Pharmacology Lecture PDF

harm  It is defined as the study of substances that interact with living systems through chemical processes by binding to regulatory molecules and activating or inhibiting normal body processes.  is any substance that brings about a change in biologic function through its...

harm  It is defined as the study of substances that interact with living systems through chemical processes by binding to regulatory molecules and activating or inhibiting normal body processes.  is any substance that brings about a change in biologic function through its chemical actions  It is used in: ▪ Prevention ▪ Diagnosis ▪ Mitigation ▪ Treatment/Cure ❑ Drug-Receptor Bonds ▪ Drugs bind to receptors with a variety of chemical bonds. → Strong covalent bonds (which usually result in irreversible action) → Somewhat weaker electrostatic bonds (between a cation and an anion) → Much weaker interactions (hydrogen bond, van der Waals interactions, and hydrophobic bonds)  Functional Modifiers  Replenishers  Diagnostic Agents  Chemotherapeutic Agents Classification of drugs according to use alter or modulate the normal physiologic functions Examples: ✓Analgesic drugs ✓Anti-pyretic drugs ✓Anti-inflammatory drugs ✓Anti-hypertensive drugs Classification of drugs according to use Supplement endogenous substances that are lacking or deficient in the body Examples: ✓Hormones (Insulin) ✓IV Fluids/Electrolyte/ORS ✓Multivitamins Classification of drugs according to use In the case of pernicious anemia which is caused by an autoimmune disease that destroys parietal cells which secretes HCl and intrinsic factor, take Vitamin B12 PPIs, H2 Note: Pernicious anemia may also be caused by Blockers, and Fish Tape worms.  Classification of drugs according to use Agents used to determine the presence or absence of a condition or a disease. Examples: ✓Edrophonium (Tensilon’s Test) ✓Histamine ✓some Radiopharmaceuticals ✓Barium sulfate ✓Dobutamine and Dipyridamole for “Pharmacologic Stress Testing” for CAD and MI. NOTE: Stress Test is an electrocardiographic test of heart function before, during, and after a controlled period of increasingly strenuous exercise. Classification of drugs according to use Agents used to kill or inhibit growth of cells or nucleic acid considered as foreign to the body. Selective toxicity is considered Examples: ✓Antineoplastics ✓Anti-infectives ABSORB… PRACTICE Qs to follow. 10 5 minutes minutes a End 1. Vitamin C 2. Barium sulfate 3. Insulin 4. Ibuprofen 5. Amoxicillin 6. Histamine 7. Paracetamol 8. Ferrous sulfate 9. Antineoplastics 10. Cyanocobalamin 1. Pharmacokinetics 2. Pharmacodynamics  The study of the fate of drugs in the body :  drug disposition= the way in which the body handles drugs - A branch of pharmacology that focuses on the study of the biochemical and physiological effects of drugs and the mechanisms by which they produce such effects.  Target Protein mediated mechanism  Non – target protein mediated mechanism  Colligative mechanism – osmotic pressure  Chemical reaction ▪ NEUTRALIZATION ▪ LOCAL ▪ SYSTEMIC ▪ CHELATION ▪ OTHERS ▪ CN + Sodium thiosulfate  Counterfeit incorporation mechanism SITES OF DRUG ACTION Target protein - biologic site of action of drugs Microtubule - important site of action Drugs that inhibit microtubule synthesis/ spindle protein Griseofulvin Vinca alkaloids Colchicine  ❑ mediates the transmission of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. 1. Transports/Channels 2. Enzymes 3. Carrier Molecules 4. Receptors 20  1. Channels/transport Proteins that take part in transmembrane signaling and regulates ionic composition Voltage-gated Na channel Voltage-gated Ca channel e.g. drugs act on: Na channel- Local anesthetic,CBZ, PHENYTOIN Ca++ channel – Ca++ channel blockers 2. Carrier molecules Na+-K+ ATPase pump - Digitalis glycosides (inhibitor) H+-K+ ATPase pump - PPI Na+-K+-2Cl- cotransport  3. Enzymes protein catalysts Xanthine oxidase - allopurinol Cyclooxygenase - NSAIDs ACE - ACE inhibitors MAO - MAOI Phenelzine Isocarbozaxid Tranylcypromine Acetylcholinesterase - Edrophonium COMT -ENTACAPONE,TOLCAPONE 4. Receptors Functional macromoleular components of cells with specific stereochemical configuration and in which a ligand interacts SPECIFICITY SELECTIVITY Ligand – any chemical that has ability to bind to a receptor 1. Type I Receptor 2. Type II Receptor 3. Type III Receptor 4. Type IV Receptor  - Controls movement of ions - Found in cell membranes - Stimulated in milliseconds GABA receptors control Cl- ions -Benzodiazepines -Barbiturates Nicotinic receptors controls the entry of Na+ inhibited by neuromuscular blocker. Neurotransmitter Ions - G-protein linked receptor / metabotropic GTP – binding signal transducer protein is G-Protein. G-protein modulates production of an intracellular second messenger. location: cell membrane onset: in seconds Examples of Type II receptors alpha receptors Beta receptors Muscarinic receptors ❑ Examples of G-proteins: Gs – stimulates adenylyl cyclase Gi – inhibits adenylyl cyclase Gq – increases IP3, DAG 30 Second messengers cyclic adenosine monophosphate (cAMP) cyclic guanosine monophosphate (cGMP) Inositol triphosphate (IP3) 3. Type III receptors/tyrosine kinases-linked receptors Tyrosine kinase - catalyze phosphorylation of tyrosine residues to modulate a number of biochemical processes  glucokinase glucose =====➔glucose-6-phosphate location: nucleus onset: hours  ❑ Examples: Imatinib-gastrointestinal stromal tumors (GIST) Gefitinib-epidermal growth factor receptor Erythropoietin receptor Receptor for Insulin – utilization of glucose 34 4. Type IV receptor/gene transcription-linked receptors Central dogma -replication (DNA copied into complimentary DNA) -transcription (DNA template is copied to RNA) -translation (RNA synthesize protein) -location: nucleus/cytosol (cytoplasm) -onset: hours  Drugs that act on Type IV receptors ▪ Corticosteroids ▪ Mineralocorticoids ▪ Sex steroids ▪ Vitamin D ▪ Thyroid hormone  PHARMACODYNAM ICS -MECHANISMS OF ACTIION Target Protein-M ediated Non-Target Protein-M ediated Regulatory Protein Structural Protein Colligative mechanism o Osmotic pressure C emical reaction Transports / Carrier Micro,tubule Enzymes Receptors o NEUTRALIZATION Channels Molecules Drugs that inhibit: o CHELATION o Colchicine Co,unterfeit incorporation o Griseofulvin mechanism o Vinca Alkaloids Types AKA Location Onset o Ex. Antimetabolites I !onotropic/ Gell membrane Millisec Ligand-gated II G-Profein-Linked I Cell membrane Sec ➔ KISS KICK Mefabotropic a-1Gq M-1G:q Ill Tyrosinekin ase- Cell membrane Hour a-2Gi M-2Gi Linked Nucleus ~1Gs M-3Gq IV Gene- ranscripoon Nucleus Hour ~2 Gs Activate I Linked C~oplasm Go.o Set"ng. ABSORB… PRACTICE Qs to follow. 10 5 minutes minutes a End Voltage-gated ion channels serve as site of actions for drugs such as I. Diltiazem and Nifedipine II.Lidocaine and Procaine III.Captopril and Losartan a.I only b.I and II c.III only d.I and III e.I, II, and III Drugs with mechanism of action that involves Tubulin-binding leading to loss of function of the structural protien include a.Cyclosporine b.Neostigmine c.Colchicine d.Glibenclamide e.Metformin What type of protien is primarily targeted by Digitalis glycosides when they exert their effect on the heart? a.Receptors b.Ion channels c.Enzymes d.Transporters e.Structural protiens Cyclic Adenosine Monophophate (cAMP) is generated as a secondary messenger by the action of the enzyme Adenylyl Cyclase. The substrate for the synthesis of cAMP is a.AMD b.ADP c.ATP d.GTP e.Adenosine Which of the following features cahracterize nicotinic, GABA-A, and Glutamate receptors? a.They control the movements of ions and out of the cell b.Their action is mediated by secondary messengers c.They all have excitatory effect on the cell membrane d.They are located on the cytoplasm Stimulation of Beta-adrenoceptor, a G- protien-linked receptor involves a generation of a secondary messenger known as a.IP3 b.cGTP c.DAG d.cAMP e.Calcium ions Pharmacodynamics is A. The science that examines the interrelationship of the physicochemical properties of the drug and the route of administration on the rate and extent of systemic circulation B. The science of the kinetics of drug absorption, distribution and elimination C. The part of pharmacology, which deals with what a drug does to the body D. The science, which deals with the physicochemical properties of the drug that allow it to be designed into dosage forms E. A and B Lanoxin acts on which of the following. A.Na/K ATPase pump B.Na/H ATPase pump C.H/K ATPase pump D.Na/Ca ATPase pump E.None of the above  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after every topic.. 47 Idiosyncrasy - Unusual drug Response caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions. Hyporeactivity - the intensity of effect of a given dose of drug is diminished Hyperreactivity- the intensity of effect of a given dose of drug is increased in comparison to the effect seen in most individuals. Hypersensitivity -refers to allergic or other immunologic responses to drugs TYPE OTHER NAMES I Allergy (Immediate) II Cytotoxic, Antibody dependent III Immune Complex Disease IV Delayed-Type Hypersensitivity V Autoimmune Disease Tolerance - it refers to a decreased responsiveness to the drug a consequence of continued drug administration Tachyphylaxis- This refers to rapidly acting tolerance Responsiveness diminishes rapidly after administration of a drug Alterations in Number or Function of Receptors Down-regulation of receptors ❑ it is caused by continuous prolonged exposure of receptors to drugs that disrupt the homeostatic equilibrium and result in altered levels of the receptors. Desensitization ❑ It is the result of down-regulation. ❑ The target cells become desensitized, and the effect of subsequent exposure to the same concentration of the drug is reduced. Classification of drugs according to receptor interaction 1. AGONIST ❑ Able to bind (with affinity) ❑ With intrinsic activity 1.1 Full agonist ❑ Full response ❑ Stimulate all different variant of receptors even the new receptors K ey· Receptor.....,. Receptor ' - (inactive)...,_ (active) Full Agonist...... (high affinity) Effector.....,.. Effector (inactive) ~ (active) 1.2 Partial agonist ❑ Less than the expected response K ey: Receptor (inactive). Receptor ~ (active) Partial Q Agonist...... Effector Effector (high affinity) }II (inactive) ~ (active) 2. ANTAGONIST  With affinity but no intrinsic activity  It prevents the binding of agonist Antagonist Receptor Antagonist-Receptor DENIED! Complex  Receptor (inactive).. Receptor.....- (active) com pet it iv e Antagonist..._ Effector (inactive). Effector (high affinity) ~ (active) PHARMACOLOGIC ANTAGONIST ❑ utilizes the same receptor ❑ produce an effect opposite of agonist by binding to the same receptor ❑ Beta blocker and Beta agonist (Propranolol) (epinephrine) PHYSIOLOGIC ANTAGONIST - occurs when the drugs act independently at different receptor sites, often yielding opposing actions. e.g. HISTAMINE + EPINEPHRINE CHEMICAL ANTAGONIST ❑ no receptor is involved ❑ occurs when two drugs bind with each other to form an inactive compound. Protamine SO4 + Heparin SO4 → forms a complex devoid of action Protamine- (+) charged at physiologic pH Heparin – (-) charged at physiologic pH Chelating agents Deferoxamine – Iron (Fe) It depends on whether or not they reversibly compete with agonists for binding to receptors Competitive antagonist- Effects of Antagonist can be overcome/reversed by increasing the concentration of agonist  NO RESPONSE NON-COMPETITIVE ANTAGONISM it is also known as irreversible antagonism 1. ADDITION ❑ A drug effect that is equal in the magnitude to the sum of the individual effects of two drugs. ❑ Two different drugs with the same effect are given together. ❑1 +1=2 ❑ Alcohol + Sedative hypnotic drug 2. SYNERGISM ❑ The effect of two drugs is greater in magnitude than the sum of the individual effects of the two drugs. ❑ Two drugs with same effect are given together. ❑1 +1=3 ❑ Sulfamethoxazole + Trimethoprim 3. POTENTIATION ❑ Occurs when one drug, lacking an effect of its own, increases the effect of another drug that is active. ❑1 + 0 = 2 ❑ Tyramine-containing Foods + MAOI ABSORB… PRACTICE Qs to follow. 10 5 minutes minutes a End 1.It is the drug with affinity and intrinsic activity. 2. This drug is a physiologic antagonist of Epinephrine 3. Chelating agent for Iron poisoning 4. Agonist which stimulates all different variant of receptors even the new receptors 5. Mathematical equation for potentiation  A. Additive B. Chemical Antagonism C. Pharmacologic Antagonism D. Physiologic Antagonism E. Potentiation 1.Amoxicillin + Clavulanic Acid 2.Heparin + Protamine Sulfate 3.Ethanol + Antihistamines 4.Levodopa + Carbidopa 5.Histamine + Epinephrine  PHARMACODYNAM ICS -MECHANISMS OF ACTIION Target Protein-M ediated Non-Target Protein-M ediated Regulatory Protein Structural Protein Colligative mechanism o Osmotic pressure C emical reaction Transports / Carrier Micro,tubule Enzymes Receptors o NEUTRALIZATION Channels Molecules Drugs that inhibit: o CHELATION o Colchicine Co,unterfeit incorporation o Griseofulvin mechanism o Vinca Alkaloids Types AKA Location Onset o Ex. Antimetabolites I !onotropic/ Gell membrane Millisec Ligand-gated II G-Profein-Linked I Cell membrane Sec ➔ KISS KICK Mefabotropic a-1Gq M-1G:q Ill Tyrosinekin ase- Cell membrane Hour a-2Gi M-2Gi Linked Nucleus ~1Gs M-3Gq IV Gene- ranscripoon Nucleus Hour ~2 Gs Activate I Linked C~oplasm Go.o Set"ng.  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after every topic.. 81  AUTACOIDS  a.k.a. “Local hormones”  endogenous substances with biological activity.  not released or stored in glands.  not circulated in blood.  are formed at the site of action.  produce localized action.  Classification of Autacoids 1. Biologically active amines ✓Histamine ✓Serotonin  Classification of Autacoids 2. Lipid derived autacoids ( Eicosanoids) ✓Prostaglandins ✓Leukotrienes ✓Thromboxanes 3. Ergot Alkaloids ✓a small molecule produced by decarboxylation of the amino acid histidine ✓ itis catalyzed by the enzyme L-histidine decarboxylase in a reaction that requires pyridoxal phosphate. o Histamine is found in many tissues, including the brain. o it is stored and found in the highest amounts in mast cells and basophils.  Two processes by which HISTAMINE IS RELEASED 1. Energy- and Ca2+-dependent degranulation reaction. 2. Energy- and Ca2+ - independent release (displacement). Storage & Release: 1.Energy- and Ca2+-dependent degranulation reaction. Immunologic Release o Mast cells, if sensitized by surface IgE antibodies, degranulate when exposed to specific antigen. o Histamine released by this mechanism is a mediator of in immediate (type I) allergic reactions. o This type of release requires energy and calcium.. 2. Energy- and Ca2+ - independent release (displacement). Chemical & Mechanical Release o Occurs following chemical or mechanical injury to mast cells. o Displacement is induced by drugs such morphine, tubocurarine, guanethidine, and amine antibiotics. o This type of release does not require energy and is not associated with mast cell injury or degranulation.  Histamine ▪ R-alpha methylhistamine is an H3-specific agonist.  Betazole (histalog) ▪ tenfold greater activity at H2-receptors than at H1- receptors  Impromidine ▪ investigational agent; its ratio of H2:H1 activity is about 10,000 o Flushing o Hypotension o Tachycardia o Headache o Wheals o Bronchoconstriction o Gastrointestinal upset o Aka : ANTIHISTAMINES o competitive inhibitors at the H1- receptor. 1. 1st Generation Antihistamines a. Ethanolamines: Carbonoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Clemastine b. Ethylaminediamines: Pyrilamine, Tripelennamine c. Piperazine: Hydroxyzine, Cyclizine, Meclizine d. Alkylamines: BACphen Brompheniramine, Chlorpheniramine e. Phenothiazines: Promethazine f. Miscellaneous: Cyproheptadine ❑Piperidines ❑Miscellaneous agents o Terfenadine (Seldane) o metabolized to the active metabolite fexofenadine by a specific cytochrome P- 450. o Loratadine (Claritin). ✓ Poor CNS penetration. o Cetirizine (Zyrtec) ✓ not associated with cardiac abnormalities. ✓ has poor penetration into the CNS. ✓ less sedating; it is ineffective for motion sickness or antiemesis. A. well absorbed after oral administration. o Normal effects seen in 30 minutes (with maximal effects at 1-2 hours) o The duration of action is : ❑ 1ST generation compounds: 3-6 hours ❑ 2ND generation compounds: 3-24 hours o Treatment of allergic rhinitis and conjunctivitis. ✓ treat the common cold based on their anticholinergic properties o Treatment of urticaria and atopic dermatitis, including hives o Sedatives ✓Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids. o Prevention of motion sickness o Appetite suppressants  verse (significantly reduced with second- generation agents) o sedation (synergistic w/ alcohol, other depressants, dizziness, and loss of appetite. CAUTION: drivers and machine operators o gastrointestinal upset, nausea, constipation and diarrhea. o anticholinergic effects (dry mouth, blurred vision, and urine retention). (1) Histamine (H2)-receptor antagonists include ✓ Cimetidine (Tagamet) ✓ Ranitidine (Zantac) ✓ Famotidine (Pepcid AC) ✓ Nizatidine (Axid) (2) competitive antagonists at the H2- receptor, which predominates in the gastric parietal cell. USE/S:  treatment of gastrointestinal disorders: √ heartburn and acid-induced indigestion √ promote the healing of gastric and duodenal ulcers √ hypersecretory states such as Zollinger-Ellison syndrome Cimetidine, ranitidine, and famotidine ✓ undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. ✓ Nizatidine has little first-pass metabolism and a bioavailability of almost 100%. o inhibits binding of dihydrotestosterone to androgen receptors o (anti-ANDROGEN) o men= gynecomastia or impotence o inhibits metabolism of estradiol, and increases serum prolactin levels. o women= galactorrhea Cimetidine o Potent ENZYME INHIBITOR o interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 ✓cromolyn (Intal) ✓nedocromil sodium (Tilade) 1. poorly absorbed salts; ROUTE of admin: inhalation 2. They inhibit the release of histamine and other autacoids from the mast cell. 3. Prophylactic agents in asthma  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 2. Prepare a pen and a notepad. Most details are in the handout, if in case there are additional notes, 5 the lecturer will alert you to jot down the said minutes notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after End every topic. 112 1.Amino acid precursor of histamine 2. Mechanism of histamine release which mediates type 1 (allergic) reactions 3. Onset of action of antihistamines 4. Active metabolite ofTerfenadine 5. H2 blocker with almost 100% bioavailability A 1~ Clema.stine A. Ehanolamines: G 2. Fexofenadine 1 8. Phe,noth.iaz·ines 1 B 3. Prom,eth.aziine 1 C. Alkyiami:nes E D ,P~periaz.ine 4. Pyri amine 1 H.5 Nizatidin,e E. Ethyle,ne,d.iamines B ,6 Prom1ethazine, 1 1 F. 'Meth·y,tp1p,er1d1n,es C G. Pii·peri d'ines 7. Chlorpheniramine 1 1 A ,8,. D,oxylamine, H. N 0 ne 1 1 1 F 91.Cyproheptadine, D 1.0. Meclizine  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 2. Prepare a pen and a notepad. Most details are in the handout, if in case there are additional notes, 8 the lecturer will alert you to jot down the said minutes notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after End every topic. 115 Serotonin = 5-HT, [5-hydroxytryptamine] An indoleamine = has an indole ring structure This structure is also found in “hallucinogenic” or psychedelic drugs 1. Biosynthesis and distribution a. from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid  tryptophan 5-HTP hydroxylase decarboxylase tryptophan 5-HTP 5-HT Tissue Distribution  enterochromaffin cells of the gastrointestinal tract (90% )  Platelets -10%  MAO SEROTONIN 5-hydroxyindoleacetaldehyde aldehyde dehydrogenase hydroxyindoleacetic acid (5-HIAA) Both are found in neurons and astroglia  Outside the central nervous system: ▪ MAO-A is also found in the liver, gastrointestinal tract, and placenta. ▪ MAO-B is mostly found in blood platelets  5-HT1A 5-HT1 B 5-HT1 5-HT1 D 5-HT2A 5 - HT2 5-HT2B 5-HT2C 5-HT4 5 - HT7 1. Buspirone (Buspar)  specific 5HT1a- receptor  useful for the management of anxiety disorders ▪ effective nonbenzodiazepine anxiolytic  Triptans are a family of tryptamine-based drugs used in migraines and cluster headaches.  Sumatriptan (Imitrex]  rizatriptan (Maxalt),  Naratriptan (Amerge),  Zolmitriptan (Zomig), 3. Trazodone (Desyrel)  metabolized to m- chlorophenylpiperazine, ▪ an activator of 5HT1B and 5HT2 receptors  Anti- depressant agent 4. Cisapride (Propulsid)  gastroprokinetic agent ▪ a drug that increases motility in the upper gastrointestinal tract  a newer 5-HT4 partial agonist  used for irritable bowel syndrome with constipation 1. Fluoxetine (Prozac).  antidepressant  MOA: decreased serotonin uptake into neurons.  SSRI (fluoxetine = Prozac) 2. Dexfenfluramine (Redux)  ANORECTIC DRUG  causes serotonin release and reduces serotonin reuptake into nerve terminals.  for the treatment of obesity.  Adverse effect: pulmonary hypertension 3. Sibutramine (Reductil)  ANORECTIC DRUG no longer available in the U.S. people taking sibutramine had an increased risk of cardiovascular events such as heart attack and stroke. Cyproheptadine (Periactin) “Setron” - Ondansetron, Granisetron (Kytril) Ketanserin Ketanserin (Sufrexal) Clozapine (Clozaril) Risperidone (Risperdal)  blocks both 5HT1- and 5HT2-receptors  is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.  Used for gastric dumping  2. Ondansetron , Granisetron (Kytril)  5HT3-receptor antagonists  highly effective in treating the nausea and vomiting associated with chemotherapy and radiation therapy. ▪ intravenously or orally 4. Ketanserin (Sufrexal)  specific 5HT2-receptor antagonist  investigational drug  found to lower blood pressure in experimentally induced hypertension. 5. Antipsychotic Clozapine (Clozaril) ▪ specific 5HT2A- and 5HT2C – and dopamine receptor antagonist ▪ An atypical antipsychotic ▪ agranulocytosis. Risperidone (Risperdal) ▪ antagonist at 5HT2A-, 5HT2C-, and dopamine (D2)-receptors ▪ an atypical antipsychotic drug which is mainly used to treat schizophrenia ABSORB… PRACTICE Qs to follow. 10 5 minutes minutes a End MAO-A is the amine oxidase primarily responsible for the metabolism of Norepinephrine, Serotonin, and tyramine, while MAO-B is the specific for the metabolism of Dopamine. Which of the following agents is a selective reversible MAO-A inhibitor whose advantage is a lesser risk of causing hypertensive crisis with tyramine foods? A. Selegiline B. Nefazodone C. Moclobemide D. Trazodone E. Imipramine Which of the following drugs when given to patients will necessitate weekly WBC monitoring for the first 6 months of therapy and every 3 weeks thereafter due to its propensity to cause agranulocytosis? A. thioridazine B.Chlopromazine C. Loxapine D. Clozapine E. Molindone What is the primary mechanism of action of the drug Ondansetron and Granisetron? a.Partiaal agonist effect at the 5-HT1A receptor b.Antagonist effect at the 5-HT1B receptor c.Full agonist effect at the 5-HT2A receptor d.Antagonist effect at the 5-HT3 receptor e.Partial agonist effect at the 5-HT4 receptor What is the clinical use of the drugs Ondansetron and Granisetron? a.Appetite suppressants b.Anti-emetic c.Treatment of acute migraine attack d.Migraine prophylaxis e.Motility enhancing agent What is the clinical use of the drugs that primarily stimulate the 5-HT1B and 5- HT1D receptors? a.Appetite suppressants b.Anti-emetic c.Treatment of acute migraine attack d.Migraine prophylaxis e.Motility enhancing agent What is Rasageline? A. A selective MAO-A inhibitor B. A selective MAO-B inhibitor C A COMT inhibitor D. A Dopamine-3 receptor Agonist E. A Dopamine-2 receptor agonist EICOSANOIDS: Prostaglandin, Prostacyclin, Thromboxane,Leukotrienes 146 Eicosanoids  large group of autacoids with potent effects on virtually every tissue in the body.  derived from the metabolism of 20-carbon, unsaturated fatty acids (arachidonic acids).  released locally and act as a local hormone. distributed widely in the body. 147 Biosynthesis of Eicosanoids 148 2. Eicosanoids a. Prostaglandin H synthase pathway  a.k.a. “Cyclooxygenase” or COX  It produces thromboxane, the primary prostaglandins (PGE, PGF, or PGD), and prostacyclin (PGI2). 149 Clinical Pharmacology of Prostaglandin Female Reproductive System a. Abortion: Dinoprostone (PGE2) a synthetic preparation administered vaginally for oxytocic use. Carboprost Tromethamine (15-methyl- PGF2a) administered as a single 2.5 mg intra-amniotic injection. Antiprogestins (Mifepristone) combined with an oral oxytocic prostaglandin (Misoprostol) to produce early abortion. 150 f 1u ni ti flui 2. Male Reproductive System a. Erectile Dysfunction: Alprostadil (PGE1) 3. Cardiovascular System a. Pulmonary Hypertension: Prostacyclin b. Peripheral Vascular Disease: PGE & PGI2 c. Patent Ductus Arteriosus: Alprostadil (PGE1) 152 4. Blood a. Platelet Aggregation:TXA2 6. Gastrointestinal System Misoprostol (PGE1)-available in Europe & the USA for ulcer treatment. 153 8. Glaucoma: Latanoprost: a stable long acting PGF2a Bimatoprost, Travaprost,Unoprostone 154  NSAIDS  are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid by the enzyme arachidonate 5-lipoxygenase  One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the bronchioles; their overproduction is a major cause of inflammation in asthma and allergic rhinitis  Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes  (Zafirlukast, Montelukast)  5-Lipoxygenase Inhibitor (Zileuton)  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 2. Prepare a pen and a notepad. Most details are in the handout, if in case there are additional notes, 10 the lecturer will alert you to jot down the said minutes notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after End every topic. 158 o Collection of nerves and ganglia scattered throughout the brain o Consists of 12 pairs of cranial nerves, 31 pairs of spinal nerves and their branches to the entire body. I. Olfactory - OH -sensory II. Optic - OH - sensory III. Occulomotor - OH -motor IV. Trochlear - To - motor V. Trigeminal - Touch -mixed VI. Abducens - And - motor VII. Facial - Feel -mixed VIII. Vestibulocochlear - Virgin -sensory IX. Glossopharyngeal - Girl’s - mixed X. Vagus - Vagina - mixed XI. Accessory/Spinal - Ah! So -motor XII. Hypoglossal - Heavenly -motor 162 1. Enteric 2. Somatic 3. Autonomic ✓ Highly organized collection of neurons located in the walls of the GIT ✓ Innervated by Myenteric Plexus and the submucous plexus ▪ Largely concerned with consciously controlled functions such as: ▪movement ▪Posture In short- vOluntary  Largely Autonomous (Independent)  its activities are not under direct conscious control.  concerned primarily with visceral functions ▪ Cardiac Output ▪ Blood flow to various organs ▪ Digestion  In short-INvoluntary Preganglionic Nerve Fiber -terminates and synapses in an autonomic ganglion Postganglionic nerve fiber- originates in a ganglion and terminates in smooth cardiac muscle or a gland. S,  SYMPATHETIC NS PARASYMPATHETIC NS ORIGIN  thoraco-lumbar  Cranio (III,VII,IX,X)-sacral (III,IV) Neurotransmitter Preganglionic fiber  Acetylcholine  Acetylcholine Postganglionic fiber  Norepinephrine  Acetylcholine Preganglionic fiber  Short  Long  Long  Short Postganglionic fiber Receptors  Alpha, beta  Muscarinic, nicotinic 5 minutes End 1. Division of PNS which is responsible for controlled functions 2. Origin of the parasympathetic nervous system 3. Primary neurotransmitter of the postganglionic nerve fiber of SANS 4. Receptors of the parasympathetic nervous system 5. 6. Submucous plexus is also known as? 7. How many pairs of spinal nerves does PNS have? 8. AKA efferent neurons. 9. Other name of parasympathetic NS. 10. Other name of Norepinephrine.  Column A Column B 1. Pre-ganglionic NT – Ach A. Parasympathetic NS 2. Post-ganglionic NT – Ach B. Sympathetic NS 3. Pre-ganglionic fiber – Short C. Both 4. Post-ganglionic fiber – Long 5. Mydriasis 6. Bradycardia 7. Hypotension 8. Ejaculation 9. Autonomic Nervous System 10. Diarrhea 1. Sympathetic Nervous System  a.k.a.”ADRENERGIC system  NT- NOREPINEPHRINE and EPINEPHRINE  “FIGHT or FLIGHT “response 1 Synthesis 2 Storage 3 Release 4 Receptor binding 5 Removal of the neurotransmitter from the synaptic gap Synthesis of epinephrine  m,rosine ·. ·. t)'l'oslne Jhydro,.ylose HO ·· ·· COOH KO % r DOPA NHz DOPA Jdecarbo1yluse HO NH 2 dopaimine dopomine JOH.l· hydro1ylast IMO.· I HO NH 2 nma,d renaline phenylet hon10,!onune OM N met~·ylfi r,ande r1 ase HQ ·.. HO.···. 176 1. Diffusion 2. Metabolism 3. Reuptake 2. Metabolism Enzymes that inactivate NorEpinephrine **MAO (Monoamine oxidase) **COMT (Catechol-O-methyl transferase) Metabolites ▪ Are excreted in the urine ▪ Eg. Vanillyl mandelic acid (VMA), metanephrine, normetanephrine 3. Reuptake  recaptured by an uptake system ▪ Pulls the NE back to the neuron ▪ Involves Na+/K+ ATPase  process example site action Action Local Nerve axons Block sodium potential anesthetics, channels; propagation tetrodotoxin,1 block saxitoxin2 conduction Transmitter a-Methyltyrosine Adrenergic Blocks synthesis (metyrosine)*** nerve synthesis terminals and adrenal medulla: cytoplasm Synthesis of epinephrine  process example site action Transmitter Reserpine Adrenergic Prevents storage terminals: storage, vesicles Depletes Synthesis of epinephrine process example site action Transmitter Tyramine, Adrenergic Promote release amphetamine nerve transmitter terminals Release Bretylium, Adrenergic Inhibit Guanetidine nerve release terminals Synthesis of epinephrine process example site action Transmitter Cocaine, tricyclic Adrenergic Inhibit uptake antidepressants nerve reuptake; after terminals increase release transmitter effect on postsynaptic Receptors 6-Hydroxy- Adrenergic Destroys the dopamine nerve terminals terminals Synthesis of epinephrine  stimulate the sympathetic NS  adrenergic agonist, sympathomimetic, adrenomimetic  they mimic NE and Epinephrine  act on one or more receptor sites  Direct – acting  Indirect – acting  Mixed – acting 1. Direct-acting ▪ directly stimulate the adrenergic receptors  Rereptor subtyp e selectivity of d1r-ect sym pathon, imetics 1 a1. a1 ~1 ~2 I I I I I I Ep:ineplhri ne Dobuta1mine Pheny:le.h ine IFeno e,101 albut 1 1101 · 1lonidi1e ·rerbiu.a.line Bri 110 ~ dine tl1m.ete,1ol Naplhazoli:11e For:1111otero I 1 Oxymetazo :ine Xyl:omet rzo ,ine  stimulate the release of NE from the terminal nerve ending - amphetamine  both - ephedrine SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Alpha-1 Blood vessels Vasoconstriction Eyes Mydriasis (ciliary muscle constriction) Sphincter Constriction – urinary retention Penis/seminal vesicles Ejaculation Agonists Antagonists Nonselective Dipivefrin Irreversible - Phenoxybenzamine - prodrug of EPI; for glaucoma Reversible - Phentolamine, Tolazoline Selective Phenylphrine “-ZOSINS” Phenylpropranolamine Xylometazoline Oxymetazoline Midodrine Methoxamine SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Alpha-2 Neurons (CNS) Inhibition of NE release Platelets Aggregation Fat cells Inhibition of Lipolysis Agonists Antagonists Nonselective Dipivefrin Irreversible - Phenoxybenzamine - prodrug of EPI; for glaucoma Reversible - Phentolamine, Tolazoline Selective Clonidine Yohimbine Methyldopa Guanfacine Guanabenz SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Beta-1 Heart Increased HR (chronotropic); Inc. force of contraction (Inotropic); Inc. conduction velocity (dromotropic) Kidneys Increase renin secretion Agonists Antagonists Nonselective Isoproterenol All “-OLOL” not starting with BEAM Selective Dobutamine “-OLOL” BEAM SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Beta-2 Lungs Bronchodilation Uterus Tocolytic effect Bladder Relaxation – urinary retention Liver Increase glycogenolysis Agonists Antagonists Nonselective Isoproterenol All “-OLOL” not starting with BEAM Selective “-terol” NONE SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Beta-3 Fat cells Increase Lipolysis SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Dopa-1 Renal Blood Vessels Vasodilation Agonists Antagonists Nonselective Dopamine Selective Fenoldopam SYMPATHETIC NERVOUS SYSTEM RECEPTORS LOCATION EFFECTS Dopa-2 Neurons (CNS) Increase Dopamine release Agonists Antagonists Nonselective Dopamine Selective Bromocriptine Antipsychotics Tyramine  normal by-product of tyrosine metabolism  metabolized by MAO  inactive when taken orally because of a very high first-pass effect  Beer  Broad beans, fava beans  Cheese, natural or aged  Chicken liver  Chocolate  Sausage, fermented (eg, salami, pepperoni, summer sausage)  Smoked or pickled fish (eg, pickled herring)  Snails, red wine, Yeast Tyramine +MAO inhibitors= Hypertensive crisis  Norepinephrine levels  AO. lN lBITORS.I 0.---------- fopula -- e s 0 C ' e s An-·hyp OTC Cold '1eds 'ine r::>ickt.... d -ooas Atomoxetine Reboxetine Duloxetine Milnacipran Sibutramine Cocaine 1. air erecti,on A. Dopa ·ne 2. ncrease lipolys1s - B e a1 3. Bronc odi a ion C. Beta2 4. -ipolysis ac i:vat·:on -. Alp a 5. Ejaculation. A 1pha2 6 Pia ele aggrega ion. B,e a 3 7. Vasocons riction 8. ena blood vesse I dilatio 9. In i bit·on of - re ,ease 10. P os'tive ino ropic 11. ultipte act·on in C S 12. lnhibttion of I polysis 13. Renin secre ·:on 14. C·o. stric e·d sp : i cter 15 Tocolyt·c effec  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 2. Prepare a pen and a notepad. Most details are in the handout, if in case there are additional notes, 5 the lecturer will alert you to jot down the said minutes notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow after End every topic. 207 Neurotransmitter – acetylcholine ( Ach ) Cholinergic receptor – receptor sites on effectors that respond to acetylcholine Cholinoceptors: - muscaranic - nicotinic PARASYMPATHETIC NERVOUS SYSTEM RECEPTOR LOCATION EFFECT M-1 Upper GIT Acid secretion Cholinergic nerves Stimulation M-2 Heart (-) inotropic, chronotropic, dromotropic Cholinergic nerves Stimulation M-3 Exocrine Glands (salivary, Increase secretions (salivation, sweat, lacrimal, bronchial, lacrimation, etc.) intestinal, etc) Bronchoconstriction Lungs Increase motility~diarrhea Eyes Miosis PARASYMPATHETIC NERVOUS SYSTEM RECEPTOR LOCATION EFFECT Nm Neuromuscular Muscle contraction endplate Nn CNS ganglia CNS Stimulation  H e-nn i cho Ii i li.li fTI S Clh,--o l i _ e N er ve t e ir,m liln a l Vesam iool ,Ga. l ci u m c a el H ete-ro- r ecepto r Ca. Pre-sy ptr,c.-eoe-p,1 r.S- Botul!i t ox in A.ce lyl dh..-o l i es1! e r a.s,e ACh C>-thle r recep t ors C hol~noceo-t or:s Synthesis and Release of Acetylcholine 1. synthesis of acetylcholine - transport of choline inhibited by hemicholinium 2. uptake into storage vesicles - protected from degradation - BLOCKED by VESAMICOL 3. release of neurotransmitter - botulinum toxin- blocks release - spider venom- promotes release 4. binding to receptor 5. degradation by acetylcholinesterase Ach→ acetate + choline PARASYMPATHETIC NERVOUS SYSTEM 1. Synthesis (-) Hemicholinium 2. Storage (-) Vesamicol 3. Release (-) Botox 4. Receptor binding 5. Removal 1. Diffusion 2. Metabolism 3. Reuptake 1. Cholinergic – parasympathomimetic 2. Anticholinergic – parasympatholytic ▪ drugs that stimulate the parasympathetic NS ▪ mimic Acetylcholine ▪ selective cholinergic drugs for the muscarinic receptors that do not affect the nicotinic ▪ SYNONYMS: cholinergic agonist, cholinergic stimulant, cholinomimetic D- IARRHEA U- RINATION M- IOSIS B- RADYCARDIA B-RONCHOCONSTRICTION E- MESIS/ EXCITATION L- ACRIMATION S-ALIVATION/ SWEATING  Two classes: 1. Direct acting Cholinergic agonist 2. Indirect acting Cholinergic agonist  PARASYMPATHETIC AGONISTS DIRECT-ACTING INDIRECT-ACTING CHOLINE ESTERS ALKALOIDS REVERSIBLE IRREVERSIBLE ALCOHOL CARBAMATES ORGANOPHOSPHATES 1. Acetylcholine 1. Pilocarpine 2. Bethanechol 2. Muscarine 3. Methacholine 3. Nicotine 4. Carbachol EDROPHONIUM ‘-tigmines” ‘-phates 1. Esters of Choline/choline esters Acetylcholine Betanechol Methacholine chloride Carbachol chloride 2. Alkaloids Pilocarpine Nicotine Muscarine Two classes: 1.Reversible edrophonium Alcohol – Carbamates – Physostigmine and Neostigmine 2.Irreversible – Organophosphates: Isofluorophate and echothiophate Reversible cholinesterase inhibitors Intermediate acting cholinomimetic (CARBAMATES) Drugs for Myasthenia gravis Neostigmine Pyridostigmine Ambenonium Drugs for Glaucoma Demecarium Physostigmine 1. Edrophonium (Tensilon)  - diagnosis of MG  (Tensilon test- inc. strength, dec. ptosis)  *Spider venom- promotes release of acetylcholine Using Tensilon test Myasthenia gravis - underdose - progression of the disease Cholinergic crisis - overdose - fasciculation - fatigue Muscle weakness + edrophonium= improve (myasthenia gravis) = worsen ( cholinergic crisis) FOR ALZEIMER’S DISEASE  Donepezil (Aricept)  Tacrine (Cognex)  Rivastigmine (Exelon)  Galantamine (Reminyl) INSECTICIDES  MALATHION  PARATHION Cevimeline (Evoxac) ▪ for treatment of dry mouth associated with SJOGREN’S syndrome Smoking déterrent ▪ Varenicline, Nicotine Soman, sarin, tabun ▪ Nerve gas, used exclusively in warfare & terrorism PARASYMPATHETIC NERVOUS SYSTEM CHOLINOCEPTOR ANTAGONIST MUSCARINIC Antagonist NICOTINIC Antagonist Red as a beet Hot as hell Dry as a bone Blind as bat Ganglion Neuromuscular Mad as hatter blockers junction blockers CHOLINOCEPTOR ANTAGONIST Synonyms: Cholinergic antagonist Cholinergic blocker Anticholinergic Parasympatholytic Antimuscarinic/antinicotinic  Red as a beet  Hot as hell  Dry as a bone  Blind as bat  Mad as hatter  Muscarinic antagonist acting as INVERSE agonists Atropine Pirenzepine Trihexyphenidyl Ipratropium Glycopyrrolate Scopolamine (methyl derivative)  Cholinergic poisoning Antimuscarinic Cholinesterase therapy regenator Pralidoxime (PAM) Atropine Diacetylmonoxime (DAM) Obidoxime According to the nicotinic receptors they block: 1. Ganglionic blockers inhibit NN 2. Neuromuscular blockers inhibit NM 1. Tetraethylammonium (TEA) 2. Hexamethonium ("C6") 3. Decamethonium, the "C10" analog of hexamethonium  PHARMACOLOGY REVIEW Starting in House Rules: 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 236 4. Question and answer portion will follow after every topic.  SEIZURES characterized by an excessive, hypersynchronous discharge of cortical neuron activity, which can be measured by the ELECTROENCEPHALOGRAM (EEG). CONVULSIONS violent, involuntary contractions of the voluntary muscles. * A patient may have epilepsy or a seizure disorder without convulsions. EPILEPSY a chronic seizure disorder, or group of disorders, characterized by seizures that usually recur unpredictably in the absence of a consistent provoking factor. Phases of seizure Prodrome Ictal Post-ictal INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES I. PARTIAL SEIZURES most common seizure type occurring in approximately 80% of epileptic patients. clinical and EEG changes indicate initial activation of a system of neurons limited to part of one cerebral hemisphere that may spread to other or all brain areas. CLASSIFICATION OF PARTIAL SEIZURES SIMPLE PARTIAL SEIZURES generally do not cause loss of consciousness. SIGNS AND SYMPTOMS: primarily motor, sensory, somatosensory, autonomic or behavioral. CLASSIFICATION OF PARTIAL SEIZURES COMPLEX PARTIAL SEIZURES accompanied by impaired consciousness; however in some cases, the impairment precedes or follows the seizure. COMPLEX PARTIAL SEIZURES MANIFESTATIONS Purposeless behavior is common. The affected person may have a glassy stare, may wander about aimlessly, and may speak unintelligibly. Psychomotor (temporal lobe) epilepsy may lead to aggressive behavior (e.g., outbursts of rage or violence). II. GENERALIZED SEIZURES diffuse, affecting both cerebral hemispheres. clinical and EEG changes indicate initial involvement of both hemispheres. GENERALIZED SEIZURES ABSENCE (Petit mal) SEIZURES present as alterations of consciousness (absences) lasting 10-30 seconds. Staring (with occasional eye blinking) and loss or reduction in postural tone is typical. Enuresis  GENERALIZED SEIZURES 2. MYOCLONIC SEIZURES (bilateral massive epileptic myoclonus) present as involuntary jerking of the facial, limb, or trunk muscles, possibly in rhythmic manner. GENERALIZED SEIZURES 3. CLONIC SEIZURES characterized by sustained muscle contractions alternating with relaxation 4. TONIC SEIZURES involve sustained tonic muscle extension (stiffening). GENERALIZED SEIZURES 5. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) cause sudden loss of consciousness. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) The individual becomes rigid and falls to the ground. Respirations are interrupted. The leg extended, and the back arches; contraction of the diaphragm may induce grunting. This tonic phase lasts for about 1 minute. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) A clonic phase follows, marked by rapid bilateral muscle jerking, muscle flaccidity, and hyperventilation. Incontinence, tongue biting, tachycardia, and heavy salivation sometimes occur.  Some epileptics have serial grand mal seizures, regaining consciousness briefly between attacks. In some cases, grand mal seizures occur repeatedly with no recovery of consciousness between attacks (status epilepticus) GENERALIZED SEIZURES 6. ATONIC SEIZURES (drop attacks) characterized by a sudden loss of postural tone so that the individual falls to the ground. They occur primarily in children. Classification based on Etiology PRIMARY (idiopathic) SEIZURES have no identifiable cause. SECONDARY SEIZURES (symptomatic or acquired seizures) occur secondary to an identifiable cause. SECONDARY SEIZURES Infectious diseases (meningitis, influenza, toxoplasmosis, mumps, measles, syphilis) High fever (in children) Head trauma Metabolic disorders (hypoglycemia, hypocalcemia) Alcohol or drug withdrawal  ANTIEPILEPTIC DRUG CLASSIFICATIONS BARBITURATES HYDANTOINS SUCCIMIDES Phenobarbital Phenytoin Ethosuximide Primidone Mephenytoin Methsuximide Mephobarbital Ethotoin Phensuximide Fosphenytoin Zonisamide OXAZOLIDINEDIONES BENZODIAZEPINE MISCELLANEOUS Paramethadione Clonazepam Lamotrigine Trimethadione Diazepam Felbamate Gabapentin TYPE DRUG OF CHOICE Carbamazepine Absence ETHOSUXIMIDE Valproic acid Phenacemide Absence W/ Grand VALPROIC ACID Topiramate Mal Tiagabine Grand Mal PHENYTOIN/CARBAMAZEPINE Levetiracetam Myoclonic Seizure VALPROIC ACID Febrile Seizure PHENOBARBITAL Status Epilepticus LORAZEPAM (current); DIAZEPAM (old)  PHARMACOLOGY REVIEW Starting in House Rules: 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 258 4. Question and answer portion will follow after every topic. Anxiety is an emotional state commonly caused by the perception of real or potential danger that threatens the security of an individual  GAD-Generalized Anxiety Disorder Excessive and uncontrollable anxiety and worry  GAD-Generalized Anxiety Disorder Anxiety and worry, associated with three of the following symptoms: a. restlessness b. fatigue c. difficulty in concentrating d. irritability e. muscle tension f. sleep disturbance PANIC DISORDER It begins as a series of spontaneous, unexpected panic attacks, involving an intense, terrifying fear, similar to that caused by life-threatening danger.  Diagnostic Criteria for Panic Attacks At least four of the following symptoms developed abruptly and reached a peak within 10 minutes: Palpitations or tachycardia Dizziness, unsteadiness, Sweating lightheadedness Trembling or shaking Derealization or Sensations of shortness of depersonalization breath or smothering Feeling of choking Fear of losing control Chest pain or discomfort Fear of dying Nausea or abdominal Paresthesia distress Chills or hot flushes  Severe and pervasive anxiety about being in situations from which escape might be difficult such as being alone outside one’s home, traveling in a car or bus, or being in a crowded area Specific phobia- intense fear of particular objects or situations (e.g. snakes, heights); most common psychiatric disorder - AGORAPHOBIA - Severe and pervasive anxiety about being in situations from which escape might be difficult such as being alone outside one’s home, traveling in a car or bus, or being in a crowded area Post-traumatic stress disorder- persistent reexperience of a trauma, efforts to avoid recollecting the trauma, and hyperarousal Obsessive-compulsive disorder- recurrent obsessions and compulsions that cause significant distress and occupy a significant portion of one’s life TREATMENT A. Goals of Therapy: to reduce the severity, duration and frequency of the anxiety symptoms to improve the patient’s overall functioning to prevent anxiety symptoms to improve quality of life  Nonpharmacologic Therapy Short-term counseling Stress management Psychotherapy - for encouragement Meditation Exercise Avoidance from caffeine, nonprescription stimulants and diet pills Pharmacologic Therapy  What are CALMING Sedative- hypnotic EFFECT drugs? Sedative-hypnotic drugs SLEEP Tranquilizers Sedative-Hypnotics/Anxiolytics 1.Benzodiazepines 2.Barbiturates 3.Z-drugs (Zolpidem, Zaleplon, Eszopiclone) 4.Ramelteon 5.Buspirone Benzodiazepines Use/s Ultra-short Pre-medication Midazolam acting Short to Anxiolytics Alprazolam Intermediate Sedative- Lorazepam acting Hypnotics Flunitrazepam Long- acting Anticonvulsants Clonazepam Diazepam Barbiturates Use/s Ultra-short Pre-medication Thiopental acting Short to Sedative- Secobarbital Intermediate Hypnotics Pentobarbital acting Amobarbital Butabarbital Long- acting Anticonvulsants Phenobarbital Mephobarbital Newer Hypnotics Eszopiclone (Lunesta ™) cyclopyrrolone Zaleplon ( Sonata ™) Used in pyrazolopyrimidine SLEEP Zolpidem (Ambien™) Imidazopyridine disorders Buspirone It is an alternative for GAD to patients who cannot tolerate the sedating effects and psychomotor impairment of BZs. The agent of choice in the management of chronic, persistent anxiety. It is not cross-tolerant with BZs and will not treat or prevent symptoms of BZ withdrawal. BZ dose should be tapered before switching to buspirone. It is an appropriate choice for anxious patients with a history of alcohol or drug abuse. Ramelteon (Rozerem™) Melatonin Receptor Agonist MOA: Activates MT1 and MT2 receptors in suprachiasmatic nuclei in the CNS Rapid onset of effect with minimal rebound insomnia  ADRENERGIC BLOCKING AGENTS Propranolol and other beta-blockers may be useful in patients with prominent cardiovascular symptoms of anxiety. They are less effective anxiolytics than BZs, and their usefulness may be restricted to those anxiety patients with physical symptoms, especially cardiovascular complaints, have not adequately responded to BZ therapy. ADRENERGIC BLOCKING AGENTS Propranolol,10 mg bid should be used initially and gradually titrated to anxiolytic response. Discontinuation should be gradual to avoid rebound anxiety and cardiovascular effects. Old Sedative- Hypnotics CHLORAL HYDRATE Associated to MICKEY FINN Trichloroethanol – active metabolite Trichloroacetic acid – toxic metabolite Accumulate with the nightly administration of the drug 1. This is a drug which reduces anxiety and induces calmness. 2. DOC for chronic anxiety. 3. Barbiturate which is used as pre-medication for anesthesia 4. It is the loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories before the event remain intact. 5. A type of metabotropic receptor wherein the interaction occurs within the membrane. 6. Drug of choice for benzodiazepine poisoning 7. Toxic metabolite of chloral hydrate 8. Severe and pervasive anxiety about being in situations from which escape might be difficult 9. Major inhibitory neurotransmitter of the CNS.  PHARMACOLOGY REVIEW Starting in House Rules: 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 280 4. Question and answer portion will follow after every topic. Parkinson’s disease Paralysis Agitans Dr. James Parkinson - “shaking palsy” (1817 ) Parkinson’s disease neurodegenerative disease associated with depigmentation of the substantia nigra and the loss of dopaminergic input to the basal ganglia (extrapyramidal system); it is characterized by distinctive motor disability. Symptoms of Parkinson’s Disease Tremors (shaking usually starts on one side of the body, often in the hand or finger) Rigidity Akinesia (difficulty in initiating movement and slowness of movement) Postural instability  Classification of Drug Therapy for Parkinson’s Disease Two major categories 1. Dopaminergic agents : Promote activation of dopamine receptors 2. Anticholinergic agents : Prevent activation of cholinergic receptors Mechanisms of Action Promotion of dopamine synthesis Direct activation of dopamine receptors Prevention of dopamine degradation Promotion of dopamine release Blockade of muscarinic cholinergic receptors in the striatum ANTIPARKINSONIAN DRUGS 1. LEVODOPA + CARBIDOPA 2. DOPAMINE RECEPTOR AGONISTS - Bromocriptine, Pergolide, Pramipexole, Ropinirole 3. MAO-B INHIBITORS - Selegiline, Rasageline 4. COMT INHIBITORS - Entacapone, Tolcapone 5. AMANTADINE 6. ANTICHOLINERGICS - Benztropine mesylate, Biperiden, Trihexyphenidyl  PHARMACOLOGY REVIEW Starting in House Rules: 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 288 4. Question and answer portion will follow after every topic. “Psychosis" denotes a variety of mental disorders  clear sensorium but a marked thinking disturbance The Course of Schizophrenia Prodromal phase: Onset and buildup of schizophrenic symptoms The Course of Schizophrenia Active phase: Full-blown symptoms: severe disturbances in thinking, deterioration in social relationships, and flat or inappropriate affect The Course of Schizophrenia Residual phase: Symptoms no longer prominent Complete recovery is rare, but schizophrenics can lead productive lives. The Symptoms of Schizophrenia Characteristic symptoms: Two or more of the following, each persisting for a significant portion of at least a 1- month period: Positive symptoms Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms The Symptoms of Schizophrenia (cont’d) Positive symptoms: Symptoms which are not present in the normal individual but are added to the schizophrenic person. hallucinations and delusions Positive Symptoms Distortions or excesses of normal functioning Delusions: False beliefs firmly and consistently held despite disconfirming evidence or logic Positive Symptoms Delusions: Delusions of grandeur Delusions of control Delusions of thought broadcasting Positive Symptoms Delusions: Delusions of persecution Delusions of reference – “center of attention” Positive Symptoms Delusions: Thought withdrawal Capgras’ syndrome – “double” Positive Symptoms (cont’d) Perceptual distortion (hallucinations): Sensory perceptions not directly attributable to environmental stimuli (appear real to the schizophrenic): Auditory (hearing) Visual (seeing) Olfactory (smelling) Tactile (feelings) Gustatory (tasting) The Symptoms of Schizophrenia (cont’d) Negative symptoms: Symptoms involving characteristics, behavior or abilities that are present in a normal person but missing in the schizophrenic individual. Associated with inferior premorbid social functioning The Symptoms of Schizophrenia (cont’d) Negative symptoms: Flat affect (little or no emotion in situations in which strong reactions are expected) alogia (poverty of speech) The failure to respond to questions or comments Can also take the form of slow or delayed responses The Symptoms of Schizophrenia (cont’d) Negative symptoms: Avolition (inability to take action or to become goal oriented) Inactivity or early loss of interest in ongoing activity ***May indicate irreversible neuronal loss in a structurally abnormal brain Negative symptoms: Asociality Inability to form close personal relationships Anhedonia: Inability to feel pleasure Disorganized Symptoms Disorganized speech (Formal thought disorder) Incoherence Inability to organize ideas Loose associations (derailment) Rambles, difficulty sticking to one topic Disorganized Symptoms Disorganized behavior Odd or peculiar behavior Silliness, agitation, unusual dress e.g., wearing several heavy coats in hot weather Other symptoms Catatonia Motor abnormalities Repetitive, complex gestures Usually of the fingers or hands Excitable, wild flailing of limbs Catatonic immobility Maintain unusual posture for long period of time e.g., stand on one leg Other symptoms Waxy flexibility Limbs can be manipulated and posed by another person Other symptoms Inappropriate affect Emotional responses inconsistent with situation PATHOPHYSIOLOGY NEUROTRANSMITTER CHANGES Dopamine Glutamate Serotonin ANTIPSYCHOTICS Phenothiazine Aliphatic Chlorpromazine Promazine Trifluoropromazine Piperidine Thioridazine Mesoridazine Piperacetazine Phenothiazine Piperazine – more potent, more selective Fluphenazine Perphenazine Acetophenazine Trifluorophenarine Prochlorperazine  Antipsychotic/Neuroleptics Piperazine Piperazine>Piperidine>Aliphatic Piperidine Aliphatic Which is the MOST POTENT? [Drug dose] Atypical Anti-psychotics Dibenzoxazepine – Loxapine Dibenzodiazepine – Clozapine Benzisoxazole – Risperidone Thienobenzodiazepine – Olanzapine Fluorophenylindole – Sertindole ADRs - ANTIPSYCHOTICS Seizures – Clz, Chlorpromazine Agranulocytosis – Clozapine Cardiotoxicity – Thioridazine Prolong QT interval – Ziprasidone, Sertindole Cornea/Lens deposit – Chlorpromazine Retinal deposits – Thioridazine Neuroleptic Malignant Syndrome Extrapyramidal symptoms (EPS)  aka neuroleptic-induced parkinsonism  most common (15%)  coarse tremors, rigidity, bradykinesia  Risk: high potency TX: lower dose, anticholinergics These symptoms include dystonia (continuous spasms and muscle contractions),akathisia (motor restlessness), parkinsonism (characteristic symptoms such asrigidity), bradykinesia (slowness of movement), and tremor, and tardive dyskinesia (irregular, jerky movements). AFFECTIVE DISORDERS mental illnesses characterized by pathological changes in MOOD Unipolar disorders Bipolar disorder Depression (manic-depressive illness) – Mania “cycling mood“ MAJOR DEPRESSIVE DISORDER (MDD) Characterized by a DEPRESSED mood most of the time for at least 2 weeks or loss of interest or pleasure in most activities MAJOR DEPRESSIVE DISORDER (MDD) SYMPTOMS feelings of guilt or low self-worth, disturbed sleep or appetite, low energy poor concentration Suicidal attempts Therapy of depression Non-pharmacological treatment Psychotherapy (cognitive behavior therapy ) Electroconvulsive therapy (ECT) TREATMENT PHASES FOR DEPRESSION TREATMENT DURATION GOAL PHASE Acute ≈ 6 w eeks Resolve symptoms Continuation 6-9 months Prevent relapse Maintenance 3-5 years of Prevent recurrence in lifelong high risk patients* ANTIDEPRESSANTS  Selective Serotonin Re-uptake Inhibitors (SSRI)  FLUOXETINE, SERTRALINE, CITALOPRAM  Tricyclic antidepressants (TCA)  IMIPRAMINE, AMOXAPINE, AMYTRIPTYLINE, DESIPRAMINE  Monoamine oxidase inhibitors (MAOI)  PHENELZINE, ISOCARBOXAZID, TRANYLCYPROMINE, MOCLOBEMIDE  Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)  TRAZODONE, NEFAZODONE  NE and Dopamine Reuptake Inhibitors (NDRI)  BUPROPION  Noradrenaline Reuptake Inhibitors (NaRI)  REBOXITINE Other antidepressants: 1. Venlafaxine (Effexor)  Serotonin and NE reuptake inhibitor (SNRI) 2. Mirtazapine (Remeron)  noradrenergic and specific serotonergic antidepressant (NaSSA) Antimanic Agents/Mood Stabilizers Lithium carbonate (Eskalith, Quilonium) DOC unknown mechanism Narrow therapeutic index Therapeutic range: 0.6-1.2 mEq/L Adverse Effects Minor: tremor, polyuria, gastrointestinal distress, memory problems, acne exacerbation, weight gain Long-term: hypothyroidism Toxicity: ataxia, coarse tremor, confusion, coma, sinus arrest, and death Interactions:  Diuretics - dec. Na→ inc. Li;  excessive Na intake → dec.Li  Other mood stabilizers: valproic acid, carbamazepine  PHARMACOLOGY REVIEW Starting in House Rules: 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 328 4. Question and answer portion will follow after every topic.  ANTI-ULCER DRUGS H-2 BLOCKERS Cimetidine, Ranitidine, Famotidine, Nizatidine PROTON PUMP INHIBITORS Omeprazole, Lansoprazole, “-prazoles” ANTACIDS NaHCO3, NaCO3 SUCRALFATE BISMUTH HELIDAC Bismuth subsalicylate, tetracycline and metronidazole MISOPROSTOL NSAIDs Drug Classes: Examples propionic acid derivative ibuprofen pyrrolealkanoic acid derivative tolmetin phenylalkanoic acid derivative flubiprofen indole derivative indomethacin pyrazolone derivative phenylbutazone phenylacetic acid derivative diclofenac Fenamate meclofenamate acid Oxicam piroxicam naphthylacetic acid prodrug nabumetone Salicylate ASA Drugs used in GOUT COLCHICINE acute gouty arthritis INDOMETHACIN OXAPROZIN ALLOPURINOL chronic tophaceous gout URICOSURIC AGENT PROBENECID SULFINPYRAZONE  ANTI-ASTHMA DRUGS Bronchodilators - β2 agonist – “-TEROL” - Methylxanthines – Theophylline - Anticholinergics/Antimuscarinics Anti-inflammatory agents - Leukotriene modifiers – Zileuton, Zafirluskast, Montelukast - Glucocorticoids Mast cell stabilizers Nedocromil Cromolyn Antihistamines 1. 1st Generation Antihistamines a. Ethanolamines: Carbonoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine b. Ethylaminediamines: Pyrilamine, Tripelennamine c. Piperazine: Hydroxyzine, Cyclizine, Meclizine d. Alkylamines: Brompheniramine, Chlorpheniramine e. Phenothiazines: Promethazine f. Methylpiperidine: Cyproheptadine Antihistamines 2. 2nd Generation Antihistamines a. Piperidines: Fexofenadine b. Miscellaneous: Loratidine, Cetirizine  PHARMACOLOGY REVIEW House Rules: Starting in 1. Be attentive, avoid unnecessary activities. 10 2. Prepare a pen and a notepad. Most minutes details are in the handout, if in case there are additional notes, the lecturer will alert you to jot down the said notes. 3. The topics throughout the lecture are divided strategically. There will be a 2 to 5-minute break every after a topic. And End that is followed by practice questions to assess whether you are learning. 4. Question and answer portion will follow 335 after every topic.. Stages of anesthesia: Guedel's signs of anesthesia I Analgesia and amnesia; From induction of general anesthesia to loss of consciousness. II Excitement - delirium, Inc. BP, RR III Surgical anesthesia- unconscious; normal BP, RR, muscles relaxed; no eye reflexes IV Medullary paralysis- resp. Depression, death INHALATIONAL ANESTHETICS Gas Volatile liquids Nitrous oxide Halothane, enflurane, isoflurane, desflurane, sevoflurane, and methoxyflurane INTRAVENOUS ANESTHETIC 1. barbiturates (thiopental, methohexital) 2. benzodiazepines (midazolam, diazepam) 3. opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil); 4. propofol; 5. ketamine; and 6. miscellaneous drugs (droperidol, etomidate, dexmedetomidine).  LOCAL ANESTHETICS ROUTES One “i” – ESTER Topical Two “i” – AMIDE Infiltration Field block Nerve block Most cardiotoxic – Intravenous regional BUPIVACAINE Most Neurotoxic – LIDOCAINE, CHLORPROCAINE Hemolytic anemia – PRILOCAINE Limited use – COCAINE Esters 1. Benzoic acid esters: Cocaine , piperocaine 2. Am ino-benzoic acid esters a. Soluble: Procaine, chlo roprocaine tetracaine b. Limited solubility: Benzocaine 3. Pa ra-eth oxy-be nzo ic ac1d: Int raca1ne 4 Carbamic acid esters· Diathane 5. Complex synthetics Am ides 1. Straight chain acid deriv·ativ·es of xylidide: a. Acetic acid: Xyloca1ne b. Propionic acid· Propitocaine 2. Pipecohc denv·atives of xylid1de : Mep1v·aca1ne , bupiv·acaine 3 Oxycinchoninic acid: Dibucaine 5 minutes End  Q Bood Pressure Categories American A sociation I American Heart Stroke Association. SYSTOLIC mm Hg DIASTOLIC mm Hg BLOOD PRESSURE CATEGORY {upper number) (lower number) NORMAL LESS THAN 120 and LESS THAN 80 ELEVATED 120-129 and LESS THAN 80 HIGH BLOOD PRESSURE 130-139 or 80-89 (HYPERTENSION) STAGE 1 HIGH BLOOD PRESSURE 140 OR HIGHER or 90 OR HIGHER (HYPERTENSION) STAGE 2 HYPERTENSIVE CRISIS HIGHER THAN 180 and/or HIGHER THAN 120 (consult your doctor immediately) Classifications Primary (essential) hypertension high blood pressure with no obvious underlying medical cause. 90-95% of cases Secondary hypertension caused by other conditions that affect the kidneys, arteries, heart or endocrine system.  ANTI-HYPERTENSIVE AGENTS 1. Diuretics 2. Sympathoplegic agents (B-blockers, alpha1 blockers, alpha2 agonists) 3. Calcium Channel Blockers 4. Direct vasodilators 5. Agents that block production or action of angiotensin (ACEi, ARBs) BASIC & CLINICAL PHARMACOLOGY - 12th Ed. NATRIURETICS – Increase Na excretion SITE EXAMPLE S/E THIAZIDE Distal Convulated Bendroflumethiazide -Hyponatremia -mild to Tubule (Naturetin) -Hypokalemia moderate HTN Chlorothiazide (Diuril) -Hypercalcemia - CHF Trichlorome (Diurese) -Hyperuricemia - Liver /Renal HCTZ (Hydrodiuril) -Hyperglycemia Disease Hydroflume (Saluron) -Hyperlipidemia - D. insipidus LOOP Thick Ascending -Furosemide (Lasix) -Ototoxixity Loop of Henle -Torsemide (Demodex) -Hyperuricemia -Bumethanide (Bumex) -Decrease magnesemia -Ethacrynide (Edecrin) -Hypokalemia -Metabolic alkalosis K-SPARRING Late Distal Tubule -Spironolactone (Aldactone -Hyperkalemia & Collecting Tubule -Eplenerone(Inspra) -Menstrual abnormalities -Amiloride(Midamor) -Gynecomastia -Triamterene (Dyrenium) AQUARETICS – Increase water excretion SITE EXAMPLE S/E OSMOTIC Proximal Tubule -Mannitol -Dehydration AGENTS & Descending -Glycerin.-Isosorbide -Hypernatremia Loop of -Urea Henle CARBONIC Proximal Tubule -Brinzolamide (Azopt) -GI upset ANHYDRASE -Acetazolamide (Diqmox) -Urinary infrequency INHIBITOR -Methazolamide -Metabolic acidosis (Neptazone) -Renal calculi -Dorzolamide -Drowsiness Vasodilators - Relax smooth muscle, ↓ TPR - Reflex stimulation of heart - used with Diuretic or Beta blocker ORAL, LONG TERM HTN - Minoxidil – Hirsutism - Hydralazine – SLE PARENTERAL, HTN EMERGENCY - Sodium nitroprusside - Diazoxide - Fenoldopam CALCIUM CHANNEL BLOCKER - highly protein bound - Large volume of distribution Verapamil - 5.5 L/kg Diltiazem - 5.3 L/kg Nifedipine - 0.8 L/kg Clinical Manifestation Hypotension- peripheral vasodilation Bradycardia - AV & SA node block ACE INHIBITORS - “-PRIL” - Potent vasodilator Use: HTN, CHF, diabetic nephropathy Use: tx. Mild to moderate HTN ADR: *Anorexia *Hyperkalemia *Polyuria *Oliguria *idiosyncratic dry cough ARBs - “-sartan” - used alone or in combination therapy -↓ cough & angioedema Examples: Candesartan - Atacard® - C/I to pregnancy = fetal abnormalities Irbesartan - Avapro® - assoc. w/ fetal abnormalities & death Losartan - Cozaar® Telmisartan - Micardis® Episartan - Teveten® Olmesartan – Benecar® Valsartan - Diovan® ALPHA2 AGONISTS ↓ sym pathetic outflow Anti-HTN axn = stimulate a2 adrenoceptor & (-) release of catecholamines Ex. Methyldopa (Aldomet®) Clonidine (Catapres®) Guanabenz Guanfacine  Adrenoceptor antagonists a. BETA BLOCKERS – “OLOL” b. Alpha-1 blockers “-zosin” Use: HTN & BPH Syncope – in 1st time adm of alpha1- blocker 1st dose phenomenon mgt of syncope: dose should be small and at bed time. BASIC & CLINICAL PHARMACOLOGY - 12th Ed. GANGLION-BLOCKING AGENTS Mecamylamine Trimethaphan (quaternary amine) - oral -Short acting - w/ CNS effect - IV infusion - lacks CNS effects - polar MOA: competitively block nicotinic cholinoceptors in post ganglionic neurons A/E: Sympathoplegic *Orthostatic hypotension *Erectile dysfunction Parasympathoplegic *Constipation *blurred vision *Urinary retention *dry mouth 6 minutes End 1. Site of action of Thiazide diuretics 2. Site of action of loop diuretics 3. Diuretic associated with galactorrhea and gynecomastia 4. Diuretics used for acute mountain sickness. 5. Beta-blocker with the shortest half-life. 6. A vasodilator with a toxic cyanide metabolite. 7. Prototype ACE inhibitor. 8. Inactive form of Angiotensin. 9. Diuretic that can cause hyperkalemia. 10. Anti-hypertensive drug classification associated with syncope. 11. Dopa 1 agonist for HTN. 12. Prototype alpha 1 blocker. 13. Vasodilator for eclampsia. 14. Sympathophlegic for pregnant women with HTN. 15. Normal blood pressure. Angina characterized by chest pain or discomfort due to coronary heart disease. Problem is *ischemia – inadequate amount of oxygenated blood increase oxygen demand decrease oxygen supply (It affects the blood vessel) Two parts affected by ischemia Myocardial ischemia – inadequate supply of oxygenated blood in the heart. Cerebral ischemia – inadequate supply of oxygenated blood in the brain. most fatal because it can result to stroke → paralysis which can result to comatose 3 TYPES OF ANGINA Stable Angina - aka effort angina, classic angina - most common type of angina - commonly present to smoker and hypertensive patient - main cause is atherosclerosis - chest pain is predictable or expected, when there is physical exertion or activity. Unstable Angina - aka angina at rest/crescendo angina - chest pain is unexpected, experienced during at rest - common at night - main causes are atherosclerosis and thrombosis Prinzmetal’s Angina - vasospastic or variant angina - severe form of angina - chest pain occurs at night up to early morning , takes place during at rest and during physical exertion ANTIANGINAL DRUGS Organic nitrates Calcium Channel blockers Beta blockers Ivabradine & Nicorandil hypertensive patients - monotherapy with slow release or long acting CCB or Refractory cases- CCBs Beta blockers - refractory to organic nitrates normotensive patients - with angina & normal BP Acute treatment of Vasospastic - DOC: Nitroglycerin angina - alternative: Propranolol with nifedipine DOC: verapamil/diltiazem Unstable Angina Pectoris *aspirin – inhibits thromboxane formation *cilostazol – antiplatelet with vasodilating effect, inhibit PDE3 *clopidogrel – inhibit adenosine diphosphate pathway Sildenafil - vasodilator which is used to manage erectile dysfunction - also used to manage angina pectoris → MOA: phosphodiesterase isoform-5 inhibitor (PDE5), as an inhibitor it increases CGMP which result to vasodilation men – sildenafil increases the blood flow in corpus cavernosa → erection  Arrhythmia →Defined as the abnormal firing rate, regularity or site of origin of cardiac impulse, involve irregular and abnormal heart rhythm. Normal heart rhythm: 60-90 beats per minute * heart rhythm is regulated by the SA Node (phase maker of heart) ANTIARRHYTHMIC DRUGS Type I – NA Type II – Beta Type III – K Type IV – Ca IA – Quinidine, -”OLOL” except Bretylium Verapamil Procainamide, Sotalol Amiodarone Diltiazem Dysopiramide Dronaderone CI: Nifedipine IB – Lidocaine, Sotalol Mexiletine, Phenytoin IC – Moricizine, Flecainide, Propafenone Heart Failure HEART FAILURE - medical condition characterized by impairment of left ventricle - there is no ability to pump sufficient oxygenated blood - inadequate supply of oxygenated blood coming from ventricle → can result to hospitalization Symptoms of heart failure based on exertion Class1 - asymptomatic - no limitation on physical activity Class 2 - mild to moderate moderation on - physical activity - can be relieved during at rest Class 3 - marked limitation on physical activity - can happen even during at rest Class 4 - any physical activity can trigger heart failure symptoms 2 Forms of heart failure 1. Low output most common → no metabolic demand/requirement, but the heart cannot compensate with the requirements for oxygenated blood 2. High output characterized by metabolic disorder Ex. Hyperthyroidism - increases demand for oxygenated blood because patient suffers from palpitation or tachycardia. Anemia - hematopoietic disorder characterized by low levels of haemoglobin (oxygenated blood) 1. Inotropic agent (increases the force of contraction) * cardiac glycoside - digitalis - Most important ion affected by digitalis is K channel, therefore it can cause hypokalemia - Alternative for hypokalemia is KCl or MgSO4 Deslanoside - alternative for rapid digitalization 2. Diuretics -to reduce fluid overload in patient suffering from fluid retention *Thiazide / loop diuretics - commonly used