of normal pH (7.4) this facilitates adequate RN for onset of anesthesia. Each LA has its own pKa value. WHY DO WE CARE ABOUT PH? When there is an decrease of pH, in either the tissue or the drug, there is an increases the presence of H+ and the potential more RNH+ (which will not pass through nerve membranes). Low pH = high H+ = more cation form available High pH = low H+ = more base form available Drugs with a lower pKa possess a more rapid onset of action than those with a higher pKa. EFFECT OF LOWER PH  Clinically, the lower the pH is the more likely it is to produce a burning sensation on injection, as well as a slightly slower onset of anesthesia.  However, the more basic the solution is the more unstable it is. 43  PKA AND PH VALUES Average pKa and pH values of LAs ▪ Commercially prepared solutions without a vasoconstrictor have a pH between 5.5 and 7 ▪ When injected into tissue, the buffering capacity of the tissue fluids return the pH a the injection site to a normal 7.4 ▪ LAs with a vasoconstrictor, are acidified by manufacturers with sodium bisulfite to retard oxidation and prolongs the shelf life of the drug. ▪ LAs with the addition of a vasoconstrictor have a pH of 3.8 to 5.0 ▪ pKa value 7.5 to 10 (weak base) CLINICAL APPLICATION OF PKA VALUE Example: pKa 7.9 at pH 7.4 pKa 8.1 at pH 7.4 75 % / 25% 83% / 17% 75 RNH+ 25 RN extracellular 83 RNH+ 17 RN The Higher The pKa - The More RNH+ Form is Present intracellular 19 RNH+ 6 RN 14 RNH+ 3 RN 75% /25% 75% /25% of original 17% RN of original 25% RN pKa OF INJECTABLE LOCAL ANESTHETIC DRUGS Drug Onset  Mepivacaine pKa = 7.7 2-4 min.  Lidocaine pKa = 7.7 2-4 min.  Prilocaine pKa = 7.7 2 min.  Articaine pKa = 7.8 1-6 min.  Bupivacaine pKa = 8.1 2-10 min. * Procaine pKa = 9.1 6-10 min.  Characteristic Correlate Explanation Lipid solubility Potency Greater lipid solubility enhances diffusion through neural coverings and cell membrane, allowing for a lower milligram dosage. Dissociation constant Onset Determines the portion of an administered dose that exists in the lipid-soluble, molecular state at a given pH. Agents having a lower pKa have a greater diffusible state and this hastens onset. Chemical linkage Metabolism Esters are mainly hydrolyzed in plasma by cholinesterase; amides are primarily biotransformed with the liver. Protein binding Duration Affinity for plasma proteins also corresponds to affinity for protein at the receptor site within sodium channels, prolonging the presence of anesthetic at the site of action. 47  VASOACTIVITY All LADs Express Vasoactivity  Dental LADs are peripheral vasodilators of the vascular bed into which they are deposited  All exhibit some degree of both vasodilatation and vasoconstriction  This limits their duration and efficacy unless vasoconstrictors are added  Clinical effects are dependent on concentration of LAD VASOACTIVITY COMPARISON ▪ Procaine Most potent vasodilator of dental LADs ▪ Cocaine Initially vasodilator Subsequent vasoconstriction ▪ Intense and Prolonged  PHARMACOKINETICS THE MANNER IN WHICH THE BODY MANAGES A DRUG TERMINOLOGY - PHARMACOKINETICS  Pharmacokinetics refers to the manner in which the body manages a drug  Uptake (Absorption into body)  Distribution (Circulation through body)  Metabolism (Biotransformation/breakdown) ▪ Hydrolysis (adds H2O) ▪ Oxidation (adds O2) ▪ Reduction (takes O2)  Excretion (Elimination from body)  UPTAKE  When injected:  Las exert pharmacologic action on blood vessels in the area.  The vasoactivity, produces dilation of the vascular bed into which they are deposited.  Procaine is the most potent vasodilator  Cocaine is the only local anesthetic that consistently produces vasoconstriction. Initial action is vasodilation followed by intense and prolonged vasoconstriction.  Vasodilation increases the rate of absorption.  Enters into bloodstream  Dilutes the anesthetic effect in the area  VASODILATOR  After deposition of LA as close to the nerve as possible, the solution diffuses in all directions according to the prevailing concentration gradients. A portion of the LA diffuses toward the nerve and into the nerve. However, a portion of the drug also diffuses away from the nerve. ONSET OF ACTION  Onset is the period of time from LA deposition near the nerve to profound conduction blockage.  The pKa of the LA determines the amount of the drug that exists in in base form to enter the nerve membrane.  Lower the pKa the higher the PH – more base is available  Higher the pKa, the lower the PH – more cations in the tissue  Size of nerve trunk determines the onset  Presence of inflammation affects the onset  Accuracy of the clinician 54  SYSTEMIC EFFECTS OF LA  Nature of the drug  Route of administration  Rate of injection  Vascularity of the area injected  Age of the patient – children and older adults  Weight of patients – MRD  Patient’s health 55  The route and rate of metabolism and excretion of the drug ABSORPTION AND DISTRIBUTION Absorption and Distribution Once absorbed into the systemic circulation, drugs are distributed to all tissues throughout the body. ABSORPTION AND DISTRIBUTION Blood level of LA is influenced by: ▪ Absorption rate ▪ Distribution rate ▪ Elimination ▪ Metabolic ▪ Excretory ▪ Potential toxicity relative to plasma level in target organs.  ABSORPTION AND DISTRIBUTION Greatest percentage of Local anesthetic drugs by mass … Skeletal Muscle ▪ Largest mass of tissue in the body Blood level of LAD influenced by rate of absorption and distribution  ABSORPTION AND DISTRIBUTION Greatest percentage of LA by volume … ▪ Brain ▪ Head ▪ Liver ▪ Kidneys ▪ Lungs ▪ Spleen (blood perfused organs) EFFECT OF THE CNS AND CVS CNS and CVS Actions of Local Anesthetics  CNS is particularly susceptible Biphasic, temporary signs of excitation followed by CNS depression Impact CNS well before CVS CVS effects require higher concentrations Vasodilation occurs, leading to depression of the myocardium 61  Reactions to Elevated Levels of Local Anesthesia Type Signs Symptoms Minimal to Moderate blood levels of CNS: Lightheadedness anesthetic Stimulation Restlessness Excitedness Nervousness Apprehension Dizziness Talkativeness Headache Confusion Blurred vision Nervousness Tinnitus Slurred, stuttered speech Oral paresthesia Muscular twitching and tremor Chills/flushing CVS: Drowsiness Elevated BP, HR, resp. rate Disorientation High blood levels of anesthetic CNS: Loss of consciousness Gerneralized tonic-clonic siezures Generalized CNS depression CVS: Fallen BP, HR, respiratory rate PHARMACOKINETICS  Biotransformation The mean which the body biologically transforms the active drug in the blood through the processes of tissue uptake and metabolism. PHARMACOKINETICS  Biotransformation of Amides In the liver by hepatic p450 isoenzyme system  Biotransformation of Esters In the blood by pseudocholinesterase PHARMACOKINETICS  Elimination Half-Life The length of time for all drugs to go through the process of metabolism The rate at which a drug is removed from the systemic circulation The time necessary to metabolize and excrete 50 percent of a drug ELIMINATION HALF-LIFE 100 100% ▼1st ½ life 50 50% ▼2nd ½ life 25 50% ▼3rd ½ life 12.5 50% ▼4th ½ life 6.25 50% ▼5th ½ life ELIMINATION HALF-LIFE VALUE REINJECTION OF LA  If the procedure last longer that the duration of the anesthetic, a second injection may be required to finish.  When the patient experiences pain, the nerve has returned to function and is more difficult to achieve profound anesthesia again.  Remember that anesthesia begins with the mantle bundles and it is important to reinject before the fibers have fully recovered. Will take a smaller volume of anesthetic, but a higher concentration.  If mantle and core fibers have fully recovered, reinjection of LA will be ineffective.  Called Tachyphylaxis DURATION OF ANESTHESIA  Influenced by:  Protein Binding to receptor site. Increase protein binding allows for a stronger RNH+ bind.  Vascularity of the injection  Presence or absence of a vasoconstrictor drug RECOVERY OF LA  Mantle bundles begin to lose anesthesia before the core bundles.  The core bundles then diffuse into the mantle bundles.  The mantle bundles will retain the LA the longest and be the last fibers to completely recover.  Example: With the IA nerve block, because of the above concept the anterior teeth, lip and chin will recover before the molar teeth.  Slower process than induction because of the LA binding to the receptor sites