Pharmacology Notes for Board Exam Reviewer PDF

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SUMMATIVE LECTURE IN PHARMACOLOGY 1 Pharmacology Study of substances that interact with living systems through chemical processes binding to regulatory molecules and activate in or inhibiting normal body processes. Drug It is any substance that brings about change in biological function through its ...

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SUMMATIVE LECTURE IN PHARMACOLOGY 1 Pharmacology Study of substances that interact with living systems through chemical processes by binding to regulatory molecules and activate in or inhibiting normal body processes. Drug It is any substance that brings about change in biological function through its chemical actions. Use for the: 1. Prevention – to prevent or hinder the occurrence of disease (e.g. MMR Vaccine, Vitamin A) 2. Diagnosis – to determine the presence or absence of disease (e.g Barium Sulfate, Edrophonium) 3. Mitigation – to stop progression of disease (e.g. anti-parkinsons drugs, captopril) 4. Treatment – to manage symptoms of disease (e.g. antibiotic, analgesic) 5. Cure- the total recovery or relief from disease

Ms. Rizza A. Caluag

DRUG TARGET SITES Structural Protein Constitute “Cytoskeleton” ______________________- important site of action Drugs that inhibit microtubule synthesis Spindle protein Griseofulvin Vinca alkaloids Colchicine Etoposide Regulatory Proteins Mediates the transmission of endogenous chemical signals such as neurotransmitters, autacoids or hormones Transport Channels Enzymes Carrier Molecules Receptors __________________________________ Voltage Gated Na- Channel Inhibitors Na Channel Blocker Local Anesthetics Carbamazepine Phenytoin Tetrodotoxin Voltage Gated Ca- Channel Calcium channel blockers “dipines” ____________________________________ Na- K ATPase Pump – Digoxin H – K ATPase Pump – PPI Na- K- 2 Cl Transport – Furosemide Na – Cl – transporter – Thiazides _____________________________ Acetylcholinesterase - Edrophonium COMT – Entacapone

PHARMACODYNAMICS

_________________________ Functional macromolecular components of cells with specific stereo chemical configuration and in which ligand interacts

SUMMATIVE LECTURE IN PHARMACOLOGY 1

Ms. Rizza A. Caluag

*____________________ – any chemical that has ability to bind to a receptor

Partial - ________________________

Type I ______________________________ Found in cell. Ligand membrane receptors stimulated in nicotinic milliseconds receptor

Antagonist _______________________ – with affinity but no intrinsic activity a. Pharmacodynamic antagonist – same receptor (e.g. Propranolol + Epinephrine) b. Pharmacokinetic antagonist – reduce the effect of one drug by alteration of time (e.g. Digoxin + Cholestyramine)

Type II _____________________________________________________ ___________________________________________________ Located in the cell membrane receptors Type III _____________________________ Located in nucleus. Receptor for insulin utilization of glucose. Onset: hours Type IV _____________________________ Located in steroid nucleus/ Vit D cytosol. Onset: hours Theories of Drug Receptors Interaction Occupancy Theory Drug effects is directly proportional to the number of receptors occupied Lock and Key Mechanism

______________________ - different receptor sites (e.g. Histamine + Epinephrine; Glucocorticoid + Insulin) _______________________ - it prevents the binding of agonist, no receptor is involved (e.g. Protamine sulfate + Heparin Sulfate; Paracetamol + N- Acetyl cysteine; Warfarin + Vitamin K) NATURE OF ANTAGONISM Competitive antagonist- Effects of Antagonist can be overcome/reversed by increasing the concentration of agonist NON-COMPETITIVE ANTAGONISM it is also known as irreversible antagonism

Induced Fit Theory ENHANCEMENT OF DRUG EFFECTS Ariens / Stephenson Theory Occupational theory of response Rate Theory The activation of receptor is directly proportional to the total number of encounters of drug with its receptor per unit time Classification of Drugs According to Receptor Interaction Agonist Drug that binds to same binding site as an agonist for that receptor or reverses constitute activity of receptors Full – ___________________________

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. 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.

SUMMATIVE LECTURE IN PHARMACOLOGY 1 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 Autacoids “Autos” (self) and “acos” (relief, drug) Aka “Local Hormones” Localized effect: Self Release 5 classes: 1. Biologically active amine Serotonin and histamine 2. Lipid derived autacoids (Eicosanoids) Prostaglandins Leukotrienes Thromboxanes

Ms. Rizza A. Caluag Rece ptor Type

Distribution

Post Receptor

Mechanism

H1

Smooth muscle endothelium, Brain

↑Ip3, DAG (Gq)

Vasodilatio n, increase in permeabili ty

H2

Gastric mucosa, cardiac muscle, mast cells, brain

↑ cAMP (Gs) stimulati on of adenyl cyclase

Increase release of HCL

↓ cAMP, Ca (Gi)

Decreased Ach Release

H3

H4

Myenteric plexus, presynaptic brain Eosinophils, Neutrophils, CD4 T-cells

↓cAMP, Ca (Gi)

3. Ergot Alkaloids 4. Vasoactive Polypeptides Angiotensin Endothelin Kinins Natriuretic Peptide Substance P Vasopressin 5. Endothelium-derived Autacoids Nitric Oxide Biologically active amines Histamine Precursor: Histamine Process: Decarboxylation Storage: Mast Cells Process: 1. Energy and Ca-dependent Degranulation reaction (Immunologic release) 2. Energy and Ca-independent release (Displacement) Types of Histamine Receptors:

Histamine Agonist _____________________________ – used in allergy testing _____________________________ – used to test of gastric secretory function Impromidine Histamine (H1) receptor antagonist Aka: Antihistamine Competitive inhibitor at the H1 receptor Anti-Histamines 1st Gen ______________________________ Carbonoxamine Dimenhydrinate Diphenhydramine Doxylamine _____________________________ Pyrilamine Tripelenamine ____________________________ Hydroxyzine Meclizine ___________________________ Brompheniramine

SUMMATIVE LECTURE IN PHARMACOLOGY 1

Ms. Rizza A. Caluag C. metabolized in the liver;  many induce microsomal enzymes and alter their own metabolism

Chlorpheniramine ___________________________ Promethazine Miscellaneous: Cyproheptadine 2nd Gen Adv: less sedating effect and less frequency of administration Piperidines: Fexofenadine Ferfenadine Astanizole Miscellaneous: Loratidine Cetirizine Uses: o 

 

 

H2 receptor antagonist Used in the treatment of gastrointestinal disorders, heart burn or acid induced indigestion, promote the healing of gastric or duodenal ulcers, hypersecretory states such as Zollinger Ellison Syndrome

Treatment of allergic rhinitis and conjunctivitis. treat the common cold based on their anticholinergic properties  Diphenhydramine also has an antitussive effect not mediated by H1-receptor antagonism. Treatment of urticaria and atopic dermatitis, including hives Sedatives  Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids. Prevention of motion sickness Appetite suppressants

Pharmacokinetic Blocking Drugs

ADVERSE EFFECTS o sedation (synergistic w/ alcohol, other depressants, dizziness, and loss of appetite. o gastrointestinal upset, nausea, constipation and diarrhea. o anticholinergic effects (dry mouth, blurred vision, and urine retention).

Properties

of

_____________________ (Tagamet) – Anti androgenic activity; potent enzyme inhibitor _____________________ – 100% Bioavailable Famotidine 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%. Inhibitors of histamine release Mast cell stabilizers: Cromolyn (Intal) Nedocromil Sodium (Tilade)

H1

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 B. lipid-soluble = cross the blood-brain barrier

Inhibitors of Histamine release 1. Poorly absorbs salts 2. Inhibit release of histamine or other autacoids from the mast cells 3. Prophylactic agent in asthma 4. Nedocromil Sodium – appears to be more effective in reducing bronchospasm caused by exercise or cold air 5. ADR: Sore throat/ dry mouth

SUMMATIVE LECTURE IN PHARMACOLOGY 1

Serotonin = 5-HT (5- hydroxytryptamine) An indole amine has an indole ring structure This structure is also “hallucinogenic” or psychedelic drugs Serotonergic systems Plays important role in sleep, elevated mood, decreased appetite, increase temperature regulation, pain perception * Serotonin – melatonin (sleep hormone) through pineal gland. Serotonin synthesis Undergo decarboxylation Tryptophan → Tryptophan hydroxylase → 5-HTP → 5-HTP decarboxylase →5HT Tissue Distribution _______________________ of GI tract (90%) Platelets (10%) Metabolism Phase I Serotonin → (MAO) → 5-hydroxyindole acetaldehyde → (Acetaldehyde dehydrogenase)→ ______________________________ 5HT1 Contract arterial esp in carotid smooth muscle 5HT2 Platelet “causes aggregation” CNS – mediated hallucinogenic effects Contraction of vascular smooth muscle 5HT3 Stimulation of receptor in area postrema Causes nausea and vomiting Peripheral sensory or neurons causes pain or afferent vagal nerve – chemoreceptor reflex Also known as Bezold Harish reflex Bradycardia/ hypotension 5HT4

Ms. Rizza A. Caluag GIT these receptors mediate an increase in secretion or peristalsis Serotonin in muscles – contraction SEROTONIN AGONISTS Buspirone (Buspar) Sumatriptan (Imitrex) Trazodone (Desyrel) Cisapride (Propulsid) Tegaserod (indirect agonist) Fluoxetine Dexfenfluramine Sibutramine Serotonin Antagonists 1. Cyproheptadine (Periactin) 2. “Setron” - Ondansetron, Granisetron (Kytril) 3. Ketanserin Ketanserin (Sufrexal) 4. Clozapine (Clozaril) 5. Risperidone (Risperdal)

Ergot – from Claviceps Purpurea Powerful hallucinogen Affects the following receptors:  Adrenoceptors  Dopamine receptors  Serotonin receptors Ergotism Accidental ingestion of ergot alkaloids in contaminated grain Most dramatic effects of poisoning are: Dementia with hallucinations, prolonged vasospasm, gangrene, stimulation of uterine smooth muscles “St. Anthony’s Fire” Effects: Vascular smooth muscle = Contraction Uterus = contraction Endocrine = suppress prolactin secretion from pituitary cells USES: I. Migraine

SUMMATIVE LECTURE IN PHARMACOLOGY 1 1. Ergotamine, Cafergot (caffeine and ergotamine] 2. Methysergide Its therapeutic effect in migraine prophylaxis has been associated with its antagonism at the 5-HT2B receptor It has a known side effect, retroperitoneal fibrosis, which is severe, although uncommon. II. Post-partum hemorrhage  Ergonovine maleate This medication is used after childbirth to help stop bleeding after delivery of the placenta (afterbirth). III. Hyperprolactinemia - the presence of abnormally high levels of prolactin in the blood o Prolactin (PRL), also known as lactotrope, is a protein that in humans is probably best known for its role in enabling female mammals to produce milk

Ms. Rizza A. Caluag

USES: Female Reproductive System a. Abortion:  Dinoprostone (PGE2) a synthetic preparation administered vaginally for oxytocic use.  Carboprost Tromethamine (15methyl-PGF2a) administered as a single 2.5 mg intraamniotic injection.  Antiprogestins (Mifepristone) combined with an oral oxytocic prostaglandin (Misoprostol) to produce early abortion. Male Reproductive System Erectile Dysfunction – Alprostadil (PGE1) need vasodilator Pulmonary Hypertension PGI2 lowers peripheral pulmonary or coronary resistance Prostaglandin (PGI2, Epoprosterol, Iloprost)

Bromocriptine  Bromocriptine (INN; trade names Parlodel, Cycloset), an ergoline derivative,  is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome Pergolide  is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease.

Peripheral Vascular Disease PGE & PGI2

Eicosanoids

Glaucoma Latanoprost – a tablet; long acting PGF 2a Bimatoprost Tavaprost Unoprostone

Derived from lipids Large group of autacoids with potent effects on virtually every tissue in body Derived from metabolism of 20-carbon, unsaturated form (Arachidonic)

Patent ductus arteriosus Alprostadil (PGE1) Blood Platelet aggregation: TXA2

Gastrointestinal System Misoprostol (PGE1) Available in Europe/ USA DOC for NSAID induced ulcer

SUMMATIVE LECTURE IN PHARMACOLOGY 1

Ms. Rizza A. Caluag

PG ANTAGONISTS 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

mefenamic

Oxicam

piroxicam

naphthylacetic acid prodrug

nabumetone

Inhibition of COX prostaglandin Common ADR: GI irritation or upset Ex. Aspirin – inhibition of TXA2 – antiinflammatory activity COX-2 Inhibitor- “Coxib” Celecoxib, Valdecoxib, Enterocoxib Lipooxygenase Pathway Produces:

Leukotrienes Leukotriene Receptor inhibitors Leukotriene antagonists are used to treat these disorders by inhibiting the production or activity of leukotrienes Respiratory System  Leukotriene Receptor Inhibitors (Zafirlukast, Montelukast)  5-Lipoxygenase Inhibitor (Zileuton)

PERIPHERAL NERVES -collection of nerves and ganglia scattered throughout the brain -consist of 12 pairs of cranial nerves, 31 pairs of spinal nerve and their branches to the entire body CRANIAL NERVES: I. OLFACTORY NERVE II. OPTIC NERVE III. OCCULOMOTR NERVE IV. TROCHLEAR NERVE V. TRIGEMINAL NERVE VI. ABDUCNES NERVE VII. FACIAL NERVE VIII. AUDITORY OR VESTIBULOCOCHLEAR NERVE IX. GLOSSOPHARYNGEAL NERVE X. VAGUS NERVE XI. SPINAL ACCESSORY NERVE XII. HYPOGLOSSAL NERVE

SUMMATIVE LECTURE IN PHARMACOLOGY 1 Major Subdivision of PNS 1. Autonomic 2. Somatic 3. Enteric NS Enteric Nervous System- include the myenteric plexus (plexus of auerbach) and submucous plexus (plexus of meissner) Somatic Nervous System- concerned with consciously controlled functions such as movement, respiration and posture Autonomic Nervous System- autonomous (independent) -concerned primarily with visceral functions, cardiac output, blood flow to organ, it’s activities are not under direct conscious control 2 DIVISIONS: 1. Sympathetic NS 2. Parasympathetic (Please utilize the space at the back)

Sympathetic NS 5 Steps of Neurotransmission 1. Synthesis 2. Storage 3. Release •Bretylium •Guanethidine 4. Receptor Binding 5. Reuptake/Removal •Cocaine •TCA Removal of Norepinephrine 1. Diffusion 2. Metabolism -enzymes that inactivate NE •MAO (Monoamine Oxidase Enzymes) •COMT (Catechol o-methyl transferase) Metabolites- are extracted in the urine 3. Reuptake- recaptured by an uptake system -pulls the NE back to neuron

Ms. Rizza A. Caluag Adrenergic Drugs - stimulate the sympathetic NS - adrenergic agonist, sympathomimetic and adrenomimetic -they mimic norepinephrine and epinephrine -act on one or more receptor sites Classification of Sympathomimetic/ Adrenergic Drugs according to their effect DIRECT ACTING- stimulates the adrenergic receptors INDIRECT ACTING- stimulate the release of NE from the terminal nerve ending amphetamine MIXED ACTING- both-ephedrine MIXED ALHPA AND BETA AGONIST •EPINEPHRINE (beta 2) -rapidly acting bronchodilator (alpha 1)- used to prolong the acitivity of local anesthetic (beta 1)- used to restore the cardiac activity in cardiac arrest (alpha 1)-topically treatment of glaucoma (2% solution ) •NOREPINEPHRINE (Levarterenol, Noradrenaline) ALPHA AGONIST Methoxamine- for hypertension (parenteral) Midodrine- used in the treatment of postural hypertension -prodrug that is hydrolyzed is desglymidodrine

B. DECONGESTANTS B.1 Phenylephrine - has longer duration of action than the catecholamine -mydriatic and decongestant *REBOUND CONGESTIONrhinitis medicamentosa B.2 Phenylpropanolamine

SUMMATIVE LECTURE IN PHARMACOLOGY 1

Ms. Rizza A. Caluag

B.3 Xylometazoline and Oxymetazoline OTHER SYMPATHOMIMEMTIC Ephedrine ALPHA 2 AGONIST • Clonidine • Methyldopa • Guanfacine • Guanabenz Use in the treatment of hypertension MOA: inhibit the release of NE sympathetic nerve endings

CNS stimulants Amphetamine Methylphenidate/Pemoline for ADHD Use: narcolepsy- uncontrollable state from

BETA AGONIST Isoproterenol (Isoprenaline) B1 = B2 >>> a Effects: positive chronotropic/ inotropic actions bronchodilation peripheral vasodilation BETA 2 AGONIST Anti-asthma drugs: Albuterol Terbutaline Metaproterenol Salmeterol Tocolytic drugs: Ritodrine Terbutaline BETA 1 SELECTIVE AGONIST Dobutamine Major limitations: • Tolerance- prolong use • Chronic cardiac stimulation in patient w/ heart failure may worsen long term outcome DOPAMINE 1 AGONIST Fenoldopam -for treatment of severe HTN DOPAMINE AGONIST Dopamine -the immediate metabolic precursor of norepinephrine -activates D1 receptor several vascular beds which leads to vasodilator

*Tyramine -normal by product of tyrosine metabolism metabolized by MAO -inactive when taken orally because of a very high 1st pass effect CATECHOLAMINE REUPTAKE INHIBITORS Atomoxetine - for ADHD Reboxetine - for ADHD Duloxetine - antidepressant Milnacipran - fibromyalgia Sibutramine – anti-obesity agent Cocaine -CNS stimulant/LA

ALPHA BLOCKERS

– vasodilating

effect into the blood vessels NONSELECTIVE ALPHA BLOCKING AGENTS Phentolamine (reversible) Phenoxylamine (irreversible) Uses: pheochromocytoma erectile dysfunction relieve vasospasm Reynaud’s syndrome SELECTIVE APLHA 1- AGONIST “Zosins” • Terazosin • Doxazosin • Alfusozin Tamsulosin- oral route, increase IFIS (Intraoperative Floppy Iris Syndrome) for patients undergoing cataract surgery Alfuzosin- risk: QT prolongation Silodosin- for BPH Indoramin- antihypertensive Urapidil- antihypertensive/BPH Adverse effects: “syncope”

1st

dose

phenomenon

SUMMATIVE LECTURE IN PHARMACOLOGY 1 -adjust the dose to 1/3 or ¼ of normal dose -admin a bedtime

Ms. Rizza A. Caluag • • • •

Bronchoconstriction Arrhythmias Sexual impairment Disturbance in metabolism

Orthostatic hypotension *Nadolol- with long duration of action *Esmolol- ultra short acting beta blocker ALPHA 2 BLOCKERS Yohimbine –erectile dysfunction Rauwolscine Tolazoline NON SELECTIVE BETA BLOCKERS *Propranolol- prototype agent Carteolol Nadolol Penbutolol Pindolol Sotalol Propranolol Actions: -Cardiovascular • Decrease cardiac output, (-) inotropic/chronotropic • Oxygen consumption decrease –used in angina • Decrease cardiac output and blood pressure  Bronchoconstriction □ Due to blockade of Beta2 □ Can ppt reapiratory crisis in patient with COPD and asthma • Decrease BP  Disturbance in glucose metabolism o Beta blocker –decrease glycogenolysis  Blocks action of Isoproterenol Uses: • Prophylaxis of angina pectoris, supraventricular and ventricular dysrhythmias • Migraine headache • Anti-hypertensive • Negative chronotropic agent ...