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 will review all of the pharmacology concepts tested on the INBDE including: amides and esters, pharmacodynamics, pharmacokinetics, cal...

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 main groups: amides and esters. Below, we will discuss all of the relevant information that you will need to know about local anesthetics for the INBDE. 1 Types of Local Anesthetics Amides • Amides are metabolized by the liver and their names commonly end with the suf x “-caine.” Some important amide local anesthetics are listed below: ‣ Lidocaine (Xylocaine) - Safest for use in children - 2% in solution ‣ Mepivacaine (Carbocaine, Polocaine) - Causes the least amount of vasodilation - 2-3% in solution ‣ Articaine (Septocaine) - Shortest duration of all the local anesthetics - Has an ester chain attached; it is metabolized by BOTH the liver and in plasma - 4% in solution ‣ Prilocaine (Citanest) - Risk of methemoglobinemia (blood disorder where there is an abnormal amount of hemoglobin production) → can lead to insuf cient O2 delivery to cells ‣ Bupivacaine (Marcaine) - Longest duration of all local anesthetics - Not safe for use in children due to prolonged soft tissue anesthesia - 0.5% in solution Esters • Esters are metabolized in plasma by pseudocholinesterase enzymes. Like amides, their names also end in the “-caine” suf x. • Esters are usually more toxic and cause more allergic reactions than amides due to methylparabens. • The following are some important esters to know for the INBDE: ‣ Benzocaine - Commonly used as a topical anesthetic prior to injection - Risk of methemoglobinemia ‣ Cocaine - Potentiates vasoconstriction ‣ Procaine INBDE Pro Tip: Know the unique points associated with each local anesthetic. This is a heavily tested topic on the INBDE. fi fi fi INBDE Booster | Booster PrepTM PHARMACOLOGY 2 2 Pharmacodynamics/Pharmacokinetics Pharmacodynamics • Pharmacodynamics refers to the effect that a drug has on the body. Generally, local anesthetics have the following pharmacodynamic characteristics described below. ‣ Sodium channel blockers: - Sodium channels in neurons allow the in ux of sodium ions for depolarization to signal pain - Local anesthetics block these channels from initiating depolarization ‣ Non-ionized (free-base form): - Only non-ionized drug forms can cross the hydrophobic neuron membrane - Blocking the sodium channel can only be done from inside of the cell ‣ Less effective in in amed tissue: - In amed tissue has a lower pH - Excess H+ ions favor an equilibrium where the drug is in an ionized form = cannot cross the neuron membrane Require a critical length: ‣ - Complete anesthesia – achieved when 3 consecutive nodes of Ranvier are blocked - There is a better chance of anesthesia when there is a longer length of nerve bathed in anesthetic Pharmacokinetics • Pharmacokinetics describes the response that an individual’s body has to a drug. Key principles of pharmacokinetics are provided below, demonstrating how the body may be impacted by local anesthetics. It is important to know these concepts for the INBDE. ‣ ↑ protein binding leads to ↑ duration of action ‣ ↓ pKa = faster onset of action - Why? ↓ pKa ! drug gives up proton more easily ! drug becomes nonionized ! drug crosses membrane Drug pKa Mepivicaine 7.6 Articaine 7.8 Lidocaine 7.9 Prilocaine 7.9 Bupivacaine 8.1 3 Calculating Local Anesthetics A carpule/cartridge of local anesthetic represents 1.8mL. Therefore, local anesthesia at a concentration of 1% has 18mg of local anesthetic. For 100% solution there are 1.8g or 1,800mg of the drug. It is important to know these numbers for the INBDE. Example 1.31 Question: The most common local anesthetic used in dentistry is 2% lidocaine (1:100,000 epinephrine). How many mg of lidocaine are present in a carpule (1.8mL) of this iteration? Solution: The calculation is simple for lidocaine: 1% contains 18mg of lidocaine, hence, 18mg/ 1% x 2% = 36 mg of lidocaine. Therefore, there are 36mg of lidocaine in a 2% solution. fl fl fl INBDE Booster | Booster PrepTM PHARMACOLOGY 4 4 3 Vasoconstriction & Toxicity Example 1.41 Vasoconstriction • As mentioned, epinephrine and other kinds of vasoconstrictors are often packaged in solution with a local anesthetic. • There are 3 main purposes for the addition of vasoconstrictors: 1. Hemostasis ‣ Counteracts vessel dilation of local anesthetic 2. Longer anesthesia ‣ Decreased blood ow to the injection site decreases the amount of anesthetic carried away from nerves 3. Reduced toxicity ‣ Increased blood vessel constriction decreases the systemic impact of the drug Question: The most common local anesthetic used in dentistry is 2% lidocaine (1:100,000 epinephrine). How many mg of epinephrine are present in a carpule of this iteration? Solution: With epinephrine, the amount is given as a ratio, which should rst be converted into a percentage: 1/100,000 x 100% = 0.001%; hence 0.001% x 18mg/1% = 0.018mg of epinephrine. Therefore, there are 0.018mg of epinephrine in one carpule of the iteration described above. 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. fi fl INBDE Booster | Booster PrepTM PHARMACOLOGY 4 Needles & Injections 1 Measurements Length • Two options: ‣ Long needle = 32mm ‣ Short needle = 20mm Diameter • Three options: ‣ 30-gauge = 0.3mm ‣ 27-gauge = 0.4mm ‣ 25-gauge = 0.5mm • Larger diameter (smaller gauge) needles are often advantageous for the following reasons: ‣ They do not bend or break as often ‣ They provide better aspiration - Aspiration = lightly drawing one’s nger back on the syringe to detect presence of blood (vessel perforation) 2 Injection Techniques There are several different techniques for local anesthetic injection. Aiming to deliver the anesthetic slowly over the course of 60 seconds will decrease the discomfort of the patient. Inferior Alveolar Nerve Block (IAN Block) • Injection is in the center of the area bordered by the: ‣ Coronoid notch ‣ Pterygomandibular raphe ‣ Upper maxillary molars • High failure rate due to dif culty of the injection • Numbs all of the mandibular teeth of the quadrant • Numbs lips and gingiva of all teeth in the quadrant, except gingiva of the molar region • Tongue is numbed in the quadrant if the lingual nerve is blocked as well Techniques • Vazirani-Akinosi = closed mouth technique, which can be useful in cases of truisms • Gow-Gates = open mouth method, which blocks practically the entirety of V3 Injection Steps 1. Approach from the opposite side of the mouth towards the molars/premolars • Aim 10-15mm above the mandibular occlusal plane and parallel to that plane 2. Advance the needle slowly until bone is felt 3. Slowly withdraw the needle ~1mm and aspirate 4. If no blood is detected, inject at rate of 1 carpule/min Buccal Nerve Block • Anesthetizes soft tissue buccal to molars (the tissue the IAN block does not target) Injection Steps 1. Inject from the buccal to the distal most molar, approximately parallel to the occlusal plane Mental Nerve Block • Anesthetizes soft tissue facial to anterior teeth • Does not numb the teeth itself Injection Steps 1. Locate the rubbery neurovascular bundle with your nger fi fi fi INBDE Booster | Booster PrepTM PHARMACOLOGY 2. Insert needle anterior to the mental foramen by the apices of the premolars 3. Aspirate and slowly inject Incisive Nerve Block • Anesthetizes the anterior teeth and premolars of the quadrant Injection steps 1. Follow the same steps as the mental nerve block, inject over 20 seconds 2. Hold pressure on injection site for 2 minutes in order to increase the volume of anesthetic into the mental foramen Posterior Superior Alveolar Block • Anesthetizes maxillary molars and buccal tissue • Does not numb the mesio-buccal root of the 1st molar in 28% of patients ‣ Supplied by the middle superior alveolar nerve block • High risk of hematoma due to injection being close to groups of blood vessels Injection Steps 1. Palpate for zygomatic process and aim needle posterior to that 2. Retract cheek; and inject needle into mucosa above 2nd maxillary molar at a 45degree angle to occlusal and vertical plane 3. Inject until the needle is 16mm in depth (half the length of a long needle) 4. Swing the needle so it is 45 degrees to the back of the maxillary tuberosity Infraorbital Block • Also known as true anterior superior alveolar block ‣ Targets anterior superior and middle superior alveolar nerves • Anesthetizes maxillary anteriors and premolars 5 Injection Steps 1. Inject at the mucobuccal fold directly over the 1st premolar into the infraorbital foramen Greater Palatine Nerve Block • Anesthetizes posterior hard palate and overlying tissue from 3rd molar to 1st premolar up to the midline • Target needle into the greater palatine foramen • Often painful Injection Steps 1.Use a cotton tip to push gently along the area where the alveolar ridge meets the hard palate; the site where the cotton tip dips down is your injection site Nasopalatine Block • Most painful injection • Anesthetizes the hard palate from canine to canine on the maxilla • Most painful injection Injection Steps 1. Inject palatal mucosa lateral to the incisive papilla Local In ltration • Local anesthetic diffuses through bone to numb the terminal branching nerves entering the pulp of the tooth • Septocaine (articaine) is often used ‣ Best for bone penetration • Works well in anterior teeth ‣ Facial cortical plate is thin = better diffusion of anesthetic Injection Steps 1. Inject the needle into the vestibule above the tooth of interest and aim for the root apex fi INBDE Booster | Booster PrepTM PHARMACOLOGY 6 Summary Figure 2.21 Injection sites INBDE Booster | Booster PrepTM PHARMACOLOGY 7 Antibiotics Requirement of Antibiotic Prophylaxis 1 The use of antibiotic prophylaxis in dental practice is not common. However, there are certain instances when their use is required for invasive treatments that involve manipulation of gingival tissue or manipulation of the periapical region of a tooth. Appropriate Use of Antibiotic Prophylaxis • Patients with cardiac conditions: ‣ Prosthetic cardiac valve ‣ Previous or recurrent infective endocarditis ‣ Congenital heart disease ‣ Cardiac transplant patients with valvulopathy • Consider a consultation with one’s primary physician for: ‣ Immunosuppression secondary to neutropenia, cancer chemotherapy, or solid organ transplant ‣ Sickle cell anemia ‣ High-dose corticosteroid use ‣ Poorly controlled diabetes ‣ Diseases of autoimmunity Types of Antibiotics 2 Tetracyclines • “-cycline” suf x ‣ doxycycline, tetracycline • Protein synthesis inhibitor – binds to 30S ribosomal subunit • *Broadest antimicrobial spectrum • Bacteriostatic Carbapenems • “-nem” suf x ‣ Meropenem • β-lactam – inhibits cell wall synthesis • Bactericidal Penicillins • Majority have “-cillin” suf x • β-lactam – inhibits cell wall synthesis • Cross-allergenic with cephalosporins ‣ Penicillin is chemically related, so the immune system might see them both as the same if the patient is allergic to either one • Bactericidal The following are speci c types of penicillin and their associated characteristics: 1. Penicillin V – oral administration 2. Penicillin G – IV administration 3. Amoxicillin – broad spectrum 4. Augmentin – includes amoxicillin and clavulanic acid (works against β-lactamase resistant bacteria) 5. Carbenicillin – for use against pseudomonas Monobactams • “-am” suf x ‣ Aztreonam • β-lactam – inhibits cell wall synthesis • Bactericidal fi fi fi fi fi INBDE Booster | Booster PrepTM PHARMACOLOGY Cephalosporins • “Ceph-“ pre x • β-lactam – inhibits cell wall synthesis • Grouped into generations based on their spectrum against speci c bacteria ‣ 1st Gen = Cephalexin (Ke ex) ‣ 2nd Gen = Cefonicid ‣ 3rd Gen = Ceftriaxone ‣ 4th Gen = Cefepime • Bactericidal Fluoroquinolones • “- oxacin” suf x is common ‣ Cipro oxacin • DNA synthesis inhibitor • Bactericidal Sulfonamides • “Sulfa-“ pre x ‣ Sul soxazole • Folate synthesis inhibition ‣ Results in folate de ciency that impacts DNA synthesis • Bacteriostatic Macrolides • “-thromycin” suf x ‣ Azithromycin • Protein synthesis inhibitor – binds to 50S ribosomal subunit • Bacteriostatic 8 Lincosamides • “-mycin” suf x ‣ Clindamycin, Lincomycin • Protein synthesis inhibitor – binds to 50S ribosomal subunit • Bacteriostatic 3 Medical Prescriptions (Rx) Prescription of antibiotics will vary with each patient based on their age, medical history, current medications, and other factors. Rx for Infective Endocarditis Prophylaxis Patient / Case Rx Time of Admin First choice Amoxicillin 2g 60 mins prior to tx Children Amoxicillin 50mg/kg 60 mins prior to tx Penicillin allergy Azithromycin 500mg 60 mins prior to tx Children with Penicillin allergy Azithromycin 15mg/kg 60 mins prior to tx IV Ampicillin 2g 30 min before tx Children, IV Ampicillin 50mg/ kg 30 min 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. fl fi fi fi fi fi fi fi fl fi fl INBDE Booster | Booster PrepTM PHARMACOLOGY 9 Side Effects Knowing the side effects of antibiotics is not only important for general knowledge, but is also important when considering prescriptions. • For example, it is best not to prescribe tetracycline to a patient with liver disorders Side Effect Associated Antibiotic Pseudomonas colitis Clindamycin Superinfection Very broad-spectrum antibiotics Aplastic anemia Chloramphenicol Liver damage Tetracycline Drug Concentration • Tetracycline concentrates well in gingival crevicular uid • Clindamycin concentrates well in bone Antivirals & Antifungals The following are common antivirals and antifungals prescribed in dental practice: • Acyclovir, Valcyclovir ‣ “-vir” = antiviral ‣ Used for herpes • Fluconazole ‣ “-azole” = antifungal ‣ Used for Candidiasis 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 fl fl INBDE Booster | Booster PrepTM PHARMACOLOGY 10 Analgesics 1 Acetaminophen Acetaminophen is commercially known as Tylenol, and there are several key points to know about this drug. • Maximum daily dose = 4,000 mg • Inhibits pain in the central nervous system • Drug of choice for a feverish child ‣ Aspirin is known to cause Reye’s Syndrome • Negatively impacts the liver ‣ Toxic at higher doses ‣ Greater damage when combined with alcohol 2 NSAIDS Types of NSAIDS NSAIDS work by inhibiting COX 1 and/or COX 2. Normally, COX1 and COX2 promote in ammation by generating prostaglandins (PG). By blocking COX1 and 2 there is a corresponding reduction in the effects of PGs. Below is a table summarizing important NSAIDS to study for the INBDE. Name Blocking Association Aspirin (ASA) COX 1 & 2 (irreversible) Impacts GI Ibuprofen (Motrin, Advil) COX 1 & 2 (reversible) Impacts kidney Naproxen (Aleve) COX 1 & 2 (reversible) Ketorolac (Acular) COX 1 & 2 (reversible) Celecoxib (Celebrex) COX 2 Meloxicam (Mobic) COX 2 Treatment of arthritis Therapeutic Effects of Aspirin • Anti-in ammatory and analgesic ‣ Inhibits COX 1 & 2 (PG synthesis) • Antipyretic ‣ Inhibits PG synthesis in the hypothalamus (temperature regulation center) • Inhibits clotting ‣ Inhibits TXA2 synthesis = inhibits platelet aggregation The mechanism of action for aspirin is very important to know and highly testable on the INBDE. Toxic Effects of Aspirin • GI bleeding • Metabolic acidosis • Salicylism • Tinnitus • Nausea & vomiting • Delirium • Hyperventilation INBDE Pro Tip: The maximum daily dose of ibuprofen is 3,200 mg. IV, IM, or oral route fl fl INBDE Booster | Booster PrepTM PHARMACOLOGY Steroids 3 Corticosteroids Corticosteroids are man-made steroids, which mimic the action of cortisol (produced in the adrenal cortex of the adrenal gland); the common suf x of corticosteroids is “-sone.” • Prednisone • Dexamethasone • Hydrocortisone Therapeutic Effects • Analgesic and anti-in ammatory ‣ Inhibits phospholipase A2 = inhibits arachidonic acid synthesis Side Effects of Steroids • Immunosuppression if used chronically • Gastric ulcers • Osteoporosis • Fat redistribution • Hyperglycemia • Acute adrenal insuf ciency ‣ Follows the Rule of Twos - Adrenal suppression can occur if a patient is taking 20mg of cortisone (or its equivalent) for 2 weeks within 2 years of dental treatment - Patient may need supplemental doses of steroids prior to therapy 4 Narcotics/Opioids Types of Narcotics • Codeine • Hydrocodone • Oxycodone • Oxycontin • Meperidine • Morphine 11 • • • • Tramadol Fentanyl Sufentanil Heroin Combination Narcotics Therapeutic Effects & Side Effects of Morphine The effects of morphine can easily be memorized using the following acronym: Miosis (pupil constriction) Out of it (sedation) Respiratory depression Pneumonia (aspiration pneumonia) Hypotension Infrequency of urination & constipation Nausea & vomiting Euphoria & dysphoria Overdose & Addiction The following drugs can be used when an overdose or addiction of morphine occurs: • Naloxone ‣ Competitive opioid antagonist, for emergencies • Naltrexone ‣ Antagonist, treats addiction In emergencies, the half-life of naloxone may be shorter than the half-life of the opioid, therefore, multiple doses of naloxone may be required. INBDE Pro Tip: Methadone is a synthetic opioid agonist that can be used not only for relief of pain, but also, for opioid addiction. fl fi fi INBDE Booster | Booster PrepTM 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 fi fi fi fl INBDE Booster | Booster PrepTM PHARMACOLOGY 13 Pharmacokinetics 1 Steps of Pharmacokinetics Pharmacokinetics, in simple words, is the study of what the body does to a drug. Pharmacokinetics does not study what the drug binds to nor its therapeutic or toxic effects. After administration, the following are the sequential steps of a drug’s path through the body: 1. Absorption 2. Distribution 3. Metabolism 4. Elimination Routes of Administration • Enteral: oral, sublingual, or rectal • Parenteral: intravenous, intramuscular, or subcutaneous • Other routes: intranasal, inhalation, topical, or vaginal Absorption Generally, drugs must cross several epithelial or endothelial cell layers (barriers) to enter the body in order for absorption to take place. Different methods of administration determine which barriers the drug must cross to enter to be absorbed. Below are a few facts to know: • Epithelial cell layers must be crossed when administering drugs to be absorbed through the skin, intestines, respiratory system, and genitourinary tract • Endothelial cells must to be crossed for drugs to reach blood vessels • Local drugs are active at the site of 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 • 100% bioavailability can only occur if a drug is administered intravenously (IV) pH is also important to consider when discussing drug absorption. The ways in which an acidic or basic drug interacts with its environmental pH can alter the charge of the drug and subsequently its absorption. Generally, drugs should be of neutral charge for absorption to take place. • Weak acids: pH < pKa for absorption • Weak bases: pH > pKa for absorption Acidic Drug Basic Drug Acidic Environment Non-ionized Ionized Basic Environment Ionized Non-ionized • We want the drug to be non-ionized for it to be absorbed at the appropriate location Distribution • For adequate systemic distribution, a drug must rst reach the blood stream ‣ Topical drugs are an exception to this rule • Once the drug arrives at the target tissue, it passes through endothelial cells, cellular interstitium, and nally the basolateral membrane of the tissue cell type • Systemic drugs normally reach vessel-rich organs quickly for example: ‣ Heart, liver, and lungs fi fi INBDE Booster | Booster PrepTM PHARMACOLOGY First Pass Effect • Drugs absorb through the GI system and are sent from the hepatic portal system to the liver • The liver metabolizes the drug, leaving a smaller fraction of the drug to travel through the circulatory system • Oral drugs undergo the above noted process, which is known as the “First Pass Effect” Volume of Distribution (Vd) • Volume (L) of total body water in which a drug will partition • Describes the distribution of a drug across three body water compartments ‣ Plasma (4%) ‣ Interstitial (16%) ‣ Intracellular (40%) • People who have less body water than the average male adult should be given a lower drug dose to properly aid distribution ‣ Women ‣ Obese ‣ Elderly • Brain and muscle have the highest water content, while adipose tissue has the lowest water content 14 Phase I • Functionalization (oxidation, reduction, hydrolysis) ‣ Oxidation is the most common • Achieved through Cytochrome P450 (CYP450) enzymes Phase II • Conjugation (glucuronide, glutathione, glycine) ‣ Covalently adds polar side chains to the drug ‣ Glucuronide is the most common side chain added via UDPglucuronosyltransferase Phase I and II reactions share the following common characteristics: • Drugs sometimes go through both phases or just one phase • Both phases decrease the ef cacy of the drug/inactivate the drug • Both phases increase drug polarity, which prevents passive diffusion and facilitates renal and GI clearance of the drug 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 fi INBDE Booster | Booster PrepTM PHARMACOLOGY 15 Elimination Elimination refers to how a drug is removed from the body • Elimination occurs mostly in the kidneys • Phase I creates polar molecules, which go to the kidneys for urinary clearance • Phase II creates polar and larger molecules, which tend to clear in the GI tract as feces 2 Drug-Drug Interactions When drugs interact, one drug can affect the pharmacokinetics of the other drug. These interactions normally occur in the metabolism phase. There are commonly two kinds of effects from drug interactions: • 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 Drug Interaction risk NSAIDS Lithium ↑ lithium toxicity NSAIDS Hypotensives ↓ effect of hypotensive NSAIDS Anticoagulants ↑ risk of bleeding Penicillins Oral contraceptives ↓ oral contraceptive effect NSAIDS Methotrexate ↑ methotrexate toxicity Metronidazole Warfarin Examples of Dental Drug-Drug Interactions Factors In uencing Drug Effectiveness The effect of the same drug can vary amongst different people due to several factors: 1. Prescribed dose ‣ Medical errors ‣ Patient compliance 2. Administered dose (effected by pharmacokinetics) ‣ Absorption ‣ Distribution ‣ Metabolism ‣ Elimination 3. Active dose (effected by pharmacodynamics) ‣ Drug-receptor interaction 4. Intensity of effect ↑ risk of bleeding fl INBDE Booster | Booster PrepTM 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 1 Interactions Agonists Agonists mimic the effects and cause the same actions as an endogenous agonist molecule. Agonists can produce a full 100% of its intended effect (full agonist) or less than 100% (partial agonist). Antagonist Antagonists work opposite to agonists in that these will inhibit the action of the endogenous agonist. The mechanism in which this inhibition occurs is through 2 main ways: 1. Competitive antagonist – competing directly with an agonist for the same binding site located on the receptor. This site is called an active site. 2. Non-competitive antagonist – binds to a position other than the active site, while preventing the agonist from binding. Oftentimes, non-competitive antagonism will change the shape or conformation of the receptor at the active site. Inverse Agonist Inverse agonists do not bind at the same active site as an agonist (preventing their interactions) but will produce an effect that is opposite that of the agonist Figure 6.11 Response Curve 2 Dose-Response Curves Type I Dose-Response Curve A type I dose-response curve is used to correlate the response/ef cacy of a drug (yaxis) to the drug dose (x-axis). Its shape can either be log form or hyperbolic. A dose-response curve can be used to describe drug characteristics as follows: • Intrinsic activity (Emax) – maximal effect of a drug ‣ Full agonist Emax = 1 ‣ Partial agonist Emax = 0-1 ‣ Antagonist Emax = 0 • Ef cacy – effect of a drug when it binds to the target • Af nity – level of attraction of a drug to its receptor ‣ Dissociation constant (Kd) – concentration of drug needed to occupy 50% of receptors ‣ Lower Kd represents a higher or greater af nity • Potency – strength of a drug at a certain concentration ‣ Effective concentration (EC50) – describes the concentration at which half the maximal effect is achieved ‣ The more potent the drug, the lower the EC50 fi fi fi fi INBDE Booster | Booster PrepTM 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 Figure 6.21 Type 1 Response Type II Dose-Response Curve In a type II dose-response curve, the x-axis measures the drug dose; and the y-axis measures the quantity of subjects responding to the drug. Type II dose-response curves can show 3 different curves representing the following scenarios: • Therapeutic effect curve ‣ ED50 – dose at which the desired effect effect is produced in 50% of the population • Toxic effect curve ‣ TD50 – dose at which a toxic effect is produced in 50% of the population • Lethal effect curve ‣ LD50 – dose at which a lethal effect is produced in 50% of the population Effects of Drug Interaction Additive • Drugs interact to combine their individual degrees of effect • Effects are combined Antagonist • Drugs interact to lessen the effect than if one drug were to be used alone • Chemical antagonism – a drug binds to another drug to prevent the other’s function • Receptor antagonism – competition between two drugs for the same receptor • Pharmacokinetic antagonism – one drug affects the pharmacokinetics of another drug • Physiologic antagonism – two drugs with opposing effects on the same tissue on distinct receptors Synergist • Combining drugs leads to a greater effect than the sum of their independent effects INBDE Booster | Booster PrepTM PHARMACOLOGY 18 Autonomic Nervous System 1 ANS Physiology The sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) are branches of the ANS. In many systems they have opposing effects. • SNS effects promote “ ght or ight” • PNS effects promote “rest and digest” • Some important exceptions to this rule are: ‣ The vasculature to skeletal muscles are controlled by the SNS ‣ The sweat glands are controlled by the SNS All nerve pathways originate from the CNS (brain & spinal cord) • 12 cranial nerves – PNS • 0 cervical nerves – autonomic nerves do not originate here • 12 thoracic nerves – SNS • 5 lumbar nerves – SNS • 5 sacral nerves – PNS Figure 7.11 Autonomic Nervous The following are examples of the opposing effects of the SNS and PNS: Fight or Flight (SNS) Rest & Digest (PNS) Slows digestion Increases digestion ↑ Heart rate ↓ Heart rate ↓ Saliva production ↑ Saliva production Pupillary dilation Pupillary constriction Bladder relaxation, increase urination Bladder constriction, decrease urination Bronchi dilation Bronchi constriction 2 Receptors in the ANS Receptors in the ANS can be described in different ways. Ionotropic – ion channel Metabotropic – G-protein coupled receptor (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 o Receptors in the SNS fl fi INBDE Booster | Booster PrepTM PHARMACOLOGY SNS vs. PNS Differences between the SNS and PNS can be distinguished by the following methods: • Effect on organs ‣ SNS – ght or ight ‣ PNS – rest and digest • The spinal cord region they originate in ‣ SNS – thoracolumbar ‣ PNS – craniosacral • Neurotransmitters used ‣ SNS – Ach to ganglion, NE from nerves and Epi/NE from adrenal gland ‣ PNS – Ach throughout • Neurotransmitter receptors used ‣ SNS – adrenergic metabotropic receptors at target organs ‣ PNS – muscarine metabotropic receptors at target organ • Length of pre & postganglionic neurons ‣ SNS – short preganglionic to sympathetic trunk, long post-ganglionic ‣ PNS – long preganglionic, short postganglionic Synthesis of Neurotransmitters • Acetyl CoA + choline = acetylcholine ‣ The enzymes involved in the creation and breakdown of acetylcholine are acetyltransferase and acetylcholinesterase respectively • Tyrosine ! L-DOPA ! dopamine ! NE ! Epi ‣ Catecholamines = dopamine, NE, epi ‣ Monoamines = dopamine, NE, epi, serotonin (5-HT), histamine 19 Muscarinic Receptors There are different types or isoforms of muscarinic post-ganglionic receptors, differentiated by their target organ. 1. M1 = CNS – autonomic ganglia 2. M2 = heart ‣ Bradycardia = ↓ heart rate + electrical conduction 3. M3 = smooth muscle & exocrine glands ‣ Salivation, urination, defecation, sweating ‣ Smooth muscle contraction ‣ Vascular endothelium vasodilation 4. M4 = CNS 5. M5 = CNS 3 M Agonist Drugs M agonists activate muscarinic receptors in the PNS. Some are non-selective to target all M receptors, while others are selective to certain M receptor types. • Non-selective M agonists will effect M1-5 receptors if systemic in its distribution, and should not be used systemically in patients with these following conditions: ‣ Asthma/COPD – these conditions result in air ow obstruction to the lungs. Muscarinic agonists can cause bronchoconstriction, thereby exacerbating the disease ‣ Peptic ulcers – muscarinic agonists can cause an increase in the secretion of gastric acid, worsening peptic ulcers ‣ Coronary Heart Disease – the cardiac 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. fl fi fl INBDE Booster | Booster PrepTM 20 M-Agonists List Direct acting Activates M-receptor Pilocarpine Used to stimulate saliva or eye drops to constrict pupils and reduce pressure Indirect acting Non-competitively inhibits acetylcholinesterase Physostigmine & Neostigmine Reversible inhibit cholinesterase Insecticides and Nerve gases Irreversibly inhibits cholinesterase. High poison potential! Treatment with Pralidoxime M-Antagonists/Ganglionic Blockers Competitive Inhibitors Block Muscarinic receptor, compete with acetylcholine Scopolamine Helpful in the reduction of saliva Atropine 4 Helpful in the reduction of saliva, as well as the treatment of acute bradycardia. Nicotinic Antagonist Drugs Non-depolarizing Allosteric inhibitor Mecamylamine & Hexamethonium Previously used as an antihypertensive N-Antagonists/Neuromuscular Blockers Neuromuscular blockers block nicotinic receptors of the somatic nervous system. Depolarizing Irreversible N-antagonist Succinylcholine Relieve laryngospasm & helps to facilitate tracheal intubation during surgery 5 Sympathetic Nervous System In the sympathetic nervous system, epinephrine (epi) and norepinephrine (NE) act on the effector organs to elicit the ght or ight autonomic response. These neurotransmitters are synthesized through the following process: Tyrosine ! L-DOPA ! dopamine ! NE ! Epi • • Dopamine, Epinephrine, Norepinephrine = catecholamines Dopamine, Epinephrine, Norepinephrine, serotonin (5-HT), histamine = monoamines Adrenergic Receptors There are different types of adrenergic postganglionic receptors based on the organ they effect: 1. ⍺1 – smooth muscle in blood vessels ‣ Vasoconstriction, urinary retention, pupil dilation (mydriasis) 2. ⍺2 – smooth muscle in blood vessels i. Vasoconstriction INBDE Booster | Booster PrepTM fi fl PHARMACOLOGY 21 3. β1 – heart ‣ ↑ cardiac output, heart rate, electrical conduction, and strength of contraction ‣ Renin release from kidneys, leading to vasoconstriction 4. β2 – smooth muscle ‣ Bronchodilation, vasodilation, thickened salivary secretions Adrenergic Agonist Name Receptor Activated Phenylephrine (Sudafed) ⍺1, reduces swelling through peripheral vasoconstriction Norepinephrine ⍺ & β1 receptors Epinephrine ⍺ & β receptors Albuterol β2 receptor, bronchodilator used as an emergency inhaler for asthma Adrenergic Antagonist Sympathomimetics Sympathomimetics are agents that are used in order to increase the effects of endogenous catecholamines. They can be direct (act at an adrenergic receptor) or indirect (by other means). Name Effect Amphetamine & Ephedrine Stimulates release of stored norepinephrine Tricyclic antidepressants Inhibits reuptake of serotonin & norepinephrine Monoamine oxidase inhibitors Prevents the breakdown of monoamines Methylphenidate Psychostimulant for AHD, prevents the reuptake of monoamines Cocaine Prevents the reuptake of monoamines Sympatholytics Sympatholytics oppose the effects of neuron ring at effector organs by the sympathetic nervous system. This can be done through any mechanism. With this de nition, one could argue that adrenergic antagonists are also considered sympatholytics. Name Receptor Blocked Phentolamine Blocks all ⍺ receptors, used in the reversal of soft tissue anesthesia Chlorpromazine (CPZ) ⍺1 receptor Metoprolol & Atenolol β1 receptor (cardioselective) Guanethidine Inhibits release of catecholamines Propranolol β receptors, prolongs lidocaine duration Reserpine Depletes the stored not epinephrine Clonidine & Metyldopa ⍺2 agonist (CNS) which blocks SNS signal. It is NOT potentiating the SNS signal Name Effect INBDE Booster | Booster PrepTM fi fi PHARMACOLOGY 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 23 Cardiovascular Pharmacology The Circulatory System 1 The human circulatory system is a system which consists of a heart (the pump) pumping blood (the uid) through vessels (the tubing) to their target organs. Another way to describe the circulatory system is as follows • Heart = cardiac output (CO) • Vessels = peripheral resistance (PR) • Blood = blood volume (SV) Blood pressure (BP) and cardiac output (CO) can be calculated using the following formulas: BP = CO X PR CO = SV X HR Additional terms include: • Preload – the amount of lling pressure of the heart at the end of diastole • Afterload – the pressure the heart gives to eject the blood during systole • Systole – period of heart contraction and ejection • Diastole – period of heart relaxation and lling Cardiovascular Drugs 2 Antihypertensives Antihypertensives are used in treatment of high blood pressure and have several different 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 2. Hydralazine causes vasodilation by opening K+ channels in cells and allowing easier ow of blood 3. Calcium channel blockers block in ux of calcium in cells to cause vasodilation ‣ Verapamil ‣ Amlodipine ‣ Nifedipine 4. ACE inhibitors inhibits the conversion of angiotensin I ! angiotensin II (potent vasoconstrictor) ‣ “-prils” (suf x) 5. Angiotensin receptors blockers (ARBs) competitive antagonist at angiotensin II receptor ‣ “-sartans” (suf x) Antihypertensive drugs Side Effects Diuretics Xerostomia, nauseas Adrenergic Blocking Agents Xerostomia, depression, sedation, sialadeuosis Lichenoid reaction AngiotensinConverting Enzyme Inhibitors (ACEIs) Lichenoid reaction, burning mouth, loss of taste Calcium Antagonists Gingival hyperplasia, xerostomia Other Vasoldilators Cephalgia, nauseas fl fi fl fi fi fl INBDE Booster | Booster PrepTM fl fi PHARMACOLOGY PHARMACOLOGY 24 INBDE Pro Tip: It’s easier to understand the mechanism of action of ARBs and ACE inhibitors by learning the process of angiotensin II synthesis. Angina Management Anti-angina medications help to treat individuals who have insuf cient oxygen to supply the heart. 1. Propranolol – reduces oxygen demand by 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-arrhythmic An arrhythmia is simply an irregular heart beat. With this being said, anti-arrhythmic drugs work to suppress and treat the irregular or abnormal rhythms of the heart. There are 4 classes of anti-arrhythmic drugs: • Class I - Na+ channel blockers for cardiac muscle only • Class II – Beta-blockers • Class III – Potassium-channel blockers • Class IV – Calcium channel blockers (CCBs) 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 fl fi fi INBDE Booster | Booster PrepTM PHARMACOLOGY 25 Central Nervous System 1 Central Nervous System CNS drugs target receptors in the brain and spinal cord. In the CNS, there is a continuum of excitability from too little stimulation to excessive stimulation. Generally, from low to high excitability, the continuum is: Anesthesia ! sedation ! homeostasis ! activation ! excitation ! seizure 2 CNS Drugs Antipsychotics Antipsychotics, known as neuroleptics in some circles, are used when the brain is too active. This can include conditions such was schizophrenia, and psychosis. They work through two main mechanisms of action: 1. Dopamine D2 receptor blockers – blocking the dopamine receptors of the brain to decrease the effect of dopamine. Haloperidol and chlorpromazine are two examples in this category with a main side effect being tardive dyskinesia. 2. Serotonin 5-HT receptor blockers – inhibition of serotonin receptors all along the central nervous system. These tend to bind long enough to produce their antipsychotic effects, but not too long so that their side effects are kept low. INBDE Pro Tip: Xerostomia is the most likely oral side effect of antipsychotic medications. Antidepressants Antidepressants are used to increase stimulation, an opposite of antipsychotics • This is achieved through increasing the number of monoamines (dopamine, epinephrine, norepinephrine, serotonin, histamine) in the brain • Generally, all antidepressants have anticholinergic side effects, because an excess can activate adrenergic receptors in the ANS Some examples of classes of antidepressants and medications that fall into them include: • SSRI – selective serotonin reuptake inhibitor ‣ Fluoxetine • SNRI – serotonin and NE reuptake inhibitor ‣ Duloxetine • TCA – tricyclic antidepressants ‣ Amitriptyline • MAOI – monoamine oxidase inhibitors ‣ Phenelzine • NDRI – norepinephrine-dopamine reuptake inhibitor ‣ Bupropion General Anesthetics General anesthetics induce a coma in patients during surgery. The onset of anesthesia is inversely proportional to the solubility of the anesthetic in blood. There are 4 stages of general anesthesia: 1. Stage I – analgesia/feeling better 2. Stage II - delirium 3. Stage III – surgical anesthesia 4. Stage IV – medullary paralysis 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 Parkinson’s Disease • Dopamine is made in the brain from LDOPA • 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 fl INBDE Booster | Booster PrepTM fi 3