INBDE Pharmacology Notes PDF

PHARMACOLOGY 1 Local Anesthetics Pharmacology is one of the most tested topics on the INBDE, so a strong foundation is highly recommended. In this set of notes, we wil...

PHARMACOLOGY 1 Local Anesthetics Pharmacology is one of the most tested topics on the INBDE, so a strong foundation is highly recommended. In this set of notes, we will review all of the pharmacology concepts tested on the INBDE including: amides and esters, pharmacodynamics, pharmacokinetics, calculation of local anesthetic dosage, vasoconstriction, toxicity, needle characteristics, injection techniques, classes of antibiotics, types of analgesics, and cardiovascular/ANS/CNS pharmacology. Local anesthetics can be categorized into two ‣ Bupivacaine (Marcaine) main groups: amides and esters. Below, we - Longest duration of all local anesthetics will discuss all of the relevant information that - Not safe for use in children due to you will need to know about local anesthetics prolonged soft tissue anesthesia for the INBDE. - 0.5% in solution Esters 1 Types of Local Anesthetics Esters are metabolized in plasma by pseudocholinesterase enzymes. Like Amides amides, their names also end in the Amides are metabolized by the liver and “-caine” suf x. their names commonly end with the suf x Esters are usually more toxic and cause “-caine.” Some important amide local more allergic reactions than amides due to anesthetics are listed below: methylparabens. ‣ Lidocaine (Xylocaine) The following are some important esters to - Safest for use in children know for the INBDE: - 2% in solution ‣ Benzocaine ‣ Mepivacaine (Carbocaine, Polocaine) - Commonly used as a topical anesthetic - Causes the least amount of vasodilation prior to injection - 2-3% in solution - Risk of methemoglobinemia ‣ Articaine (Septocaine) ‣ Cocaine - Shortest duration of all the local - Potentiates vasoconstriction anesthetics ‣ Procaine - Has an ester chain attached; it is metabolized by BOTH the liver and in plasma INBDE Pro Tip: - 4% in solution Know the unique points associated with ‣ Prilocaine (Citanest) each local anesthetic. This is a heavily - Risk of methemoglobinemia (blood tested topic on the INBDE. disorder where there is an abnormal amount of hemoglobin production) → can lead to insuf cient O2 delivery to cells INBDE Booster | Booster PrepTM fi fi fi  PHARMACOLOGY 2 2 Pharmacodynamics/Pharmacokinetics ‣ ↓ pKa = faster onset of action - Why? ↓ pKa  drug gives up proton Pharmacodynamics more easily  drug becomes non- Pharmacodynamics refers to the effect that ionized  drug crosses membrane a drug has on the body. Generally, local anesthetics have the following Drug pKa pharmacodynamic characteristics described below. Mepivicaine 7.6 ‣ Sodium channel blockers: Articaine 7.8 - Sodium channels in neurons allow the in ux of sodium ions for depolarization Lidocaine 7.8 to signal pain Prilocaine 7.8 - Local anesthetics block these channels from initiating depolarization Bupivacaine 8.1 ‣ Non-ionized (free-base form): - Only non-ionized drug forms can cross the hydrophobic neuron membrane 3 Calculating Local Anesthetics - Blocking the sodium channel can only be done from inside of the cell ‣ Less effective in in amed tissue: A carpule/cartridge of local anesthetic - In amed tissue has a lower pH represents 1.8mL. Therefore, local anesthesia - Excess H+ ions favor an equilibrium at a concentration of 1% has 18mg of local where the drug is in an ionized form = anesthetic. For 100% solution there are 1.8g cannot cross the neuron membrane or 1,800mg of the drug. It is important to ‣ Require a critical length: know these numbers for the INBDE. - Complete anesthesia – achieved when 3 consecutive nodes of Ranvier are Example 1.31 blocked - There is a better chance of anesthesia Question: The most common local when there is a longer length of nerve anesthetic used in dentistry is 2% lidocaine bathed in anesthetic (1:100,000 epinephrine). How many mg of lidocaine are present in a carpule (1.8mL) Pharmacokinetics of this iteration? Pharmacokinetics describes the response that an individual’s body has to a drug. Key Solution: principles of pharmacokinetics are provided The calculation is simple for lidocaine: 1% below, demonstrating how the body may contains 18mg of lidocaine, hence, 18mg/ be impacted by local anesthetics. It is 1% x 2% = 36 mg of lidocaine. important to know these concepts for the INBDE. Therefore, there are 36mg of lidocaine in a ‣ ↑ protein binding leads to ↑ duration of 2% solution. action INBDE Booster | Booster PrepTM fl fl fl PHARMACOLOGY 3 4 4 Vasoconstriction & Toxicity Example 1.41 Vasoconstriction Question: The most common local As mentioned, epinephrine and other kinds anesthetic used in dentistry is 2% of vasoconstrictors are often packaged in lidocaine (1:100,000 epinephrine). How solution with a local anesthetic. many mg of epinephrine are present in a There are 3 main purposes for the addition carpule of this iteration? of vasoconstrictors: 1. Hemostasis Solution: ‣ Counteracts vessel dilation of local With epinephrine, the amount is given anesthetic as a ratio, which should rst be 2. Longer anesthesia converted into a percentage: 1/100,000 ‣ Decreased blood ow to the injection x 100% = 0.001%; hence 0.001% x site decreases the amount of anesthetic 18mg/1% = 0.018mg of epinephrine. carried away from nerves 3. Reduced toxicity Therefore, there are 0.018mg of ‣ Increased blood vessel constriction epinephrine in one carpule of the decreases the systemic impact of the iteration described above. drug Maximum Epinephrine Dosages The following are important numbers to remember for maximum dosage limits in healthy, as well as, cardiac patients: Drug Max dose Healthy Patient 0.2 mg Cardiac Patient 0.04 mg Maximum Local Anesthesia Dosages The maximum dosage of lidocaine with and without epinephrine is 7mg/kg and 4.5mg/kg respectively. The maximum dosage of articaine with epinephrine is 7mg/kg. INBDE Booster | Booster PrepTM fl fi  PHARMACOLOGY 4 Needles & Injections 1 Measurements Numbs lips and gingiva of all teeth in the quadrant, except gingiva of the molar Length region Two options: Tongue is numbed in the quadrant if the ‣ Long needle = 32mm lingual nerve is blocked as well ‣ Short needle = 20mm Techniques Diameter Vazirani-Akinosi = closed mouth technique, Three options: which can be useful in cases of truisms ‣ 30-gauge = 0.3mm Gow-Gates = open mouth method, which ‣ 27-gauge = 0.4mm blocks practically the entirety of V3 ‣ 25-gauge = 0.5mm Injection Steps Larger diameter (smaller gauge) needles 1. Approach from the opposite side of the are often advantageous for the following mouth towards the molars/premolars reasons: Aim 10-15mm above the mandibular ‣ They do not bend or break as often occlusal plane and parallel to that plane ‣ They provide better aspiration 2. Advance the needle slowly until bone is - Aspiration = lightly drawing one’s nger felt back on the syringe to detect presence 3. Slowly withdraw the needle ~1mm and of blood (vessel perforation) aspirate 4. If no blood is detected, inject at rate of 1 carpule/min 2 Injection Techniques Buccal Nerve Block There are several different techniques for local Anesthetizes soft tissue buccal to molars anesthetic injection. Aiming to deliver the (the tissue the IAN block does not target) anesthetic slowly over the course of 60 seconds will decrease the discomfort of the Injection Steps patient. 1. Inject from the buccal to the distal most molar, approximately parallel to the Inferior Alveolar Nerve Block (IAN Block) occlusal plane Injection is in the center of the area bordered by the: Mental Nerve Block ‣ Coronoid notch Anesthetizes soft tissue facial to anterior ‣ Pterygomandibular raphe teeth ‣ Upper maxillary molars Does not numb the teeth itself High failure rate due to dif culty of the injection Injection Steps Numbs all of the mandibular teeth of the 1. Locate the rubbery neurovascular bundle quadrant with your nger INBDE Booster | Booster PrepTM fi fi fi  PHARMACOLOGY 5 2. Insert needle anterior to the mental Injection Steps foramen by the apices of the premolars 1. Inject at the mucobuccal fold directly over 3. Aspirate and slowly inject the 1st premolar into the infraorbital foramen Incisive Nerve Block Anesthetizes the anterior teeth and Greater Palatine Nerve Block premolars of the quadrant Anesthetizes posterior hard palate and overlying tissue from 3rd molar to 1st Injection steps premolar up to the midline 1. Follow the same steps as the mental nerve Target needle into the greater palatine block, inject over 20 seconds foramen 2. Hold pressure on injection site for 2 Often painful minutes in order to increase the volume of anesthetic into the mental foramen Injection Steps 1.Use a cotton tip to push gently along the Posterior Superior Alveolar Block area where the alveolar ridge meets the Anesthetizes maxillary molars and buccal hard palate; the site where the cotton tip tissue dips down is your injection site Does not numb the mesio-buccal root of the 1st molar in 28% of patients Nasopalatine Block ‣ Supplied by the middle superior alveolar Most painful injection nerve block Anesthetizes the hard palate from canine to High risk of hematoma due to injection canine on the maxilla being close to groups of blood vessels Most painful injection Injection Steps Injection Steps 1. Palpate for zygomatic process and aim 1. Inject palatal mucosa lateral to the incisive needle posterior to that papilla 2. Retract cheek; and inject needle into mucosa above 2nd maxillary molar at a 45- Local In ltration degree angle to occlusal and vertical plane Local anesthetic diffuses through bone to 3. Inject until the needle is 16mm in depth numb the terminal branching nerves (half the length of a long needle) entering the pulp of the tooth 4. Swing the needle so it is 45 degrees to the Septocaine (articaine) is often used back of the maxillary tuberosity ‣ Best for bone penetration Works well in anterior teeth Infraorbital Block ‣ Facial cortical plate is thin = better Also known as true anterior superior diffusion of anesthetic alveolar block ‣ Targets anterior superior and middle Injection Steps superior alveolar nerves 1. Inject the needle into the vestibule above Anesthetizes maxillary anteriors and the tooth of interest and aim for the root premolars apex INBDE Booster | Booster PrepTM fi PHARMACOLOGY 6 Summary Figure 2.21 Injection sites INBDE Booster | Booster PrepTM  PHARMACOLOGY 7 Antibiotics 1 Requirement of Antibiotic Prophylaxis Carbapenems “-nem” suf x ‣ Meropenem The use of antibiotic prophylaxis in dental β-lactam – inhibits cell wall synthesis practice is not common. However, there are Bactericidal certain instances when their use is required for invasive treatments that involve manipulation Penicillins of gingival tissue or manipulation of the Majority have “-cillin” suf x periapical region of a tooth. β-lactam – inhibits cell wall synthesis Cross-allergenic with cephalosporins Appropriate Use of Antibiotic Prophylaxis ‣ Penicillin is chemically related, so the Patients with cardiac conditions: immune system might see them both as ‣ Prosthetic cardiac valve the same if the patient is allergic to either ‣ Previous or recurrent infective one endocarditis Bactericidal ‣ Congenital heart disease ‣ Cardiac transplant patients with The following are speci c types of penicillin valvulopathy and their associated characteristics: Consider a consultation with one’s primary physician for: 1. Penicillin V – oral administration ‣ Immunosuppression secondary to 2. Penicillin G – IV administration neutropenia, cancer chemotherapy, or 3. Amoxicillin – broad spectrum solid organ transplant 4. Augmentin – includes amoxicillin and ‣ Sickle cell anemia clavulanic acid (works against β-lactamase ‣ High-dose corticosteroid use resistant bacteria) ‣ Poorly controlled diabetes 5. Carbenicillin – for use against ‣ Diseases of autoimmunity pseudomonas Monobactams “-am” suf x 2 Types of Antibiotics ‣ Aztreonam β-lactam – inhibits cell wall synthesis Tetracyclines Bactericidal “-cycline” suf x ‣ doxycycline, tetracycline Protein synthesis inhibitor – binds to 30S ribosomal subunit *Broadest antimicrobial spectrum Bacteriostatic INBDE Booster | Booster PrepTM fi fi fi fi fi  PHARMACOLOGY 8 Cephalosporins Lincosamides “Ceph-“ pre x “-mycin” suf x β-lactam – inhibits cell wall synthesis ‣ Clindamycin, Lincomycin Grouped into generations based on their Protein synthesis inhibitor – binds to 50S spectrum against speci c bacteria ribosomal subunit ‣ 1st Gen = Cephalexin (Ke ex) Bacteriostatic ‣ 2nd Gen = Cefonicid ‣ 3rd Gen = Ceftriaxone 3 Medical Prescriptions (Rx) ‣ 4th Gen = Cefepime Bactericidal Prescription of antibiotics will vary with each Fluoroquinolones patient based on their age, medical history, “- oxacin” suf x is common current medications, and other factors. ‣ Cipro oxacin DNA synthesis inhibitor Rx for Infective Endocarditis Prophylaxis Bactericidal Patient Time of Rx Sulfonamides / Case Admin “Sulfa-“ pre x First choice Amoxicillin 2g 60 mins ‣ Sul soxazole prior to tx Folate synthesis inhibition ‣ Results in folate de ciency that impacts Children Amoxicillin 60 mins DNA synthesis 50mg/kg prior to tx Bacteriostatic Penicillin Azithromycin 60 mins allergy 500mg prior to tx Macrolides “-thromycin” suf x Children with Azithromycin 60 mins Penicillin 15mg/kg prior to tx ‣ Azithromycin Protein synthesis inhibitor – binds to 50S allergy ribosomal subunit IV Ampicillin 2g 30 min Bacteriostatic before tx Children, IV Ampicillin 50mg/ 30 min kg before tx Rx for Prosthetic Joint Prophylaxis Antibiotic prophylaxis before dental treatment is no longer recommended for prevention of prosthetic joint infections according to the ADA. INBDE Booster | Booster PrepTM fl fi fl fi fi fi fi fi fi fi fl  PHARMACOLOGY 9 Side Effects Drug Concentration Knowing the side effects of antibiotics is not Tetracycline concentrates well in gingival only important for general knowledge, but is crevicular uid also important when considering prescriptions. Clindamycin concentrates well in bone For example, it is best not to prescribe tetracycline to a patient with liver disorders Antivirals & Antifungals The following are common antivirals and Associated antifungals prescribed in dental practice: Side Effect Acyclovir, Valcyclovir Antibiotic ‣ “-vir” = antiviral Pseudomonas colitis Clindamycin ‣ Used for herpes Fluconazole Very broad-spectrum ‣ “-azole” = antifungal Superinfection antibiotics ‣ Used for Candidiasis Aplastic anemia Chloramphenicol Liver damage Tetracycline Drug Interactions The following drug combinations are not recommended and should not be prescribed: 1. Bactericidal and bacteriostatic drugs ‣ Bactericidal kills bacteria when they are rapidly growing; bacteriostatic drugs inhibit this rapid growth = the drugs cancel each other out 2. Antibiotics and oral contraceptives ‣ Antibiotics suppress normal gastrointestinal ora involved in recycling of active steroids in the contraceptive 3. Penicillin and probenecid ‣ Probenecid alters renal clearance of penicillin 4. Tetracycline + antacids/dairy ‣ Antacids and dairy reduce the absorption of tetracycline via calcium/ion binding 5. Broad-spectrum antibiotics and anticoagulants ‣ Anticoagulants’ actions are enhanced INBDE Booster | Booster PrepTM fl fl  PHARMACOLOGY 10 Analgesics 1 Acetaminophen Celecoxib COX 2 (Celebrex) Acetaminophen is commercially known as Tylenol, and there are several key points to Meloxicam COX 2 Treatment of know about this drug. (Mobic) arthritis Maximum daily dose = 4,000 mg Inhibits pain in the central nervous system Therapeutic Effects of Aspirin Drug of choice for a feverish child Anti-in ammatory and analgesic ‣ Aspirin is known to cause Reye’s ‣ Inhibits COX 1 & 2 (PG synthesis) Syndrome Antipyretic Negatively impacts the liver ‣ Inhibits PG synthesis in the hypothalamus ‣ Toxic at higher doses (temperature regulation center) ‣ Greater damage when combined with Inhibits clotting alcohol ‣ Inhibits TXA2 synthesis = inhibits platelet aggregation 2 NSAIDS The mechanism of action for aspirin is very Types of NSAIDS important to know and highly testable on the NSAIDS work by inhibiting COX 1 and/or COX INBDE. 2. Normally, COX1 and COX2 promote in ammation by generating prostaglandins Toxic Effects of Aspirin (PG). By blocking COX1 and 2 there is a GI bleeding corresponding reduction in the effects of PGs. Metabolic acidosis Below is a table summarizing important Salicylism NSAIDS to study for the INBDE. Tinnitus Nausea & vomiting Delirium Name Blocking Association Hyperventilation Aspirin (ASA) COX 1 & 2 Impacts GI (irreversible) INBDE Pro Tip: Ibuprofen COX 1 & 2 Impacts The maximum daily dose of ibuprofen is (Motrin, Advil) (reversible) kidney 3,200 mg. Naproxen (Aleve) COX 1 & 2 (reversible) Ketorolac (Acular) COX 1 & 2 IV, IM, or oral (reversible) route INBDE Booster | Booster PrepTM fl fl PHARMACOLOGY 11 3 Steroids Tramadol Fentanyl Corticosteroids Sufentanil Corticosteroids are man-made steroids, which Heroin mimic the action of cortisol (produced in the adrenal cortex of the adrenal gland); the Combination Narcotics Therapeutic Effects & common suf x of corticosteroids is “-sone.” Side Effects of Morphine Prednisone The effects of morphine can easily be Dexamethasone memorized using the following acronym: Hydrocortisone Miosis (pupil constriction) Out of it (sedation) Therapeutic Effects Respiratory depression Analgesic and anti-in ammatory Pneumonia (aspiration pneumonia) ‣ Inhibits phospholipase A2 = inhibits Hypotension arachidonic acid synthesis Infrequency of urination & constipation Nausea & vomiting Side Effects of Steroids Euphoria & dysphoria Immunosuppression if used chronically Gastric ulcers Overdose & Addiction Osteoporosis The following drugs can be used when an Fat redistribution overdose or addiction of morphine occurs: Hyperglycemia Naloxone Acute adrenal insuf ciency ‣ Competitive opioid antagonist, for ‣ Follows the Rule of Twos emergencies - Adrenal suppression can occur if a Naltrexone patient is taking 20mg of cortisone (or ‣ Antagonist, treats addiction its equivalent) for 2 weeks within 2 In emergencies, the half-life of naloxone may years of dental treatment be shorter than the half-life of the opioid, - Patient may need supplemental doses therefore, multiple doses of naloxone may be of steroids prior to therapy required. 4 Narcotics/Opioids INBDE Pro Tip: Methadone is a synthetic opioid agonist that Types of Narcotics can be used not only for relief of pain, but Codeine also, for opioid addiction. Hydrocodone Oxycodone Oxycontin Meperidine Morphine INBDE Booster | Booster PrepTM fi fi fl  PHARMACOLOGY 12 Drug Schedule Drugs and substances are classi ed into ve schedules or categories based on their potential to be abused. Substances in the Schedule I category have the highest abuse potential. Examples of opioids in various categories are included in the table below, but note that these schedules are not exclusive to opioids. Name Opioid Schedule I Heroin Schedule II Oxycodone, fentanyl, meperidine Schedule III Acetaminophen + codeine Schedule IV Tramadol Schedule V Cough medicines with codeine 5 Nitrous Oxide Nitrous oxide is commonly known as laughing gas, and is often stored in a blue-colored tank in dental of ces. The following are a few characteristics of nitrous oxide: Tingling sensation before onset A ow rate of 5-6L is generally acceptable Patient must breathe through their nose Nausea (side effect) Peripheral neuropathy from longterm exposure Minimum alveolar concentration (MAC) = 105% ‣ MAC – concentration in alveoli required for 50% of patients to be immobile ‣ Impossible to go over 100%, so 105% implies that N2O has very low potency Diffusion hypoxia ‣ N2O can get trapped in lungs ‣ Always give patient 100% O2 for 5 minutes to eliminate N2O from the body INBDE Booster | Booster PrepTM fl fi fi fi  PHARMACOLOGY 13 Pharmacokinetics 1 Steps of Pharmacokinetics 100% bioavailability can only occur if a drug is administered intravenously (IV) Pharmacokinetics, in simple words, is the study of what the body does to a drug. pH is also important to consider when Pharmacokinetics does not study what the discussing drug absorption. The ways in which drug binds to nor its therapeutic or toxic an acidic or basic drug interacts with its effects. After administration, the following are environmental pH can alter the charge of the the sequential steps of a drug’s path through drug and subsequently its absorption. the body: 1. Absorption Generally, drugs should be of neutral charge 2. Distribution for absorption to take place. 3. Metabolism Weak acids: pH < pKa for absorption 4. Elimination Weak bases: pH > pKa for absorption Routes of Administration Acidic Drug Basic Drug Enteral: oral, sublingual, or rectal Parenteral: intravenous, intramuscular, or Acidic Non-ionized Ionized subcutaneous Environment Other routes: intranasal, inhalation, topical, Basic Ionized Non-ionized or vaginal Environment Absorption We want the drug to be non-ionized for it Generally, drugs must cross several epithelial to be absorbed at the appropriate location or endothelial cell layers (barriers) to enter the body in order for absorption to take place. Distribution Different methods of administration determine For adequate systemic distribution, a drug which barriers the drug must cross to enter to must rst reach the blood stream be absorbed. Below are a few facts to know: ‣ Topical drugs are an exception to this rule Epithelial cell layers must be crossed when Once the drug arrives at the target tissue, administering drugs to be absorbed it passes through endothelial cells, cellular through the skin, intestines, respiratory interstitium, and nally the basolateral system, and genitourinary tract membrane of the tissue cell type Endothelial cells must to be crossed for Systemic drugs normally reach vessel-rich drugs to reach blood vessels organs quickly for example: Local drugs are active at the site of ‣ Heart, liver, and lungs administration/absorption Systemic drugs must enter the bloodstream to reach the rest of the body ‣ Cross cell lumen  apical membrane  basolateral membrane  interstitium  endothelial lining  reaches bloodstream INBDE Booster | Booster PrepTM fi fi PHARMACOLOGY 14 First Pass Effect Phase I Drugs absorb through the GI system and Functionalization (oxidation, reduction, are sent from the hepatic portal system to hydrolysis) the liver ‣ Oxidation is the most common The liver metabolizes the drug, leaving a Achieved through Cytochrome P450 smaller fraction of the drug to travel (CYP450) enzymes through the circulatory system Oral drugs undergo the above noted Phase II process, which is known as the “First Pass Conjugation (glucuronide, glutathione, Effect” glycine) ‣ Covalently adds polar side chains to the Volume of Distribution (Vd) drug Volume (L) of total body water in which a ‣ Glucuronide is the most common side drug will partition chain added via UDP- Describes the distribution of a drug across glucuronosyltransferase three body water compartments ‣ Plasma (4%) Phase I and II reactions share the following ‣ Interstitial (16%) common characteristics: ‣ Intracellular (40%) People who have less body water than the Drugs sometimes go through both phases average male adult should be given a lower or just one phase drug dose to properly aid distribution Both phases decrease the ef cacy of the ‣ Women drug/inactivate the drug ‣ Obese Both phases increase drug polarity, which ‣ Elderly prevents passive diffusion and facilitates Brain and muscle have the highest water renal and GI clearance of the drug content, while adipose tissue has the lowest water content Metabolism Metabolism refers to the way a drug is chemically altered and inactivated in the body. There are two main phases of drug metabolism reactions: Figure 5.11 Drug metabolism INBDE Booster | Booster PrepTM fi  PHARMACOLOGY 15 Elimination Examples of Dental Drug-Drug Interactions Elimination refers to how a drug is removed Factors In uencing Drug Effectiveness from the body The effect of the same drug can vary amongst Elimination occurs mostly in the kidneys different people due to several factors: Phase I creates polar molecules, which go 1. Prescribed dose to the kidneys for urinary clearance ‣ Medical errors Phase II creates polar and larger molecules, ‣ Patient compliance which tend to clear in the GI tract as feces 2. Administered dose (effected by pharmacokinetics) ‣ Absorption 2 Drug-Drug Interactions ‣ Distribution ‣ Metabolism When drugs interact, one drug can affect the ‣ Elimination pharmacokinetics of the other drug. These 3. Active dose (effected by interactions normally occur in the metabolism pharmacodynamics) phase. There are commonly two kinds of ‣ Drug-receptor interaction effects from drug interactions: 4. Intensity of effect Induction: drug A induces liver cytochrome enzymes = ↑ metabolism = ↓ effect of drug B Inhibition: drug A competes for metabolism or inhibits liver cytochrome enzymes = ↓ metabolism of drug B = ↑ toxicity of drug B Dental Drug Interacting Interaction risk Drug NSAIDS Lithium ↑ lithium toxicity NSAIDS Hypotensives ↓ effect of hypotensive NSAIDS Anticoagulants ↑ risk of bleeding Penicillins Oral ↓ oral contraceptives contraceptive effect NSAIDS Methotrexate ↑ methotrexate toxicity Metronidazole Warfarin ↑ risk of bleeding INBDE Booster | Booster PrepTM fl  PHARMACOLOGY 16 Pharmacodynamics Pharmacodynamics, in simple words, is the study of the effects that drugs have on the body. These effects can be viewed from two different perspectives: 1. Drug targets – these are often protein carriers, channels, enzymes, or receptors 2. Drug interactions – these often involve agonists, inverse agonists, and antagonists Figure 6.11 Response Curve 2 Dose-Response Curves 1 Interactions Type I Dose-Response Curve Agonists A type I dose-response curve is used to Agonists mimic the effects and cause the same correlate the response/ef cacy of a drug (y- actions as an endogenous agonist molecule. axis) to the drug dose (x-axis). Its shape can Agonists can produce a full 100% of its either be log form or hyperbolic. intended effect (full agonist) or less than 100% (partial agonist). A dose-response curve can be used to describe drug characteristics as follows: Antagonist Intrinsic activity (Emax) – maximal effect of Antagonists work opposite to agonists in that a drug these will inhibit the action of the endogenous ‣ Full agonist Emax = 1 agonist. The mechanism in which this inhibition ‣ Partial agonist Emax = 0-1 occurs is through 2 main ways: ‣ Antagonist Emax = 0 1. Competitive antagonist – competing Ef cacy – effect of a drug when it binds to directly with an agonist for the same the target binding site located on the receptor. This Af nity – level of attraction of a drug to its site is called an active site. receptor 2. Non-competitive antagonist – binds to a ‣ Dissociation constant (Kd) – position other than the active site, while concentration of drug needed to occupy preventing the agonist from binding. 50% of receptors Oftentimes, non-competitive antagonism ‣ Lower Kd represents a higher or greater will change the shape or conformation of af nity the receptor at the active site. Potency – strength of a drug at a certain concentration Inverse Agonist ‣ Effective concentration (EC50) – Inverse agonists do not bind at the same describes the concentration at which half active site as an agonist (preventing their the maximal effect is achieved interactions) but will produce an effect that is ‣ The more potent the drug, the lower the opposite that of the agonist EC50 INBDE Booster | Booster PrepTM fi fi fi fi PHARMACOLOGY 17 The presence of antagonists may change the shape of the type I dose-response curve Competitive antagonists will shift the curve to the RIGHT Non-competitive antagonists will shift the curve DOWN Figure 6.22 Type 2 Response Therapeutic Index (TI) is an indicator of drug safety. A larger index indicates a safer drug, as it implies a larger difference in dose between the therapeutic dose and the toxic dose. In animal studies…. TI = LD50/ED50 In human studies…. TI = TD50/ED50 3 Effects of Drug Interaction Figure 6.21 Type 1 Response Additive Type II Dose-Response Curve Drugs interact to combine their individual In a type II dose-response curve, the x-axis degrees of effect measures the drug dose; and the y-axis Effects are combined measures the quantity of subjects responding to the drug. Antagonist Drugs interact to lessen the effect than if Type II dose-response curves can show 3 one drug were to be used alone different curves representing the following Chemical antagonism – a drug binds to scenarios: another drug to prevent the other’s Therapeutic effect curve function Receptor antagonism – competition ‣ ED50 – dose at which the desired effect effect is produced in 50% of the between two drugs for the same receptor population Pharmacokinetic antagonism – one drug Toxic effect curve affects the pharmacokinetics of another ‣ TD50 – dose at which a toxic effect is drug produced in 50% of the population Physiologic antagonism – two drugs with Lethal effect curve opposing effects on the same tissue on ‣ LD50 – dose at which a lethal effect is distinct receptors produced in 50% of the population Synergist Combining drugs leads to a greater effect than the sum of their independent effects INBDE Booster | Booster PrepTM PHARMACOLOGY 18 Autonomic Nervous System The following are examples of the opposing 1 ANS Physiology effects of the SNS and PNS: The sympathetic nervous system (SNS) and Fight or Flight (SNS) Rest & Digest (PNS) parasympathetic nervous system (PNS) are branches of the ANS. In many systems they Slows digestion Increases digestion have opposing effects. ↑ Heart rate ↓ Heart rate SNS effects promote “ ght or ight” PNS effects promote “rest and digest” ↓ Saliva production ↑ Saliva production Some important exceptions to this rule are: Pupillary dilation Pupillary constriction ‣ The vasculature to skeletal muscles are controlled by the SNS Bladder relaxation, Bladder constriction, ‣ The sweat glands are controlled by the decrease urination increase urination SNS Bronchi dilation Bronchi constriction All nerve pathways originate from the CNS (brain & spinal cord) 2 Receptors in the ANS 12 cranial nerves – PNS 0 cervical nerves – autonomic nerves do Receptors in the ANS can be described in not originate here different ways. 12 thoracic nerves – SNS Ionotropic – ion channel 5 lumbar nerves – SNS Metabotropic – G-protein coupled receptor 5 sacral nerves – PNS (GPCR) 7-transmembrane domain Activates a secondary messenger system All receptors in target organs of the autonomic nervous system are metabotropic Receptors in the ANS are most often referred to as cholinergic and adrenergic. Cholinergic – responds to acetylcholine (Ach) and are found in the PNS and SNS ‣ Nicotinic (nAchR) - Also binds nicotine, ionotropic - All receptors in the medulla + ganglion ‣ Muscarinic (mAChR) – - Also binds muscarine, GPCR Adrenergic = binds epinephrine and norepinephrine, GPCR Figure 7.11 Autonomic Nervous o Receptors in the SNS INBDE Booster | Booster PrepTM fi fl  PHARMACOLOGY 19 SNS vs. PNS Muscarinic Receptors Differences between the SNS and PNS can be There are different types or isoforms of distinguished by the following methods: muscarinic post-ganglionic receptors, Effect on organs differentiated by their target organ. ‣ SNS – ght or ight 1. M1 = CNS – autonomic ganglia ‣ PNS – rest and digest 2. M2 = heart The spinal cord region they originate in ‣ Bradycardia = ↓ heart rate + electrical ‣ SNS – thoracolumbar conduction ‣ PNS – craniosacral 3. M3 = smooth muscle & exocrine glands Neurotransmitters used ‣ Salivation, urination, defecation, sweating ‣ SNS – Ach to ganglion, NE from nerves ‣ Smooth muscle contraction and Epi/NE from adrenal gland ‣ Vascular endothelium vasodilation ‣ PNS – Ach throughout 4. M4 = CNS Neurotransmitter receptors used 5. M5 = CNS ‣ SNS – adrenergic metabotropic receptors at target organs ‣ PNS – muscarine metabotropic receptors 3 M Agonist Drugs at target organ Length of pre & postganglionic neurons M agonists activate muscarinic receptors in the ‣ SNS – short preganglionic to sympathetic PNS. Some are non-selective to target all M trunk, long post-ganglionic receptors, while others are selective to certain ‣ PNS – long preganglionic, short M receptor types. postganglionic Non-selective M agonists will effect M1-5 receptors if systemic in its distribution, and Synthesis of Neurotransmitters should not be used systemically in patients Acetyl CoA + choline = acetylcholine with these following conditions: ‣ The enzymes involved in the creation and ‣ Asthma/COPD – these conditions result breakdown of acetylcholine are in air ow obstruction to the lungs. acetyltransferase and Muscarinic agonists can cause acetylcholinesterase respectively bronchoconstriction, thereby exacerbating the disease Tyrosine  L-DOPA  dopamine  NE  ‣ Peptic ulcers – muscarinic agonists can Epi cause an increase in the secretion of ‣ Catecholamines = dopamine, NE, epi gastric acid, worsening peptic ulcers ‣ Monoamines = dopamine, NE, epi, ‣ Coronary Heart Disease – the cardiac serotonin (5-HT), histamine inhibition observed with muscarinic agonists can worsen cases of coronary heart disease ‣ Hyperthyroidism – muscarinic agonists can depress the cardiac system, causing the body to compensate and release epinephrine. Epinephrine in patients with hyperthyroidism can cause arrhythmias. INBDE Booster | Booster PrepTM fl fi fl  PHARMACOLOGY 20 M-Agonists List N-Antagonists/Neuromuscular Blockers Neuromuscular blockers block nicotinic Direct acting Activates M-receptor receptors of the somatic nervous system. Pilocarpine Used to stimulate saliva or eye drops to constrict pupils and Depolarizing Irreversible N-antagonist reduce pressure Succinylcholine Relieve laryngospasm & helps to facilitate tracheal intubation Indirect acting Non-competitively during surgery inhibits acetylcholinesterase Physostigmine & Reversible inhibit 5 Sympathetic Nervous System Neostigmine cholinesterase Insecticides and Irreversibly inhibits In the sympathetic nervous system, Nerve gases cholinesterase. High epinephrine (epi) and norepinephrine (NE) act poison potential! on the effector organs to elicit the ght or Treatment with Pralidoxime ight autonomic response. These neurotransmitters are synthesized through the M-Antagonists/Ganglionic Blockers following process: Competitive Block Muscarinic receptor, Tyrosine  L-DOPA  dopamine  NE  Epi Inhibitors compete with acetylcholine Dopamine, Epinephrine, Norepinephrine Scopolamine Helpful in the reduction of = catecholamines saliva Dopamine, Epinephrine, Norepinephrine, Atropine Helpful in the reduction of serotonin (5-HT), histamine = saliva, as well as the treatment monoamines of acute bradycardia. Adrenergic Receptors There are different types of adrenergic post- ganglionic receptors based on the organ they effect: 4 Nicotinic Antagonist Drugs 1. ⍺1 – smooth muscle in blood vessels ‣ Vasoconstriction, urinary retention, pupil dilation (mydriasis) Non-depolarizing Allosteric inhibitor 2. ⍺2 – smooth muscle in blood vessels Mecamylamine & Previously used as an i. Vasoconstriction Hexamethonium antihypertensive INBDE Booster | Booster PrepTM fl fi  PHARMACOLOGY 21 3. β1 – heart Sympathomimetics ‣ ↑ cardiac output, heart rate, electrical Sympathomimetics are agents that are used in conduction, and strength of contraction order to increase the effects of endogenous ‣ Renin release from kidneys, leading to catecholamines. They can be direct (act at an vasoconstriction adrenergic receptor) or indirect (by other 4. β2 – smooth muscle means). ‣ Bronchodilation, vasodilation, thickened salivary secretions Name Effect Adrenergic Agonist Amphetamine & Stimulates release of stored Ephedrine norepinephrine Name Receptor Activated Tricyclic Inhibits reuptake of antidepressants serotonin & norepinephrine Phenylephrine ⍺1, reduces swelling through (Sudafed) peripheral vasoconstriction Monoamine Prevents the breakdown of oxidase inhibitors monoamines Norepinephrine ⍺ & β1 receptors Methylphenidate Psychostimulant for AHD, Epinephrine ⍺ & β receptors prevents the reuptake of Albuterol β2 receptor, bronchodilator monoamines used as an emergency inhaler Cocaine Prevents the reuptake of for asthma monoamines Adrenergic Antagonist Sympatholytics Sympatholytics oppose the effects of neuron Name Receptor Blocked ring at effector organs by the sympathetic nervous system. This can be done through any Phentolamine Blocks all ⍺ receptors, mechanism. With this de nition, one could used in the reversal of argue that adrenergic antagonists are also soft tissue anesthesia considered sympatholytics. Chlorpromazine ⍺1 receptor (CPZ) Name Effect Metoprolol & β1 receptor Guanethidine Inhibits release of Atenolol (cardioselective) catecholamines Propranolol β receptors, prolongs Reserpine Depletes the stored not lidocaine duration epinephrine Clonidine & ⍺2 agonist (CNS) which blocks Metyldopa SNS signal. It is NOT potentiating the SNS signal INBDE Booster | Booster PrepTM fi fi PHARMACOLOGY 22 Epinephrine Reversal Epinephrine has a vasoconstrictive effect In the presence of an alpha blocker, such as phentolamine, β2 vasodilatory effect dominates and becomes the major vascular response INBDE Booster | Booster PrepTM  PHARMACOLOGY 23 Cardiovascular Pharmacology 1 The Circulatory System 2. Hydralazine causes vasodilation by opening K+ channels in cells and allowing The human circulatory system is a system which easier ow of blood consists of a heart (the pump) pumping blood 3. Calcium channel blockers block in ux of (the uid) through vessels (the tubing) to their calcium in cells to cause vasodilation target organs. ‣ Verapamil Another way to describe the circulatory system ‣ Amlodipine is as follows ‣ Nifedipine Heart = cardiac output (CO) 4. ACE inhibitors inhibits the conversion of Vessels = peripheral resistance (PR) angiotensin I  angiotensin II (potent Blood = blood volume (SV) vasoconstrictor) ‣ “-prils” (suf x) Blood pressure (BP) and cardiac output (CO) 5. Angiotensin receptors blockers (ARBs) can be calculated using the following formulas: competitive antagonist at angiotensin II BP = CO X PR receptor CO = SV X HR ‣ “-sartans” (suf x) Additional terms include: Preload – the amount of lling pressure of Antihypertensive Side Effects the heart at the end of diastole drugs Afterload – the pressure the heart gives to Diuretics Xerostomia, nauseas eject the blood during systole Systole – period of heart contraction and Adrenergic Blocking Xerostomia, depression, ejection Agents sedation, sialadeuosis Diastole – period of heart relaxation and Lichenoid reaction lling Angiotensin- Lichenoid reaction, 2 Cardiovascular Drugs Converting Enzyme burning mouth, loss of Inhibitors (ACEIs) taste Antihypertensives Calcium Antagonists Gingival hyperplasia, Antihypertensives are used in treatment of xerostomia high blood pressure and have several different Other Vasoldilators Cephalgia, nauseas mechanisms of action. 1. Diuretics block renal absorption of sodium increases urination and uid loss = ↓ BP ‣ Furosemide – acts on the ascending limb of the Loop of Henle ‣ Hydrochlorothiazide (HCTZ) – thiazide (hypokalemia) acts in distal tubule ‣ Spironolactone – K+ sparing (hyperkalemia) acts in collecting duct INBDE Booster | Booster PrepTM fi fl fl fi fi fl fi fl  PHARMACOLOGY 24 Anti-arrhythmic INBDE Pro Tip: An arrhythmia is simply an irregular heart beat. It’s easier to understand the mechanism of With this being said, anti-arrhythmic drugs action of ARBs and ACE inhibitors by learning work to suppress and treat the irregular or the process of angiotensin II synthesis. abnormal rhythms of the heart. There are 4 classes of anti-arrhythmic drugs: Angina Management Class I - Na+ channel blockers for cardiac Anti-angina medications help to treat muscle only individuals who have insuf cient oxygen to Class II – Beta-blockers supply the heart. Class III – Potassium-channel blockers 1. Propranolol – reduces oxygen demand by Class IV – Calcium channel blockers (CCBs) reducing heart stimulation, resulting in reduced heart rate 2. Nitroglycerin – vasodilation of the coronary arteries to aid in increasing oxygen supply. The use of phosphodiesterase-5 (PDE5) inhibitors (ex: Sildena l (Viagra®)) is contraindicated in patients 3. Calcium Channel Blockers – reduces oxygen demand by reducing peripheral resistance via vasodilation and decreasing the contraction force of the heart Anti-Cardiac Heart Failure Drugs Anti-cardiac heart failure drugs are used to help pump blood through the heart during heart failure. 1.Cardiac glycosides work by blocking Na+/ K+ ATPase to increase calcium in ux and promote positive force in cardiac muscle cells. An example of a cardiac glycoside is: ‣ Digoxin INBDE Booster | Booster PrepTM fi fi fl PHARMACOLOGY 25 Central Nervous System 1 Central Nervous System Antidepressants Antidepressants are used to increase stimulation, an opposite of antipsychotics CNS drugs target receptors in the brain and This is achieved through increasing the spinal cord. In the CNS, there is a continuum of number of monoamines (dopamine, excitability from too little stimulation to epinephrine, norepinephrine, serotonin, excessive stimulation. Generally, from low to histamine) in the brain high excitability, the continuum is: Generally, all antidepressants have anticholinergic side effects, because an Anesthesia  sedation  homeostasis  excess can activate adrenergic receptors in activation  excitation  seizure the ANS Some examples of classes of antidepressants 2 CNS Drugs and medications that fall into them include: SSRI – selective serotonin reuptake Antipsychotics inhibitor Antipsychotics, known as neuroleptics in some ‣ Fluoxetine circles, are used when the brain is too active. SNRI – serotonin and NE reuptake inhibitor This can include conditions such was ‣ Duloxetine schizophrenia, and psychosis. They work TCA – tricyclic antidepressants through two main mechanisms of action: ‣ Amitriptyline 1. Dopamine D2 receptor blockers – MAOI – monoamine oxidase inhibitors blocking the dopamine receptors of the ‣ Phenelzine brain to decrease the effect of dopamine. NDRI – norepinephrine-dopamine reuptake Haloperidol and chlorpromazine are two inhibitor examples in this category with a main side ‣ Bupropion effect being tardive dyskinesia. 2. Serotonin 5-HT receptor blockers – General Anesthetics inhibition of serotonin receptors all along General anesthetics induce a coma in patients the central nervous system. These tend to during surgery. The onset of anesthesia is bind long enough to produce their anti- inversely proportional to the solubility of the psychotic effects, but not too long so that anesthetic in blood. There are 4 stages of their side effects are kept low. general anesthesia: 1. Stage I – analgesia/feeling better 2. Stage II - delirium 3. Stage III – surgical anesthesia INBDE Pro Tip: 4. Stage IV – medullary paralysis Xerostomia is the most likely oral side effect of antipsychotic medications. GA example: Halothane can be toxic to the liver INBDE Booster | Booster PrepTM PHARMACOLOGY 26 Anxiolytics/Sedatives 1. Benzodiazepines ‣ ↑ GABA binding and Cl- in ux = slow down CNS ‣ Ideal oral sedative for dentistry ‣ Wider therapeutic index, less addiction potential and less respiratory depression compared to other counterparts ‣ Diazepam, Triazolam, Midazolam INBDE Pro Tip: Benzodiazepines can be used for dental oral sedation, as well as for the treatment of seizures. 2. Barbiturates ‣ GABA receptor agonists ‣ Contraindicated in those with intermittent porphyria and severe asthma ‣ Like most sedatives, overdoses can cause respiratory depression ‣ Methohexital = rapid onset, short duration of action, and predictability Pathophysiology Caused by a dopamine de ciency in the brain 3 Parkinson’s Disease Dopamine is made in the brain from L- DOPA L-DOPA has the ability to cross the blood brain barrier (BBB), while dopamine does not DOPA decarboxylase is an enzyme that normally breaks down L-DOPA Carbidopa – blocks DOPA decarboxylase o This allows L-DOPA to cross the BBB, so that it can be converted to dopamine once in the brain INBDE Booster | Booster PrepTM fi fl