Mansoura Clinical Pharmacology [2]

Table of contents :
cover
contents
CHAPTER 4: AUTACOIDS AND ANTI-INFLAMMATORY DRUGS
Part 1: Autacoids
Part 2: Non-steroidal anti-inflammatory drugs (NSAIDs)
Part 3: Acute rheumatic fever
Part 4: Drug therapy of rheumatoid arthritis
Part 5: Drug therapy of gout
Review questions
CHAPTER 5: CARDIOVASCULAR PHARMACOLOGY
Part 1: Systemic hypertension and antihypertensive drugs
Part 2: Therapy of peripheral vascular disease
Part 3: Therapy of ischemic heart disease
Part 4: Therapy of congestive heart failure
Part 5: Management of shock
Cardiac arrhythmia and antiarrhythmic drugs
Review questions
CHAPTER 6: PHARMACOLOGY OF THE BLOOD
Part 1: Hyperlipidemia and drugs that lower plasma lipids
Part 2: Drugs affecting hemostasis
Part 3: Drugs used in the treatment of anemia
Review questions
CHAPTER 7: PHARMACOLOGY OF THE RESPIRATORY SYSTEM
Part 1: Agents used to treat cough
Part 2: Therapy of bronchial asthma
Part 3: Oxygen therapy
Review questions

Citation preview

 

 

hts © 2016 by b the Deparrtment of Clin nical Pharma acology at Fa aculty of Meedicine, Mnas soura Copyrigh Universitty, Egypt. 015, 2014, 20 013, 2012, 2011, 2010, 2009, 2 2008, 22000 by the Previouss editions copyright © 20 Departm ment of Clinic cal Pharmaco ology at Facu cine, Mnasou ura Universitty, Egypt. ulty of Medic distributed in n any form orr by any meaans, or stored d in a No part of this book may be reprroduced or d e or retrievall system, witthout the prio or written pe ermission of the t copyrighhts owner, database Departm ment of Clinic cal Pharmaco ology at Facu ulty of Medic cine, Mansou ura Universitty. d work and is s protected b by the Egypttian Intellectu ual Property Law 82 of 2002. Use This is a copyrighted work is subjec ct to this law w. The Depart rtment of Clin nical Pharma acology at M Mansoura Fac culty of of this w Medicine e reserves alll rights in an nd to the worrk.

2000 ‫سنة‬ ‫ لس‬1456 :‫رقم اإليداع بدار الككتب‬ ‫م‬ 2000/9/6 ‫ بتاريخ‬ 

Preface

C

linical training for undergraduate students often focuses on diagnostic rather than therapeutic skills. Sometimes students are only expected to copy the prescribing behavior of their clinical teachers, or existing standard treatment guidelines, without explanation as to why certain treatment is chosen. Books may not be much help either. Pharmacology reference works and formularies are drug-centered, and although clinical textbooks and treatment guidelines are disease-centered and provide treatment recommendations, they rarely discuss why these therapies are chosen. Different sources may give contradictory advice. This book in primarily intended for under graduate medical students who are about to enter the clinical phase of their studies. It will provide step by step guidance to the process of rational prescribing together with many illustrative examples. It teaches also skills that are necessary throughout a clinical career. Postgraduate students and practicing doctors may also find it a source of straightforward information. I wish to acknowledge the ongoing efforts of my contributing authors, and we are deeply grateful to all those who have with such good grace given us their time and energy to supply valuable facts and opinions, they principally include:

 Prof. Hussein El-Beltagi who took over the preparation of all books since the 1st edition in 1995 including the revision process, printing control, distribution and selling control.

 Assist. Prof. Mohamed-Hesham Daba who took over the revision process and amendments of the last two editions.

 Assist. Prof. Abdel-Motaal Fouda who prepared the last two editions in a readable upto-date text to provide essential information necessary throughout the clinical career.

 Dr. Sameh Abdel-Ghany who assisted in the revision process. Much of any merit this book may have is due to the generosity of those named above.

Gamal M. Dahab (MD, PhD) Professor Emeritus in Clinical Pharmacology Mansoura Faculty of Medicine  

iii

Miss sion and a Vis sion Our mission The Clin nical Pharm macology Department D is seeking excellence e and leadeership in fou ur major core ac ctivities: edu ucation, res search, com mmunity serrvice, and faculty f and staff development. gh innovattive and We are e connectin ng basic medical m sc iences with clinical care c throug disciplin ned teachin ng of clinica al pharmaco ology in an integrative i manner m

Our v vision The dep partment off Clinical Ph harmacolog gy is aiming g to be a premier acad demic model in the field of pharmacolo ogy and the erapeutics in Egypt an nd Middle East E throug h promoting use of the bestt therapeutics and dev veloping new wer experim mental and clinical reseearch proje ects.

Value es The gu uiding prin nciples and beliefs ffor the dep partment

 Excellence, creativity, innovation, fairness, honesty, transparenncy, collab boration,   

iv

mwork and lifelong learning team Rec cognition tha at our stude ent comes ffirst All m members of o our department musst see them mselves as integral to the succes ss of our misssion and ou ur departme ent as integ ral to their personal p su uccess. As we subscrribe to the ese values,, we shall be profes ssionals in the profes ssion of education.

Contributers

Effat A. Haroun MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Somaya A. Mokbel MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Elhamy M. El-Kholy MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Amany A. Shalaby MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Gamal M. Dahab MD, PhD, MSc (Int.Med) Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Amal Abdel-Hamid MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Farida M. El-Banna MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Essam A. Ghyati MD, PhD Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Aly M. Gaballah MD, PhD, MSc (int.Med) Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Mohamed-Hesham Y. Daba MD, PhD Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Layla T. Hanna MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Abdel-Motaal M. Fouda MD, PhD Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Mohamed Kheriza MD, PhD, MSc (Int.Med) Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Vivian Boshra MD, PhD Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Abdel-Rahman A. Yassin MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Hala A. Al-Ashri MD, PhD Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Mohmmad A. Attia MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Nageh Rizk MD, PhD Lecturer in pharmacology Mansoura Faculty of Medicine

Mohamed Abdel-Ghani MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Elsayed A. Hassan MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Hussien M. El-Beltagi MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Mohamed Abdel-Monem MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Karawan M. Abdel-Rahman MD, PhD Prof. of Clin Pharmacology Mansoura Faculty of Medicine

Mahmoud A. Naga MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

   

v

Ahmad Hassan MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Mohamed Abou El-khair MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Ahlam El-masry MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Sameh A. Abdel-Ghani MSc. Assist. Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

Rehab Hamdy MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine

vi

   

Table of Contents  

CHAPTER 4: AUTACOIDS AND ANTI-INFLAMMATORY DRUGS Part 1: Autacoids Histamine Serotonin Kinins Endothelins Purines Fatty acid derivatives

111 111 114 117 117 118 119

Part 2: Non-steroidal anti-inflammatory drugs (NSAIDs) Acetylsalicylic acid Other NSAIDs

122 122 127

Part 3: Acute rheumatic fever

130

Part 4: Drug therapy of rheumatoid arthritis

133

Part 5: Drug therapy of gout

136

Review questions

142

CHAPTER 5: CARDIOVASCULAR PHARMACOLOGY Part 1: Systemic hypertension and antihypertensive drugs Basic information Management of hypertension Angiotensin-converting enzyme inhibitors Calcium channel blockers Vasodilators Endothelin receptor blockers Specialized vasodilators Management of hypertensive emergencies

149 149 150 152 157 160 161 162 163

Part 2: Therapy of peripheral vascular disease

164

Part 3: Therapy of ischemic heart disease Basic information Management of stable angina Management of acute myocardial infarction

165 165 166 172

Part 4: Therapy of congestive heart failure Basic information Therapy of heart failure Management of acute pulmonary edema

173 173 174 180

Part 5: Management of shock

182

Part 6: Cardiac arrhythmia and antiarrhythmic drugs

184

vii

Basic information Antiarrhythmic drugs Review questions

184 185 194

CHAPTER 6: PHARMACOLOGY OF THE BLOOD Part 1: Hyperlipidemia and drugs that lower plasma lipids Basic information Lipid lowering drugs

203 203 204

Part 2: Drugs affecting hemostasis Anticoagulant drugs Fibrinolytic drugs Antiplatelet drugs Hemostatic agents Drugs affecting blood viscosity

207 210 212 213 215 217

Part 3: Drugs used in the treatment of anemia Iron deficiency anemia Red cell deficiency anemia Megaloblastic anemia Hemopoietic growth factors Drug induced aplastic anemia

218 218 220 221 223 223

Review questions

226

CHAPTER 7: PHARMACOLOGY OF THE RESPIRATORY SYSTEM

viii

Part 1: Agents used to treat cough Antitussives Mucolytics Expectorants

231 232 233

Part 2: Therapy of bronchial asthma Bronchodilators Reduction of bronchial inflammation Prophylactic treatment Other drugs Treatment of acute severe asthma

234 235 238 239 240 240

Part 3: Oxygen therapy Basic information Oxygen therapy

241 241 242

Review questions

245

 

                                         

Part 1 1:

Auttacoids

Inflamm mation is the comp plex biolo gical resp ponse of vascular v tisssues to harmful stimuli.. Injury pro oduces locally-acting g substanc ces that inittiate inflam mmatory re esponse and acttivate the repair r proc cess. Thesse substances are terrmed 'auta acoids'. Examp ples of auttacoids:    

Amino acid derivatives d s: e.g. hista amine and d 5-HT (serrotonin). Vas soactive peptides: p e.g. e angiote ensin, kinin ns and end dothelins. Fattty acid de erivatives: e.g. prost aglandins, thrombox xanes, leukkotrienes, etc. e The e family of cytokines:: e.g. interle eukins, inte erferones, TNF, T growthh factors, etc. e

█ Histtamine 



Hisstamine is formed frrom the a amino acid d histidine by the aaction of histidine h dec carboxylase and storred mainly in mast ce ells. Non-m mast cell hhistamine is found in sseveral tisssues includ ding the brrain. No clinically useful dru ugs affect the synthe esis or me etabolism of histamiine, but cerrtain drugs can cause e release o of histamin ne from ma ast cells ass a side efffect.

Histam mine releas se: can oc ccur throug gh 2 proce esses:



Ca22+ dependent mech hanism: byy fixation of o IgE to th he surfacee of mast cell c with 2+ sub bsequent activation of the complem ment, this causes Ca influ ux and deg granulation n of mast cells. c Manyy drugs can induce th his type e. g. penicillin.



Ca22+ indepen ndent mec chanism: – Displacem ment of his stamine fro om storag ge granules s by drug gs: e.g. mo orphine, tubocurarrine, vanco omycin, an nd amine antibiotics. – Mast cell damage: by b venomss, or mechanical trauma. 111

Pharmacological effects of histamine Histamine acts on at least 4 types of receptors: R

Postreceptor Site mechanism

H1 Gq ↑ IP3 & DAG

Effect

CNS Nonvascular smooth ms

Functions related to appetite and satiety Spasm (→ bronchoconstriction, GIT spasm).

Blood vessels

– VD of microcirculation (arterioles and precapillary sphincters) → ↑ capillary permeability (edema) and fall of BP. – This VD is due to release of NO from vascular endothelium.

Exocrine glds

↑ exocrine secretions (bronchial, lacrimal, etc)

Sensory nerves Pain and itching H2 Gs ↑ cAMP

Gastric parietal ↑ HCl secretion. cells ↑ cardiac contractility and HR. Heart ↓ histamine release (-ve feed back effect). Mast cells

H3 Gi ↓ cAMP

CNS and presynaptic nerve endings

Wakefulness and modulation of other neurotransmitters release.

H4 Gi ↓ cAMP

Inflammatory cells

Regulation of the inflammatory response 

Clinical uses of histamine

 Histamine itself has no clinical applications.  Some selective agonists are available for diagnostic purposes only e.g. test for gastric secretion. Histamine antagonists

■ Physiological antagonists (adrenaline): adrenaline reverses all the effects of histamine by action on different receptors (see ANS).

■ Histamine receptor antagonists: – H1-blockers: e.g. diphenhydramine, loratidine, etc. (see below) – H2-blockers: e.g. cimetidine, ranitidine, famotidine, etc. (see GIT) – H3 and H4 -blockers: are not yet available for clinical use. ■ Histamine release inhibitors (mast cell stabilizers): ketotifen and cromoglycate They inhibit Ca2+ influx into mast cells and prevent mast cell degranulation. 112

■ Desensitization therapy (immunotherapy): Immunotherapy is a process in which an allergic patient can become desensitized to antigens that trigger allergic responses. Small doses of the allergic substance are injected weekly. Each week the dose is increased. Gradually a protective antibody (IgG) is formed to block the allergic reaction. Many patients notice an improvement within 6 months.

█ H1-receptor antagonists 1st generation H1 blockers

2nd generation H1 blockers

Diphenhydramine Dimenhydrinate Clemastine Antazoline Cyclizine - Meclizine Chlorpheniramine Promethazine Cyproheptadine

Loratidine Azelastine Cetirizine Fexofenadine

CNS effects

They can cross BBB (more lipophilic) and exert significant CNS actions

Cannot cross BBB (less lipophilic) and have little or no CNS actions

Potency

Less potent H1 blockers

More potent H1 blockers

Effects related to H1 blocking

– Relief of itching, pain and allergic response. – ↓ capillary permeability and inflammatory edema induced by

Other effects

Sedation: but excitation or even convulsions may occur in some cases (especially in children or with high doses).

Examples

Ketotifen is a 2nd gen H1 blocker and mast cell stabilizer (see respiratory pharmacology).

histamine – ↓ bronchoconstriction, bronchial secretions, lacrimation, etc.

Atropine-like actions: most of the first generation drugs can block peripheral muscarinic receptors leading to urine retention and blurred vision.

Not present

Antiemetic action: useful in preventing motion sickness. α-receptor blocking action: 113

leading to orthostatic (postural) hypotension in susceptible individuals. 5-HT receptor blocking action (especially cyproheptadine): so it is useful drug for treating carcinoid syndrome. Duration of action Therapeutic uses

3-8 h

3-24 h

■ Allergic conditions: – The use of H1-blockers is effective in allergic conditions in which histamine is the primary mediator (e.g. allergic rhinitis and urticaria). – N.B. In bronchial asthma, which involves several mediators, the use of H1-blockers is generally ineffective.

■ Motion sickness and vestibular disturbances: – The first-generation H1-blockers (especially diphenhydramine and promethazine) are effective in preventing motion sickness, but their efficacy in Ménièrs's disease is not established. – They act by blocking H1 and muscarinic receptors in the vestibulocerebellar pathway. – N.B. Scopolamine remains the most effective treatment for motion sickness.

■ Carcinoid syndrome: – Carcinoid syndrome is caused by a serotonin-secreting neoplasm of the enterochromaffin cells of the GIT. – When the tumor is not operable, cyproheptadine and other 5-HT blockers can be used to block 5-HT receptors. Adverse effects

– Sedation with impaired concentration, but rarely excitation and convulsions may occur in children after toxic doses.

– Anticholinergic (atropinelike) actions: this may cause urine retention, dry mouth and blurred vision.

114

The second-generation drugs are metabolized by the hepatic CYP450 enzymes. Some of the early drugs in this group prolonged the QT interval and caused serious arrhythmia (torsade de pointes) when given with other drugs that inhibit CYP450 system (e.g. ketoconazole), and in patients

– Orthostatic hypotension due to their α-receptor blocking action. Interactions These drugs can potentiate the sedative effect of hypnotics, alcohol, etc.

with liver disease. These drugs are now withdrawn from the market.

Dangerous arrhythmia when given with other drugs that inhibit CYP450 system.

█ Serotonin (5-hydroxytryptamine; 5-HT) 5-HT is formed from the amino acid tryptophane and stored mainly in the enterochromaffin tissue of the GIT (90%) and platelets (10%). Serotonin is found also as a transmitter in many areas within the CNS. Like histamine, no clinically useful drugs affect the synthesis or metabolism of 5-HT, but many drugs can act on 5-HT receptors as agonists or antagonists. Pharmacological actions of 5-HT 5-HT acts on at least 7 types of receptors: Distribution

Postreceptor mechanism

Effect

5-HT1A CNS, cranial 5-HT1B blood vessels 5-HT1D 5-HT1E

Gi ↓cAMP

Role in anxiety, cognitive function, appetite, thermoregulation, memory, nociception VC of cranial BV.

5-HT2A Platelets 5-HT2B smooth muscle, 5-HT2C CNS

Gq ↑ IP3

Platelet aggregation (5HT2A) VC and smooth muscle contraction Hallucinations

5-HT3

Area postrema, enteric nervous system

Na+ ion channel

Nausea and vomiting Nociception (pain)

5-HT4

CNS and enteric nervous system

Gs ↑ cAMP

↑ GIT motility and secretions

5-HT5A CNS

Gi ↓cAMP

?

5-HT6,7 CNS

Gs ↑ cAMP

Anxiety, cognitive function, thermoregulation, memory, nociception

115

█ Som me 5-HT agonists s and an tagonistts in clinical use ▌5-HT T agonists s ■ Bus spirone: (ssee also CN NS)

– It acctivates ceentral 5-HT T1A recepttors. It is used forr treatment of an nxiety diso orders esp pecially in elderly e patiients. – Theerapeutic effect e may take as lo ong as 2w weeks to ap ppear. ■ Trip ptans: sumatriptan n, zolmitrriptan, narratriptan (ssee also AN NS)

– Theey activate 5-HT1B/1D receptors.. – Thee major usse of tripta ans is the treatmen nt of acutte migrain ne. Activat ion of 5-H HT1D recep ptors inhibiits inflamm mation of meninges,, pain transmission , and rele ease of VD D substan nces e.g. calcitoniin gene-related peptide in trige eminal neu urons. Activation of 5-HT 5 ceptors ca auses VC of o the dilaated cerebral ves1B rec selss. About 50 0%–80% of o patients report reliief from pa ain within 2 hours. – 5-H HT1B activitty can cause corona ary spasm m so; these e drugs arre contraindicated in p patients witth ischemic c heart dissease (IHD). ■ Teg gaserod:

– It iss a specificc 5-HT4 ag gonist. It in ncreases GIT G motility y so it is uused for tre eatment of irrritable bow wel syndro ome with c constipation. ▌5-HT T antagon nists ■ Cyp proheptad dine:

– It bllocks 5-HT T2, H1, & muscarinic m c receptors s. – It is used for treatment t of o symptom ms of carc cinoid tumo or and as aantiallergic c. ■ Aty ypical antip psychotics: Olanzap pine, rispe eridone (see also CN NS)

– Theey block 5-HT2A and a dopam mine D2 receptors in the CNS lead ding to imp provement of the neg gative symp ptoms of schizophre s enia. ■ Ond dansetron n, granisettron: (see a also GIT)

– Theey selectiveely block 5-HT 5 ptors centrally (CTZ) and perip pherally (GIT). 3 recep – It is used for trreatment off nausea & vomiting asssociated with w cancerr chemothe erapy. 116

█ Kiniins (brad dykinin)  Kiniins are potent p va asodilator peptides form med from m protein substrate es called kininogen byy the effect e of kallikrein enzyme.

 Kiniins act on o at lea ast 2 sub btypes of rece eptors: B1 1 and B2 2. Activatio on of B2 rece eptors ca auses VD D and ↑ capillary perm meability, smooth ms co ontraction (bro onchoconsstriction, GIT G colic, etc.), and stim mulation of sensory nerves n caussing pain.

 Icattibant is a 2nd gene eration dec capeptide which acts as a a selec ctive anta agonist at dykinin B2 2 receptorrs. It is give brad en by s.c. injection for the t sympto omatic tre atment of acu ute attackss of hereditary angioedema. It m may also be usefu ul in drug g-induced ang gioedema, ascites, an nd pancrea atitis.

 Reccently, a 3rd generation of oraally active B2--receptor antagonists was d developed and d currently under stud dy.

█ End dothelins s  End dothelin is a vasocon nstricting p peptide pro oduced by the endotthelium. Th here are 3 issoforms. Endotheliin-1 (ET-1 1) is one of the strongest vasocons strictors currrently stud died.

 End dothelins act a on at least 2 subtyypes of rec ceptors: ET TA and ET TB.  Mosst of ET-1 effects are a mediatted throug gh ETA rec ceptors pre resent in vascular v smo ooth ms an nd other tissues. Its activation leads to potent p VC,, vascular smooth ms proliferatio on, cardiac c hypertrop phy, and elevation e off blood preessure.

 Incrreased pro oduction of ET-1 hass been imp plicated in a variety of CVS diseases, including prim mary pulm monary hyp pertension n, cardiac hypertrop phy, heart failure, athe erosclerosis, and corronary arte ery disease e.

 Bossentan is orally activve nonseleective bloc cker of ET TA and ETBB receptors s, while ambrisentan is a selec ctive ETA b blocker. Bo oth drugs are approv oved for tre eatment of p pulmonary y hyperten nsion.

117

█ Purines as mediator m rs Nucleo osides (ade enosine) an nd nucleottides (ADP P and ATP P) are extraacellular chemical mediators. ATP is i stored in vesicless and relea ased by ex xocytosis or through h tissue damage. Released ATP is s rapidly converted to ADP and adennosine. The three hree main families o of purine receptors r and exertt a wide ra ange of puriness act on th functions.

▌Drug gs acting on purine recepto ors: Adeno osine It is a sshort actin ng purine A recepto r agonist. It is given n by i.v. ro oute to inh hibit AV conduc ction and converts c supraventr s ricular tac chycardia to the sinuus rhythm in nonasthma atic patientts (see CVS S). Methy ylxanthine es Caffein ne, aminop phylline and d theophyylline are purine p A1 receptor r a antagonistts. They are use ed as bron nchodilato ors and CN NS stimula ants (see re espiratory)). 118

█ Fattty acid derivative d es (eicos sanoids) They are group of o fatty acid derivativves derived d from ara achidonic aacid (20 ca arbons). The fam mily of eico osanoids in ncludes: Prosta aglandins s (PGs) PGs arre memberrs of fatty acid deriva atives. All are derive ed from araachidonic acid by the action of cycllooxygenase (COX) e enzyme wh hich has 3 isoforms: 

COX X-1 (physiiological; constitutiv c ve): is invo olved in sy ynthesis o of protective PGs (e.g g. PGE2, PGI2) respo onsible for protection n of stoma ach from H HCl, regula ation of RBF F, inhibition of platele et aggrega ation, etc.



COX X-2 (path hological; induciblle): is invo olved in synthesis of undessirable PGss (e.g. PGF2α, PGD2) involvved in infla ammatory reac ctions, bronchoconsttriction, etc c.



COX X-3 (centrral): it is a variant off COX2 th hat found only o in the e brain an d may be included in syntthesis of PGs resp ponsible for fev ver and pain sensation. It is selectiv vely inhibitted by algesic/antipyretic drugs ana e.g. ace etaminoph hen (para acetamol)) and dipy yrone.

Throm mboxanes s (TXs)    

The ey are also products of cyclooxxygenase enzyme. e The ey are synthesized in high conc centration in platelets s. The ey are of 2 forms: TX XA2 (the acttive form) and a TXB2 (the ( inactivve form). TXA A2 is the most m potentt endogeno ous stimulator of platelet aggreegation.

Leuko otrienes (L LTs)    

The ey are derivved from arachidonic a c acid by the action of o lipooxyg genase enzzyme. The ey are of 4 main types: LTB4, LT TC4, LTD4, and LTE4. A m mixture off LTC4, LTD L 4, LTE E4 is terme ed (the slow-reactinng substa ance of ana aphylaxis = SRS-A) th hat is relea ased during g inflamma atory respo onse. LTB B4 is powerful bronchoconstri ctor and chemotact c tic for leukkocytes.

119

Pharmacological actions of eicosanoids PGs and other eicosanoids act on cell surface G-protein coupled receptors. These receptors are termed DP1-2, EP1-4, FP, etc. The following table summarizes the important effects of different eicosanoids: PGE1, PGE2

PGI2

PGF2α

TXA2

BV Edema

VD +

VC –

Bronchi

Relaxation

Constriction

Uterus Kidney

Pregnant: contraction Non-pregnant: relaxation ↑ RBF ↓aggregation

Platelets Other effects

Contraction ↓ RBF

LTB4 VD +++ Severe constriction Contraction ?

↑aggregation

- ↓ gastric HCl and ↑ mucus secretion

Chemotaxis

- Hyperpyrexia

Therapeutic uses of prostaglandins ■ PGE1:

– PGE1 (Alprostadil) is still available as urethral inserts for treatment of erectile dysfunction in men: it produces VD of the vascular smooth muscle of the corpus cavernosum and improves erection. – To maintain patency of the ductus arteriosus in infants with congenital cyanotic heart diseases until surgical correction is undertaken. The ductus arteriosus in neonates and infants is highly sensitive to VD by PGE1. Patency of the ductus is necessary in those patients to ensure additional oxygenation of the blood until surgical correction of the problem is undertaken. – Treatment of peptic ulcer: Mesoprostol is approved for use in patients taking high doses of NSAIDs to prevent gastric ulceration. ■ PGE2:

– Induction of labor near full term (Dinoprostone). – Treatment of peripheral vascular disease. ■ PGI2 (Prostacycline):

– To

inhibit platelet aggregation and prevent thrombosis during cardiopulmonary bypass surgery, hemodialysis, and retinal artery occlusion. – Treatment of pulmonary hypertension and peripheral vascular disease. 120

■ PGF F2α:

– Induction of o labor ne ear full terrm (Enzaprost). Therapeutic abortion: as va aginal supp positories. It may b be combine ed with – T PGE2 and d mifepristo one (anti-p progesterone) to prod duce moree powerful uterine c contraction. – T Treatment of open n-angle g glaucoma: to dilate e uveoscleeral vesse els and e enhance uveoscleral u l outflow (↑ drainage)) of aqueou us humor ((Latanopro ost). ■ Thrromboxanes and leu ukotrienes s: they hav ve NO currrent clinicaal uses.

█ INHIBITORS OF O EICOSA ANOIDS ■ Corrticosteroids: they inhibit p phospho olipase A2 enzyme and co onseque ently inhibit synthesis of ALL L the eico osanoids family (s see endoc crine pha armacologyy). ■ Non n-steroida al anti--inflamma atory drugs (NSA AIDs): they inhibit cycloo oxygenase e enzyme:

–

Cla assical N NSAIDs (e.g. asp pirin) noninhiibit all COX enzyme e sele ectively.

–

New wer NSAIIDs (e.g. celecoxib)) inhibit COX-2 selectively. s

■ Leu ukotriene inhibitors: i : Zaffirlukast an nd Montelukast:

– They blocck leukotrie ene recepto ors. a orally. o Zafiirlukast it is given tw wice daily b but Montelukast is – They are absorbed –

given once daily. Uses: LTss receptor antagonissts are new w drugs to be used inn the treatment of bronchiall asthma and a other i nflammato ory conditio ons.

Zile euton:

– It inhibits 5-lipooxyg genase enzzyme leading to decrrease LTs ssynthesis. b asthma and other in nflammato ry conditio ons. – Uses: treaatment of bronchial

121

Part 2:

Non-steroidal anti-inflammatory drugs (NSAIDs)

Classification ■ Non-selective COX inhibitors (inhibit COX-1 and COX-2):

– Salicylic acid derivatives: aspirin, aloxiprine, aminosalicylic acid, diflunisal, –

– – – –

methyl salicylate, etc. Acetic acid derivatives: – Carboxylic acetic acid: indomethacin, sulindac, etodolac. – Phenyl acetic acid: diclofenac Propionic acid derivatives: iboprufen, ketoprofen, fenoprufen, naproxen. Fenamic acid derivatives: mefenamic acid, fulfenamic acid. Pyrazolone derivatives: phenylbutazone, azapropazone Oxicams: piroxicam, tinoxicam.

■ Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam.

▌Acetylsalicylic acid (Aspirin) Chemistry and pharmacokinetics   



Oral absorption is complete; most of absorption occurs from the stomach and upper GIT. Widely distributed to all tissues including CNS. Metabolism of salicylates occurs by the hepatic microsomal enzymes. – At low doses, elimination is done by the first-order process. – At high doses, elimination is done by the zero-order process. Excretion is increased by alkalinization of urine (pH 8) because in alkaline urine, most of aspirin is ionized and less re-absorbable.

Mechanism and pharmacological effects Aspirin is non-selective and irreversible COX inhibitor leading to inhibition of both PGs and TXs. This distinguishes it from other NSAIDs, which reversibly inhibit COX enzyme. Analgesic action: for mild to moderate intensity pain (not severe pain). Mechanism: – Peripheral effect: decrease PGs synthesis in the peripheral inflamed tissues. – Central effect: decrease PGs synthesis in the subcortical sites (thalamus and hypothalamus). 122

Antipyretic effect: Aspirin is antipyretic but NOT hypothermic agent i.e. it can lower elevated body temperature but not normal body temperature. Mechanism: – Decrease PGE2 synthesis in the hypothalamus. – Decrease the hypothalamic response to interleukin-1 (endogenous pyrogen). – Cutaneous VD and increase sweating. Anti-inflammatory, anti-immunological and anti-rheumatic effects: Mechanism: By inhibition of COX enzyme, it ↓ synthesis of PGs and TXs, and possibly other inflammatory mediators leading to: – Decrease inflammatory cell activation and chemotaxis. – Decrease capillary permeability. – Decrease hyaluronidase enzyme and inhibits spread of inflammation. – Stabilize lysosomal membranes of inflammatory cells. Respiratory effects:

– Low

toxic doses: produce metabolic acidosis → compensatory hyperventilation to wash excess CO2 → prolonged respiratory alkalosis.

– High toxic doses: produce metabolic acidosis together with inhibition of RC → death from severe acidosis. CVS effects:

– Therapeutic doses: no significant effect on the CVS. – Toxic doses: inhibit VMC leading to circulatory failure. GIT effects: salicylates can produce 2 types of gastric ulcer:

– Acute gastric ulcer: occurs as a result of acute ingestion of large doses of salicylates. The pathogenesis is related to trapping of salicylate ions inside the gastric mucosal cells leading to acute, painful gastric bleeding.

– Chronic gastric ulcer: occurs as a result of chronic ingestion of salicylates. The pathogenesis is related to chronic inhibition of the protective PGE1, PGE2 and PGI2 synthesis leading to chronic ulceration and chronic blood loss. Hepatic effects: salicylates can produce 2 types of hepatic injury:

– Mild hepatic injury: it is dose-dependent, reversible and asymptomatic. There may be mild increase in serum transaminases (SGOT and SGPT). 123

– Sevvere hepatic injury: “Reye’s “ syyndrome”:: it is a rare e and fatal condition occurs if a aspirin is used u to con ntrol fever of some viral infectio ons (e.g. chicken c pox x, influenza a, etc.) in children below 12 2 years old.. There is severe fa atty infiltra ation of the liver, pan ncreas, and kid dney asssociated with enc cephalopatthy. The etiologyy is unk known. Man nagement is supporttive. Hemattologic efffects:

– Antiplatelet acction: aspirrin inhibit p platelet aggregation by: – – –

Irreverssible inhibition of CO OX enzyme e → ↓ TXA2 → ↓ plateleet aggregattion. Irreverssible acetylation of pla atelet cell membrane m s → ↓ platellet adhesio ons. Decrea ase platele et ADP syn nthesis → decrease platelet accuumulation.

– Asp pirin in hig gh doses (> 6 gm /day) inhiibits hepatic prothrrombin (fa actor II) synthesis → prrolong blee eding time e.

124

Renal e effects:

– Anaalgesic neephropathyy: it is cchronic re enal

Aspirin in a dose of 75-

failu ure due to chronic abuse o of analges sics, 150mg is not thought to which produc ce chronic c renal isch hemia due e to have a signnificant effe ect on dec crease syntthesis of re enal PGE2 and PGI2. plasma uraate levels - the British Socciety for RheuR – Saltt and wateer retention n: due to d decrease RBF R matology recommen nd it and d increase aldosteron ne should be continued if re– Antaagonize diuretic d efffect of d diuretics and quired for cardiovas scular s. prophylaxis antiihypertensive effects s of β-bloc ckers: due e to dec crease syntthesis of PGE P 2. – Uricc acid excrretion: sma all-to-mode erate doses of asp pirin can ↓ uric u acid ex xcretion and d thus con ntraindicate ed in patiennts with gou ut. Metabo olic effectts:

– High doses cause c unco oupling of oxidative phosphorrylation → tachycard dia and hyp perpyrexia. Uterus s:

– Prolongation of pregnancy and d delay of labo or due to inhibition of o PGs nec cessary for uterrine contra action during labor. T The use of NSA AIDs after 20 weeks of pregna ancy is not reco ommended d. Therap peutic use es of salicy ylates

 As analgesicc and anttipyretic: in mild-to-mo oderate paiin e.g. hea adache, art rthritis, etc. It should not n be used rou utinely as s antipyretic be ecause fev ver may be e a norma al pro otective me echanism.

 As anti-inflam mmatory and a anti-rrheumatic c: c fever, rheumatoid r d arthritis, in rheumatic osteoarthritis, etc.

 As antithrom mbotic: see box. 125

 As keratolytic and counter-irritant: – Salicylic acid has keratolytic action and is used for treatment of warts. – Methylsalicylic acid is used as a counter-irritant for local rheumatic pain. Adverse effects of salicylates GIT:

– Epigastric pain, nausea and vomiting. – Acute and chronic gastric ulcers (why?).

Hepatic:

– Mild reversible hepatic injury in adults. – Severe hepatic injury in children: “Reye’s syndrome”.

Kidney:

– Analgesic nephropathy (why?). – Salt and water retention. – ↓ the diuretic effect of loop diuretics and antihypertensive effects of β-blockers (why?). – Precipitation of acute gout in hyperurecemic patients.

Blood:

– Increase bleeding tendency: (why?). – Displacement of other drugs from plasma proteins.

Uterus:

– Prolongation of pregnancy and delay of labor (why?).

Hypersensitivity reactions:

– Bronchospasm (aspirin asthma) in patients with history of asthma or allergic rhinitis due to accumulation of LTs.

Precautions and contraindications        

GIT disorders: peptic ulcer, gastritis, hemorrhagic pancreatitis, etc. Hemorrhagic disorders: hemophilia, thrombocytopenia, etc. Chronic renal diseases: aspirin may aggravate renal failure Chronic liver diseases: (those patients have bleeding tendency). Uncontrolled hypertension: risk of fatal bleeding. Gout: small-to moderate doses may inhibit uric acid excretion. Before surgery: aspirin must be stopped at least 7 days before surgery. Children 100 mg/dl).

█ OTHER NSAIDS Diclofenac

– One of the most widely used NSAIDs. – Generally, it is less gastric irritant than other NSAIDs but more nephrotoxic. A dose of 150 mg/day can impair renal blood flow and GFR. – It is often combined with PGE analogue misoprostol to decrease gastric ulceration. – Topical gel is available for local rheumatic pain and osteoarthritis of the knee and hands. Sulindac and ketorolac

– Both have minimal effect on platelet aggregation. – Sulindac is a prodrug and has long t½. – Ketorolac is a potent analgesic but it can cause severe GIT bleeding. Ibuprofen, fenoprofen, ketoprofen

– – – –

They have no reported interactions with oral anticoagulants Ibuprofen is a good alternative to aspirin in children with flu fevers. Fenoprofen has been reported to induce nephrotoxic syndrome Long-term use of ibuprofen is associated with an increased incidence of hypertension in women. 127

Indom methacin

– It iss a very po otent COX inhibitor b but rela atively mo ore toxic than oth her NSA AIDs. – It iss approved d to speed the closu ure of patent ductus d arrteriosus in prem mature infants (oth herwise it is not used in children); c itt inhibits tthe prod duction of PGs wh hich preve ent clossure of the e ductus. Piroxic cam

– It haas long t½ ½ (~ 45 hours). – Likee aspirin and indomethaccin, blee eding and d ulceratio on are mo ore likely with piro oxicam tha an with oth her NSA AIDs.

▌Sele ective CO OX-2 inhibitors: Celeco oxib, etoric coxib, me eloxicam Selectivve COX-2 inhibitors s are newe er forms of NSAIDss that dire ectly targe et COX-2 enzyme e respon nsible fo or mation and d pain. Celecoxib iis inflamm approx ximately 30 0 times more m poten nt at inh hibiting COX-2 tha an COX-1 1. Meloxic cam is slightly s se elective fo or COX-2 than COX X-1 enzyme e. ectivity forr COX-2 re educes th he Sele risk of peptic ulc ceration bu ut does no ot o adve erse-effectts seem tto affect other of NSA AIDs (espec cially the risk r of rena al failure).. Selectivve COX-2 2 inhibitorrs may also incrrease the e risk o of cardiov vascular accidents a s (myocard dial infa arction, thrrombosis and a stroke e) due to relative in ncrease in TXA2 and platelet ag ggregation n (TXA2 is fformed by COX-1 where PGI2 is formed by b COX-2 ). Rofeco oxib (Vioxx x®) and valdecoxib b were withdra awn from the t market in 2004 an nd 2005 re espectively y because of these potential p adverse e effects. 128

Mechanism:

Pharmacological effects:

Non-selective COX inhibitors

Selective COX-2 inhibitors

They inhibit COX-1 (noninducible) and COX-2 (inducible) enzymes

They inhibit COX-2 (inducible) enzyme only

Both classes have equal analgesic and antipyretic effects

Gastric side effects: Frequent

Less frequent

Renal side effects:

Frequent

Frequent

Thrombotic complications:

Decreased (due to decreased platelet aggregation)

Increased (due to increased platelet aggregation)

Hypersensitivity reactions:

Frequent

Less frequent

 

 

129

Part 3 3:

Acu ute Rheu umatic F Fever (A ARF)

Definittion: It is an n inflamma atory disea ase that m may develo op as a co omplicationn of untre eated or poorly treated Grroup A β-hemolytic c streptococcal (GA ABHS) infeection of th he URT. It is cau used by an ntibody cro oss-reactivvity (i.e. autoimmune disease). nce Inciden    

Age e: 5-15 yea ars (rare 2--5 years - n never below 2 years). Envvironmenta al factors: poor p living conditions s, overcrow wding. Gen netic factors may pla ay a role. No sex differe ence in the e incidence e or pathog genesis.

Etiolog gy and patthogenesiis The au utoimmun ne theory (molecula ar mimicrry): the disease usuually follow ws URT infectio on with GABHS. G This rheu umatogenic c strain contain ssurface antigens a (hyaluro onic acid, cell wall polysaccha p arides, M protein, p etc c.) that aree immunologically similar to some host's h tissu ue. Antibod dies forme ed against these ant igens will later on cross-react with h connecttive tissue e antigens in the heart, syno ovial membranes, caudate nucleus, skin and subcutan neous tissu ue. Repea ated strepttococcal in nfection is required for se ensitization n of the im mmune system. Clinica al manifes stations: “J Jones critteria first published p 1944”: Major criteria: ■ ■ ■ ■ ■

Polyrthritis (7 70%): the joints are e swollen and a tende er. It is fleeeting (mig gratory), affe ects large joints, j and subsides without de eformity. Carrditis (50% %): murmurrs, arrhythm mia, cardio omegaly, pericardial p rub. Rhe eumatic ch horea (10% %): jerky li mb movem ments and d emotionaal instability occur mo ore in girls. It is revers sible. Sub bcutaneou us nodule es (5%): painless nod dules besid de muscle tendons. Eryythema ma arginatum (1%): red d patches ove er the limbss and trunk.

Minor criteria:      130

Fevver. Arth hralgia: pa ain in the jo oint. ↑ PR interval in the ECG G. ↑ an ntistreptolyysin O titre e (ASO). ↑C C-reactive protein p and d ESR.

Ac cute carditis oof a child 8 years y

Diagno osis: Revis sed Jones s criteria ( 1992 update e): At leasst 2 major criteria must m be pre esent OR 1 major + 2 mino or criteria PLUS evvidence of o previou us streptoc coccal infe ection: – Hisstory of ph haryngitis confirmed c by positiv ve thro oat culture e for GABH HS. – Elevvated AS SO titer > 400 U or othe er stre eptococcal antibodie es. gement Manag ▌TREAT TMENT OF F THE ACUTE EPISOD DE

d rest: ■ Bed

– – –

2 weeks in n absence of carditiss. 4 weeks in n presence e of carditis. 8 weeks in n presence e of heart ffailure or cardiomeg galy.

■ Diet: Salt and d fluid resttriction in presence of card ditis or hea art failure to t avoid vo olume overrload. ■ Anttibiotics: to o eradicate e streptoco occal infec ction

– –

First choic ce: benzylp penicillin (1 1 million IU U/6h i.v. or i.m.). Second ch hoice (in penicillin alllergy): Co--trimoxazolle or erythrromycin.

■ Antti-inflamm matory drug gs: to sup press acutte inflammation A. RF withou ut carditis: salicylattes (aspirin n) Dose: 100 0 mg/kg/d for 2 wee ks (till clinical manife estations ssubside) th hen give 75 mg/kg/d for 2 weeks w the en 50 mg//kg/d for another 2 weeks (M Max 16 ttabs/d). – Rapid breaathing (tac chypnea) i s the earliiest sign of o aspirin to oxicity. patients who w are alle ergic to asp pirin. – Naproxen is an alternative for p evere card ditis: cortiicosteroid ds (prednis solone) B. RF with se Dose: 2 mg/kg/d m forr 2 weeks (till clinica al manifesta ations sub bside) then reduce tthe dose to o 1mg/kg//d for one m month.

131

Why corticosteroids, but not aspirin, in presence of carditis?

 Aspirin produces excellent symptomatic relief of arthritis and fever but exerts  

non-specific effect on carditis. Aspirin cannot prevent pericardial rub or valve deformity, but steroids can prevent them. High doses of aspirin increase myocardial O2 consumption and heart work and so precipitate valvular lesions and CHF.

▌TREATMENT AFTER THE ACUTE EPISODE (PREVENTION OF RECURRENCE)

■ Long-acting penicillin: benzathine penicillin. Dose: 1,200,000 IU / 3-4 weeks by deep i.m. injection Duration of prophylaxis? – For mild or no carditis → for 3 years from last episode. – For moderate carditis → prophylaxis till 21 years. – In severe carditis or recurrent episodes of RF → lifelong prophylaxis.

Precaution during treatment of ARF with other disease ARF with TB

– Avoid using corticosteroids because they are immunosuppressant

ARF with CHF

– Fluid and salt restriction – If digoxin is needed, use with caution to avoid arrhythmia (the

and cause flaring of TB infection. – If it is necessary to use corticosteroids, it must be used under umbrella of antituberculos drugs.

heart is very sensitive to digoxin during Rh activity).

132

ARF with diabetes

– If corticosteroids are mandatory, consider adjusting the insulin

ARF with peptic ulcer

– Give salicylates through multiple routes or as enteric coated

dose to avoid hyperglycemia. – Consider possible interaction of salicylates with other antidiabetic drugs.

preparations to avoid gastric irritation. – Give salicylates after meals with plenty of fluids. – Use H2 blockers or proton pump inhibitors.

g therap py of rhe eumatoid arthrritis (RA)) Part 4: Drug Definittion RA is a chronic inflammato ory diseasse characte erized by symmetricc small join nt inflammatio on, swelling g, and deformity. Ext xtra-articula ar manifesttations aree also com mmon. Pathop physiology y The ex xact aetiollogy is un nclear how wever; gen netic facto ors play a n importa ant role. Activated T cells,, B cells, polymorpho p onuclear le eukocytes (PMLs), m macrophag ges, and comple ement systtem lead to productiion of solu uble media ators (lysossymes, cyttokines, e.g. TN NF-α, IL-1, etc.) tha at cause jjoint inflam mmation, cartilage c d destruction n, bone erosion n, and defformity. Why W the im mmune sys stem attac cks the jo oint structu ures as "foreign n" antigens, is unkno own.

Clinica al manifes stations

■ Artticular manifestation ns: The e disease affects a mainly small jjoints of the hands and a toes in a sym metrical fash hion. In se evere case es, large jo oints are also o affected.. Affected joints j are sswollen, painful and d with limited m mobility. Sym mptoms are a especia ally worse e in the mo orning. In late case es, chara acteristic ms of joint deformity are prese nt. form

■ Exttra-articular manifestations: The e spectrum m of clinical manifesstations off RA can extend e to include sy ystemic org gans e.g. pleural effus sion, perica arditis, anem mia, vasculitis, etc. 133

Diagnosis





Serological: – Abnormal blood antibodies "rheumatoid factor" can be found in 80% of RA patients. – Detection of Cyclic Citrullinated Peptide antibodies (anti-CCP antibodies): more specific than RF and can be detected up to 10 years before the development of RA. Joint X-ray can show joint swelling and bony erosions typical of RA.

█ Management of RA ▌Symptomatic treatment

■ NSAIDs: large doses of NSAIDs are usually required. They offer symptomatic relief of pain and inflammation but don't prevent joint destruction.

■ Corticosteroids: they are given as short-term therapy till DMARDs give their effect. ▌Disease-Modifying Antirheumatoid Drugs (DMARDs)

  

They are the most important and should be started as early as possible because their effect may take 3 weeks to 3 months to be evident. They prevent progression of the disease and slow joint destruction by modifying the immune reactions. Combinations of two or more DMARDs are more effective than a single drug.

■ Biologic DMARDs: TNF-α inhibitors TNF-α plays a crucial role in the pathogenesis of RA, and these drugs became the most important DMARDs.

134

–

Adalimumab and infliximab: they are monoclonal antibodies that complex with TNF-α and prevent its interaction with T cells and macrophages.

–

Etanercept: it is a recombinant protein that interferes with TNF-α and prevents it from binding to its receptors.

–

Acute and chronic infections, live virus vaccination, demyelinating disorders, class III or IV heart failure, and recent malignancies are contraindications to the use of TNF inhibitors.

–

Because these drugs are expensive, recent guidelines do not recommend their use until at least one nonbiologic DMARD, usually methotrexate, has been administered without sufficient success.

■ Methotrexate – – – –

It is a folic acid antagonist with cytotoxic and immunosuppressant properties. It is one of the first line drugs being used in more than 60% of RA cases. It inhibits multiple intracellular enzymes needed for activation of PMLs, T cells, and macrophages. It is given once weekly orally. Folic acid 5mg must be given 24h after methotrexate dose to compensate for folic acid deficiency. Common adverse effects: hepatotoxicity is common (monitoring liver functions is essential), myelosuppression (bone marrow), teratogenicity.

■ Hydroxychloroquine (antimalarial drug) – –

It decreases synthesis of DNA and RNA in the inflammatory cells and decrease response of T cells to antigens. It also stabilizes lysosomal membranes.

■ Sulfasalazine It is metabolized into sulfapyridine and 5-aminosalicylic acid. 5-ASA causes inhibition of IgA and IgM production, and suppresses T and B cell functions.

■ Immunosuppressant drugs –

–

Cyclophosphamide and azathioprine: suppress immune function by their cytotoxic action through a variety of mechanisms, particularly inhibition of DNA synthesis. Cyclosporine: It is a potent and specific inhibitor of T cells. It inhibits phosphorylation of calcineurin, a protein that regulates nuclear transcription factors in the T cells.

■ Gold salts Gold salts could be given i.m. or orally. Gold inhibits the functions of human macrophages and decrease the release of inflammatory cytokines and growth factors from inflammatory cells.

■ Leflunomide – –

It suppresses pyrimidine synthesis and suppresses T cell and B cell functions. It is effective as methotrexate in inhibition of bone damage.

■ Anakinra – –

It is a competitive IL-1 receptor antagonist. It has a relatively short half-life and must be administered subcutaneously daily. 135

Part 5 5:

Drug g therap py of go out

█ Basiic information Gout iss a form of inflammato ory arthritiss due to deposittion of mo onosodium m urate cryystals in the joiint tissue.. It is ca aused by chronic hyperuricemia (u uric acid > 7 mg/dll = 0.42 mmol/L L). emistry Bioche  



Uric c acid is the end product p o f purine mettabolism by b xanthene e oxidase e enzyme. The e majorityy of body’s uric acid is exc creted by the t renal PCT. P Som me drugs (e.g g. diuretics) may y interfer e with exc cretion of uric acid at this ssegment lead ding to its retention. The e renal excretion e of uric acid is enh hanced by alkalization of urine.

Causes s of hyperruricemia 

Dec creased uric u acid excretion: e account for 9 90% of ca ases of prim mary gout: – Drugs: e.g. diurettics, aspirin, pyrazina amide, ethambutol. – Kidneyy diseases.



Incrreased uric acid pro oduction: – High protein diet. – During treatmentt of some hhematologic maligna ancies (e.g.. leukemia)) due to tissue breakdown b n (tumor lyysis syndro ome). – Sex-lin nked uricac ciduria (Lessch-Nyhan n syndrome).



Mix xed causes: alcohol..

Pathog genesis off gouty artthritis   

136

Whe en serum uric acid d increase es, monosodium ura ate crystalls are selectively prec cipitated in n, and arou und the joiint tissue causing c irritation and d inflammattion. PNL Ls and ma acrophages come an nd phagoc cytose the "foreign" uric acid crystals cau using swelling and infflammation n of the artticular tissue. Leu ukocytes eventually e die d with th he release of proteolytic enzym mes and in nflammatorry mediato ors (e.g. LT TB4, IL1, PG Gs, etc) ca ausing seve ere inflamm mation.

█ HYP POURICEM MIC DRUG GS

▌Uric cosuric drugs: d Prrobeneciid anism of action: a it ha as biphasic c action: Mecha  

In S Small doses: it inhib bits tubula ar Secretiion of org ganic acid ds (e.g. uric acid, pen nicillin, rifam mpin) by in nhibiting orrganic acid d transportters in tubuular cells. In la aRge dose es (≥500 mg m twice/da ay): it inhib bits tubular Reabsorrption of uric u acid by iinhibiting the urate trransporter (URAT1), leading to ↑ excretio on of uric acid. a

Therap peutic use es

 As a uricosuriic agent in chronic goout.  To p prolong the t½ of some acidic drugs e.g. penicillin and d rifampicin n by inhibittion of theiir renal exc cretion. Advers se effects

– Gasstric irritatio on, skin ra ash, and ra arely intersttitial nephrritis and ap plastic ane emia. 137

–

If given during the acute attack, it can aggravate the inflammation because rapid lowering of serum uric acid during the acute attack causes mobilization of uric acid crystals from the tissue stores and aggravates the acute inflammation.

Precautions during the use of uricosuric drugs

– – –

They should not be used during the acute attack but 2-3 weeks after the acute attack has been subsided. Excess fluids and alkalinization of urine help uric acid excretion and prevent stone formation. Aspirin may decrease uric acid excretion and antagonize probenecid.

▌Inhibitors of uric acid synthesis: Allopurinol Mechanism of action

 

Allopurinol is a synthetic purine analogue. It inhibits xanthine oxidase enzyme leading to inhibition of uric acid synthesis. It has long duration of action because both the parent compound and its metabolite are potent inhibitors of xanthine oxidase.

Therapeutic uses



 

Recurrent attacks of gout (more than 2 attacks per year): the target uric acid level is 5 mg/dl (0.3 mmol/L). Start with 100 mg once daily then gradually increase the dose every 1-2 weeks to reach 300 mg/d. As an adjuvant therapy during treatment of hematologic malignancies (e.g. leukemia) to prevent hyperuricemia resulting from tissue destruction. Patients with Lesch-Nyhan syndrome should receive allopurinol for life.

Adverse effects

– Gastric irritation and hypersensitivity reactions (skin rash). – Precipitation of acute gout at the start of therapy due to mobilization of the deposited uric acid crystals from tissue stores leading to transient hyperuricemia Precautions:

– –

Do not give allopurinol during the acute attack of gout. Give prophylactic cover with NSAIDs or colchicine to avoid exacerbation of gout at the start of therapy.

Drug interactions Mercaptopurine, azathioprine, and theophylline are metabolized by xanthine oxidase, and coadministration with allopurinol will dramatically increase levels of these drugs.

138

▌Increase uric acid metabolism: Pegloticase   

Pegloticase is a recent recombinant form of porcine uricase, the enzyme that converts uric acid into the water-soluble allantoin. It is given as 8 mg i.v. /2 weeks. It can lower serum uric acid within 24 hours. . It is indicated in severe gout not responding to other agents.

█ ANTI-INFLAMMATORY DRUGS

Colchicine Mechanism of action

 Colchicine is a plant alkaloid. It binds to intracellular microtubular system



leading to inhibition of leukocyte motility, phagocytosis, and cell division (mitotic blocker). It inhibits the release of LTB4 and other mediators by leukocytes.

Therapeutic uses

 Acute attacks of gout: – It is specific for gouty arthritis. Other arthritic pains are not relieved by colchicine. – It has slower onset than NSAIDs and corticosteroids. Reduction of inflammation and relief from pain occur 12–24 hours after oral administration. – Because of its slow onset and high toxicity, it is not a first-choice drug in acute gouty arthritis unless the patient has contraindication for NSAIDs or corticosteroids. – The recommended dose is 1.2 mg orally (2 tablets) initially followed by one tablet (0.6 mg)/ 12 hour until the attack resolves.

Familial Mediterranean Fever (FMF) Also known as (recurrent polyserositis) is an autosomal recessive disorder which typically presents by the second decade. It is characterized by recurrent episodes of abdominal pain (due to peritonitis), pleurisy, pericarditis, arthritis. Attacks typically last 1-3 days.

 Familial Mediterranean fever (FMF): by an unclear mechanism. Adverse effects

– The most common: diarrhea. Why? Because the GIT epithelium has rapid rate of turnover. High oral doses of colchicine will inhibit this continuous renewal of GIT epithelium (by inhibiting cell 139

division) leading to accumulation of toxins and bacterial products with diarrhea.

– The most rare: alopecia and myopathy. – The most serious: aplastic anemia and agranulocytosis (bone marrow depression). NSAIDs Indomethacin and naproxen

– Indomethacin and naproxen are FDA approved NSAIDs for acute gouty arthritis although other NSAIDs can also work (but not aspirin). – They provide symptomatic relief in acute attacks faster than colchicine. – Their dose must be reduced if taken with probenecid because probenecid inhibits their renal excretion. Corticosteroids

– They are used as anti-inflammatory agents when colchicine and NSAIDs are not sufficient to control the acute attacks or when they are contraindicated. – For more details about the mechanism, see endocrine pharmacology.

140

 

141

Review Questions         

Mention uses of H1 blockers. Mention the main differences between 1st and 2nd generation antihistamines Mention the main differences between aspirin and celecoxib. Mention the main differences between aspirin and colchicine. Mention 2 uses of PGE1, PGE2, PGI2, PGF2α. Mention side effects of aspirin. Mention side effects of colchicine. Mention mechanism of aspirin as antiplatelet. Mention precautions during the use of antigout drugs.

Discuss on pharmacological basis each of the following:

    

Aspirin is contraindicated as antipyretic in children with viral infection. Aspirin is contraindicated in chronic liver disease. Allopurinol is better to be avoided during acute attack of gout. Aspirin (low dose) is contraindicated with uricosuric drugs. Diphenhydramine is contraindicated in old males with benign prostatic hypertrophy.

Discuss the pharmacodynamic principles underlying the use of:

   

PGI2 during extracorporeal shunt operations (e.g. hemodialysis). PGI1 during surgical correction of patent ductus arteriosus. Colchicine in acute gouty arthritis. Methotrexate in rheumatoid arthritis.

Mention the rationale of the following combinations:

 Mesoprostol is advised with diclofenac (NSAID).  Colchicine is given before allopurinol in acute gout.

142

Of each of the following questions, select THE BEST SINGLE answer:

1. Which of the following antihistamines has the LEAST sedation at therapeutic dose? A. Diphenhydramine B. Loratidine C. Promethazine D. Antazoline E. Cyproheptadine 2. Cyproheptadine is an antagonist at: A. B. C. D. E.

D1 and M1 receptors M1 and Nn receptors H1 and 5-HT receptors H1 and H2 receptors β1 and α1 receptors

3. Sumatriptan is effective for the treatment of acute migraine by acting as: A. An antagonist at β adrenergic receptors B. A selective antagonist at H1 receptors C. An inhibitor of prostacycline synthesis D. An agonist at nicotinic receptors E. A selective agonist at 5-HT1D receptors

4. The pharmacologic effects of acetylsalicylic acid include: A. Reduction of high body temperature B. Promotion of platelet aggregation C. Reduction of pain by stimulation of PGs synthesis D. Efficacy equals to that of diflunisal as analgesic agent E. Less gastric irritation than other NSAIDs 5. Aspirin reduces the synthesis of the following eicosanoids EXCEPT: A. TXA2 B. PGE2 C. PGF2α D. LTB4 E. PGI2

6. All the following are therapeutic uses of prostaglandins EXCEPT: A. Medical abortion

B. To produce uterine relaxation during pregnancy C. Temporary maintenance of the patency of ductus arteriosus in preterm neonates D. Prevention of gastric ulceration caused by NSAIDs E. Treatment of open angle glaucoma

7. All the following are effects of serotonin EXCEPT: A. Increased force of cardiac contraction B. Vasoconstriction of the arterioles of the pulmonary and renal beds C. Stimulation of pain response D. Contraction of bronchial smooth muscles E. Relaxation of the GIT smooth muscles 8. The following statements about NSAIDs are correct EXCEPT: A. Diclofenac may cause permanent platelet dysfunction B. Indomethacin may cause headache C. Sulindac is a prodrug D. They may impair renal function E. Aspirin may displace coumarin anticoagulants from plasma proteins 9. The following statements about aspirin are correct EXCEPT: A. May cause GIT hemorrhage after a single dose B. Enteric-coated tablets cause less gastric bleeding C. May cause metabolic alkalosis in high doses D. May cause Rye’s syndrome in children E. Its toxicity may require treatment with hemodialysis 10. In the treatment of acute rheumatic fever: A. Aspirin is used to suppress rheumatic carditis B. Polyarthritis never resolve without residual deformity C. Rheumatic chorea requires intensive therapy with corticosteroids D. Benzathine penicillin is used to prevent recurrent streptococcal infections 143

E. Erythromycin is considered the first line antibiotic to eradicate streptococcal infection

11. Which one of the following statements concerning Cox-2 inhibitors is correct: A. They show greater analgesic activity than traditional NSAIDs B. They show anti-inflammatory activity greater than traditional NSAIDs C. They increase platelet aggregation D. They harm the kidney as do nonselective cox inhibitors E. They are cardio protective

E. Aspirin

16. In the treatment of gout: A. Aspirin should be combined with a uricosuric

B. Therapy with sulphinpyrazone should be accompanied by high fluid intake and alkalinization of the urine C. Allopurinol will provide useful relief from an acute attack D. Colchicine can be used prophylacticaly to prevent recurrence E. Loop diuretics are indicated to wash the excess uric acid from blood

17. The following is true about 12. Manifestations of acute salicylate intoxication include all of the following EXCEPT: A. Hyperpyrexia B. Hyperpnoea C. Hypertension D. Convulsions E. Metabolic acidosis 13. Which of the following NSAID is used to treat patent ductus arteriosus in neonates: A. Ketoprofen B. Mefenamic acid C. Celecoxib D. Phenylbutazone E. Indomethacin

18. The following is true about PGF2α:

14. Leukotrienes:

19. All the following drugs can decrease platelet aggregation EXCEPT: A. Ketanserine B. Celecoxib C. Sulphynpyrazone D. Aspirin E. Epoprostenol (prostacyclin)

A. Are used for inducing labor in pregnant women

B. May be inhibited in patients treated with aspirin and similar drugs C. Are produced from amino acids and stored in granules D. May participate as SRS-A in asthmatic or anaphylactic reactions E. LTB4 is powerful platelet aggregator

15. Drugs used in the treatment of gout include all of the following EXCEPT: A. Indomethacin B. Allopurinol C. Colchicine D. Probenecid 144

allopurinol: A. It has short duration of action B. It can act as a uricosuric drug C. It may worsen acute gout D. The parent drug but not its metabolites are xanthine oxidase inhibitors E. Is not recommended for patients treated by anticancer drugs

A. It causes bronchodilatation B. It can be injected in the amniotic sac to induce abortion C. It increases renal blood flow D. It increases platelet aggregation E. It causes hypotension

20. All the following drugs can be used in the treatment of rheumatoid arthritis EXCEPT: A. Methotrexate B. Gold C. Leflunomide D. Prednisolone E. Colchicine

21. The most serious side effect of colchicine therapy is: A. Agranulocytosis B. Diarrhea C. Alopecia D. Amyloidosis E. Anorexia

22. Which one of the following drugs could significantly impair the ability to drive an automobile? A. Diphenhydramine. B. Ergotamine. C. Fexofenadine. D. Ranitidine. E. Sumatriptan. 23. Which one of the following is an action of colchicine? A. It produce uricosuria B. It produce constipation C. It produce polycythemia D. It stimulates cell division E. It inhibits leukocyte migration and phagocytosis

24. Which of the following is a uricosuric agent used in chronic gout? A. Sulfasalazine B. Sulfinpyrazone C. Allopurinol D. Colchicine E. Chloroquine

25. Which one of the following drugs acts by blocking interleukin-1 receptors? A. Anakinra B. Sulfasalazine C. Gold saults D. Methotrexate E. Etanercept

26. Which one of the following drugs acts by blocking soluble receptors of TNF-α? A. Anakinra B. Sulfasalazine C. Gold saults D. Methotrexate E. Etanercept

27. Inflammation is a complex tissue reaction that includes the release of cytokines, leukotrienes, prostaglandins, and peptides. Prostaglandins involved in inflammatory processes are produced from arachidonic acid by: A. Cyclooxygenase 1 B. Cyclooxygenase 2 C. Glutathione – S – transferase D. Lipoxygenase E. Phospholipase A2 28. A 60-year-old woman has glaucoma following cataract surgery. Which of the following can be used to reduce intraocular pressure? A. Leukotriene LTD4 or its analogs B. Prostaglandin E2 or its analogs C. Prostaglandin F2α or its analogs D. Slow-reacting substance of anaplylaxis (SRS-A) E. Thromboxane A2 or its analogs

29. A 45-year-old surgeon has developed symmetric early morning stiffness in her hands. She wishes to take a nonsteroidal anti-inflammatory drug to relieve these symptoms and wants to avoid gastrointestinal side effects. Which one of the following drugs is most appropriate? A. Aspirin B. Celecoxib C. Ibuprofen D. Indomethacin E. Piroxicam

30. The following drug is considered a mast cell stabilizer: A. Adrenaline B. Salbutamol C. Cromoglycate D. Loratidine E. Ondansetron

31. The following drug blocks 5HT2A receptors in the CNS and is useful in relieving the negative symptoms of schizophrenia: 145

A. B. C. D. E.

Buspirone Ondansetron Cyproheptadine Olanzapine Alosetron

32. The toxicity spectrum of aspirin does not include: A. Increased risk of encephalopathy in children with viral infections B. Increased risk of peptic ulcers C. Hyperprothrombinemia D. Metabolic acidosis E. Respiratory alkalosis

A. It is an acute exacerbation of joint pain B. C. D.

E.

33. Accidental poisonings are common with both aspirin and ibuprofen, the two drugs are available in tasty chewable tablets. In cases of overdose, aspirin is more likely than ibuprofen to cause: A. Autonomic Instability B. Hepatic necrosis C. Metabolic acidosis D. Thrombocytopenia E. Ventricular arrhythmias

34. Which of the following compounds is most likely to lower circulating levels of leukotrienes? A. Zileuton B. Montelukast C. Ibuprofen D. Aspirin E. Allopurinol 35. The action of aspirin that results in its greater efficacy as an antithrombotic (anti-platelet) drug is its ability to A. Inhibit lipoxygenase as well as cyclooxygenase B. Selectively inhibit cyclooxygenase I C. Inhibit leukocyte migration D. Promote uric acid excretion E. Acetylate cyclooxygenase 36. Which of the following statements best describes the usual course of rheumatoid arthritis?

146

treated with short-term antiinflammatory therapy It is a chronic disease characterized by acute changes within nonsynovial joints It is an acute disease that is characterized by rapid synovial changes due to inflammation It is a chronic disease characterized by acute exacerbations followed by remissions with consequences associated with chronic inflammatory changes It is a joint disease characterized by a marked loss of calcium from the bones and a resultant thinning of the bones

37. All of the following statements concerning an acute gouty arthritis attack are correct EXCEPT A. The diagonosis of gout is assured by a good therapeutic response to colchicine because no other form of arthritis responds to this drug B. To be assured of the diagnosis, monosodium urate crystals must be identified in the synovial fluid of the affected joint C. Attacks frequently occur in the middle of the night D. An untreated acute attack may last up to 2 weeks E. The first attack usually involves only one joint, most frequently the big toe (first metatarsophalangeal joint)

38. TNF- α is an example of: A. B. C. D. E.

Eicosanoids Interleukins Cytotoxic factors Interferons Colony stimulating factors

39. Potential adverse effects associated with aspirin include all of the following EXCEPT A. Gastrointestinal ulceration B. Renal dysfunction C. Enhanced methotrexate toxicity D. Cardiac arrhythmias

E. Hypersensitivity asthma

40. The cyclooxygenase isoenzymes COX-1 and COX-2 differ from each other in that: A. They catalyse different pathways in prostanoid biosynthesis B. COX–1 is inhibited by aspirin but not COX–2 C. COX–2 is inhibited by ibuprofen but not COX–1 D. COX–1 is constitutive while COX–2 is inducible E. COX–2 is essential for renal function 41. Which one of the following drugs is a selective inhibitor of central COX-3 in the brain? A. Paracetamol B. Ibuprofen C. Aspirin D. Celecoxib E. Colchicine

42. Irritable bowel syndrome with constipation can be treated by: A. Alosetron B. Tegaserod C. Ondansetron D. Olanzapine E. Buspirone Answers 1B 2C 3E 4A 5D 6B 7E 8A 9C 10 D

11 C 12 C 13 E 14 D 15 E 16 B 17 C 18 B 19 B 20 E

21 A 22 A 23 E 24 B 25 A 26 E 27 B 28 C 29 B 30 C

31 D 32 C 33 C 34 A 35 E 36 D 37 D 38 C 39 D 40 D

41 A 42 B

147

 

148

                                         

 

Part 1 1: Systtemic hy ypertens sion and d antihy ypertens sive dru ugs █ Bas sic inform mation ▌Vasc cular smo ooth musc cle contrraction an nd relaxation Vasoco onstriction n is initiated by ope ening of vo oltage gate ed L-type Ca2+ chan nnels in 2+ the me embrane off vascular smooth m muscle cells s. Increase ed intracel lular Ca triggers the pho osphorylation of myo osin light ch hain kinase e which iniitiates conttraction. Vasodiilation is in nitiated by y either:  Activation of guanylyl cyclase → ↑cGMP → dephosp phorylationn of myos sin light cha ain kinase → smooth ms m relaxatiion. +  Ope ening of K chann nels in the ar smooth muscle ccell memb brane → e vascula smo ooth ms sttabilization (hyperpolarization) → relaxation. ▌The v vascular endothellium and local vas somotor control c Beside e the neu ural contrrol of blo ood vess sels through the ssympathettic and parasympathetic systems, the vascu ular endoth helium pro oduces vaarious compounds that he elp controlling the vas scular tone e: Nitric o oxide (NO; orr EDRF)

It is a diffusible ga as with very v short half-life. It causes VD by increasing g intracellu ular cGMP P. It protec cts againsst atherosc clerosis, high blood d pressure e, heart failure and th hrombosis..

PGI2

It is synergistic to NO. It cause es VD via specific s reeceptors

Endoth helin

Is a 21-a amino-acid d peptide. By its action on ETA recep ptors, it causes se evere VC a and vascula ar smooth muscle hyypertrophy y.

149

Angiotensinconverting enzyme (ACE)

Located on the endothelial cell membrane and converts circulating angiotensin-I (synthesized by the action of renin on angiotensinogen) to angiotensin-II. By its action on AT1 receptors, Ang-II causes VC and stimulates aldosterone release.

Other factors

Histamine causes VD, bradykinin (synthesized from kininogen) causes VD, and serotonin (released by platelets) causes VC.

█ Management of systemic hypertension Systemic hypertension is persistent elevation of BP above 140/90. Classification of hypertension: ■ ■ ■

According to etiology: primary (= essential, 90%) or secondary. According to type: systolic, diastolic, or mixed. According to degree: see table.

Classification of blood pressure levels of the British Hypertension Society Category

Systolic BP (mmHg)

Diastolic BP (mmHg)

Normal blood pressure

3 mg/dl). Why? W

– In these conditions, the use off ACEIs is dangerous becausee they ↓ An ng-II → ↓

– –

a → ↓ glomerular filtrattion pressuure and ↓ GFR → VC of the efferent arterioles on of renal failure in b both kidne eys. aggravatio Dangerouss hyperkalemia may occur. Dangerouss neutrope enia may o occur.

■ Pre egnancy and a lactattion: theyy may cau use fetal pulmonary p y hypoplas sia and grow wth retardation. ■ Hyp perkalemia a. ■ Neu utropenia,, thrombo ocytopenia a, or seve ere anemia (ACEIs may caus se bone marrrow depre ession). ■ Imm mune pro oblems: whether due to autoimmune diseaases or due d to imm munosupprressive dru ugs.

155

Precautions

– Initial dose should be small and at bedtime to avoid 1st dose hypotension. – Frequent monitoring of kidney functions (S. creatinine) and potassium levels one week after treatment and then every 3 months. – Avoid use of K+ sparing diuretics to avoid severe hyperkalemia. – Remember all other contraindications… █ Angiotensin II receptor blockers (ARBs) (Losartan- Valsartan- Candesartan- Telmisartan)

 They selectively block AT1 receptors and they exert most of the pharmacological  



effects seen with ACEIs. They have no effect on bradykinin metabolism. They have the potential for more complete inhibition with ACE inhibitors because there are non-ACE chymase) that can convert Ang-I into Ang-II. The adverse effects and contraindications are inhibitors but cough and angioedema are less inhibitors.

of Ang-II action compared enzymes (cathepsin and similar to those of ACE common than with ACE

ACE inhibitors

ARBs

Class

Angiotensin converting enzyme inhibitor (ACEI)

Angiotensin receptor blocker (ARB)

Mechanism

Inhibition of ACE leading to: ↓ VC effect of Ang-II ↑ VD bradykinins

Blocking of AT-1 receptors leading to ↓ VC effect of Ang-II

Efficacy in inhibition of RAAS

Less effective because other enzymes rather than ACE can convert Ang-I into Ang-II

More effective because it blocks AT-1 receptor, the final station responsible for Ang-II effects.

Cough and angioedema

Frequent due to ↑ bradykinins

Less frequent (they do not ↑ bradykinins)

█ Direct renin inhibitors: aliskiren   

156

Activation of angiotensinogen into Ang-I by renin is the rate limiting step in formation of RAAS. Aliskiren is a recently approved drug for treatment of hyperreninemic hypertension. It inhibits renin activity and consequently the RAAS. The efficacy and side effects of aliskiren are comparable to ACEIs and ARBs.

█ Calc cium chan nnel bloc ckers (CC CBs) are drugs that t block voltage-g gated These a 2+ Ca ch hannels. Classiffication off CCBs ac ccording to o tissue selectivity y ■ CCB B with mainly cardia ac effects: vera apamil, diiltiazem. ■ CCB B with mainly vascular effectss (dih hydropyridiines): nifed dipine, pine amlodipine, nimodipin n e, nicardip B with main effect on n other tis ssue: ■ CCB flun narizine, cinnarizine c e Pharm macologica al effects CVS Heart: - Neg gative inotrropic effec ct - A-V V conductio on - HR Blood vessels: - Corronary VD - Peripheral VD D - Bloo od pressurre

Nifedip pine

Diltiazem D

Vera apamil

— — ↑ (refle ex)

++

+++

↓↓ ↓

↓↓↓ ↓↓ ↓

+++ + +++ +

++ ++

++ + ++ +

↓↓↓ ↓

↓

↓

Other e effects

  

The ey relax all smooth muscles (v (vascular, bronchial, b GIT, uterin ne, etc.). 2+ The ey ↓ Ca - mediated m cell c necro osis and ap poptosis. Verrapamil ↓ in nsulin relea ase from pa ancreatic beta b cells bu ut of little cllinical significance.

Therap peutic use es ▌Cardiio-selectiv ve CCBs (v verapamill & diltiaze em): ■ Isch hemic hea art disease e (IHD):

– They ↓↓ myocardial contractilit c ty and myo ocardial O2 demand. – They prod duce coron nary VD and d ↑ corona ary blood flow. 2 2+ – They ↓ Ca - mediate ed myocytte cell necrrosis. 157

N.B B. vasculosselective CCBs C (dihyydropyridin nes) e.g niifedipine aare also be eneficial in IIHD but they cause e conside erable peripheral VD D, so the dose sho ould be adju usted to avvoid hypotension and d reflex tac chycardia. ■ Carrdiac arrhy ythmias: supravent s ricular tac chycardia (SVT):

– SVT includ de atrial flu utter, fibrilla ation, paro oxysmal atrial tachyccardia, etc. duction, so o it protec cts the ven ntricles fro om the rap pid atrial – Verapamil ↓ AV cond β s have the same effect). rate (also β-blockers N.B B. Nifedipine is contraindicated a as it causes s hypotens sion and refflex tachyc cardia. pertrophic c obstructive cardio omyopathy y (HOCM):: ■ Hyp

– In hypertrophic obsstructive caardiomyop pathy, the wall of

–

the left ventricle v and interve entricular septum is s much thickened leading to o narrowin ng of the aortic outtlet and on of blood d flow. obstructio Increasing g contracttility worse ens the obstruction o n while decreasing g contracttility reduc es resistan nce to blood flow through the aortic ou utlet and im mprove exerrcise tolera ance.

N.B B. Nifedipin ne is contra aindicated d because it produce es reflex tach hycardia → worsening g of the ou utflow obsttruction. ■ Arte erial hypertension:

– They ↓ myyocardial contractilityy and COP. – They causse periphe eral VD d ue to ↓ Ca C 2+ influx x in the vascular smooth s ms s. ▌Vascu ulo-selecttive CCBs (Nifedipin ne and am mlodipine)::

 Arteerial hyperttension.  Perripheral vascular v disease

(e.g. Ray ynaud’s disease d udication): to improve peripherral microcirrculation. clau

aand

intermittent

 Nife edipine is sometimes used to rrelax the uterus u and delay pretterm labor..  Nim modipine has h high afffinity for c cerebral BV V. It is use ed for preveention of cerebral c vasospasm an nd ischemia complic cating sub barachnoid hemorrhaage. Advers se effects Verrapamil & diltiazem:: – Bradycard dia and hea art block. – Worsening g of CHF (d due to theiir –ve inotrropic effectt). – Constipatiion due to ↓ GIT mottility. 158

Nife edipine: – Hypotension and refflex tachyccardia. – Gingival (g gum) hyperrplasia. – Salt & watter retentio on (=ankle edema; more com mmon than with verap pamil due to significa ant VD and d hypotenssion). Contra aindication ns & preca autions Verapa amil & diltiazem:

– Con ngestive he eart failure e. – Braadycardia and a heart block. b – Wolff-Pakinso on-White syndrome: s 

In WPW syndrom me, there e is accessoryy conducting path hway between atria a and ventricles v o other tthan the e normal AV sysstem causing a uniqu ue type of atrioventric cular re-en ntry tachyc cardia.



A As a rule, most drug gs that ↓ A AV nodal co onduction (Adenosinne; Beta-bllockers; CCBs; Dig goxin) can paradoxic cally ↑ the conduction in the ab bnormal pathway p leading to worsening g of the tac chycardia.



W WPW syndrome can be man naged by amiodaro a ne but deefinitive tre eatment aser ablatio on of the a accessory pathway (s see later). includes la

– Veraapamil sh hould not be comb bined with h digitalis or β-blo ockers as it may agg gravate bra adycardia caused c byy these dru ugs (nifedip pine is the drug of ch hoice to be u used with β-blockers β s because it doesn't cause brad dycardia). Nifedip pine:

– – – –

Hyp potension. Hyp pertrophic obstructiv ve cardiom yopathy (H HOCM) Wh hy? Unsstable angina (risk off reflex tach hycardia). Sup praventricu ular tachyc cardia (SVT T) Why?

159

█ Vaso odilators Classiffication ■ Arte erio-dilato ors: Nifedipine – Hyd dralazine – Minoxid dil – Diazoxxide – T They dilate e arteries and a ↓↓ BP (→ ↓ afterlo oad) – T They are used u in sev vere system mic hypertension. ■ Ven nodilators: Nitrates – T They dilate e mainly ve eins →↓ ven nous return n (→ ↓ preload) – T They are used u in acu ute pulmon nary edema. ■ Mix xed dilatorrs: Sodium m nitropru sside – Prrazosin – ACEIs A – Trrimetapha an – T They ↓ pre eload & afte erload so tthey are us sed in CHF F. Genera al conside erations

 Vassodilators relax r vascu ular smootth ms and ↓ peripheral resistannce.  Theey usually cause reflex sympaathetic stiimulation (e.g. reflex ex tachycardia) so  

theyy can be combined c with w beta-b blockers. The ey usually cause sa alt and w water rete ention (du ue to refleex stimula ation of aldo osterone re elease) so they shou uld be combined with h diureticss. The e use of vasodilators v s is declin ning as a result of newer mo odalities, such s as ACE EIs and CC CBs, which h are more e effective with w fewerr adverse eeffects.

Hydralazine

 It is a direcct arterio olodilator by uncle ear 





mec chanism. It iis used in severe e hyperte ension an nd rd hyp pertension in pregna ancy (3 c choice aftter α-m methyldopa a and nifed dipine). It is usually combine ed with d diuretics to cou unteract sa alt and wa ater retenttion, and βbloc ckers to counteract c reflex tach hycardia. It m may cause systemic lupus eryythematos sis (SLE E)-like syyndrome especiallyy in slo ow ace etylators. Th he patient develops mild form of arthritis, renal imp pairment, and a skin rash h that usua ally disappe ear upon sttopping of the drug.

Minox xidil

 It iss a direct arteriolodilator byy opening g K+ channels → hyyperpolarizzation → rela axation of the t vascula ar smooth ms. 160

 It is given orally for chronic hypertension but its use as antihypertensive is 

declining; however, it should be combined with diuretics and β-blockers. It was found to stimulate hair growth (hypertrichosis) (by unclear mechanism), so it is now used topically to prevent hair loss in both males and females.

Diazoxide

 Structurally related to thiazides but it is not diuretic  It is a direct arteriolodilator by opening K+ channels → hyperpolarization → 

relaxation of the vascular smooth ms. It is given parenterally in hypertensive emergencies but its use is declining.

Sodium nitroprusside

 It liberates nitric oxide (NO) → ↑ cGMP → dilatation of both arteries and veins → ↓ both preload and afterload.

 It is given by i.v. infusion in hypertensive emergencies and acute heart failure 



because it has rapid action It can be converted to cyanide and thiocyanate. The accumulation of cyanide and risk of toxicity are minimized by concomitant administration of sodium thiosulfate (see angina) or hydroxocobalamin (vitamin B12). Sodium nitroprusside in aqueous solution is sensitive to light and must be made up fresh before each administration and covered with opaque foil.

Fenoldopam

 It stimulates peripheral dopamine (D1) receptors in renal and mesenteric arteries, 

leading to VD and decrease peripheral resistance. It is used parenterally as a rapid-acting vasodilator to treat emergency hypertension in hospitalized patients.

█ Endothelin-1 receptor antagonists

 Endothelin-1 is 21 amino acid peptide. It is the predominant endothelin secreted

  

by the vascular endothelium. It is elevated in patients with pulmonary hypertension and coronary artery disease. It acts on two types of receptors, ETA and ETB. ETA receptors is the main subtype in smooth ms and mediates VC and vascular smooth ms hypertrophy. Bosentan is orally active nonselective blocker of ETA and ETB receptors, while ambrisentan is a selective ETA blocker. Both drugs are approved for treatment of primary pulmonary hypertension. 161

█ Specialized vasodilators Drugs used for erectile dysfunction: Sildenafil, tadalafil

 These drugs inhibit phosphodiesterase (PDE) type 5 the enzyme responsible for breakdown of cGMP in erectile tissue (and lung) → ↑ cGMP → VD of the corpus cavernosum.

 They are very effective for treatment of erectile dysfunction in men. The effect of the drug appears after 30 min of oral administration and lasts for 4-5 hours.

 Sildenafil is also approved for treatment of pulmonary hypertension.  Side effects include blue discloration of vision, headache, and optic neuropathy.  These drugs are contraindicated in patients taking nitrates or nicorandil for treatment of angina because nitrates also act by ↑ cGMP leading to severe VD, hypotension, and reflex tachycardia → aggravation of angina and development of arrhythmia.

▌Choice of the antihypertensive drugs:

162

Clinical condition

Best choice

Starting therapy for non-complicated essential hypertension

Patient 55 years old: CCBs If not adequate, add thiazide or beta blockers.

Hypertension of pregnancy

α-methyldopa Labetalol – Nifedipine - Hydralazine

Hypertension in a diabetic patient with diabetic nephropathy (proteinuria)

ACE inhibitors

Hypertension with chronic kidney disease

S. creatinine 3 mg/dl: CCBs

Hypertension with CHF

ACE inhibitors - diuretics

Hypertension with bronchial asthma

CCBs

Hypertension with angina

CCBs - beta-blockers

Hypertension with thyrotoxicosis, sympathetic overactivity, arrhythmia, or, HOCM

Beta-blockers

Hypertension with BPH

α1 blockers

Primary pulmonary hypertension

Endothelin receptor antagonists

▌Management of hypertensive emergencies: Hypertensive emergencies are clinical situations associated with one or more of the following:  BP > 180/120mmHg.  Target organ damage e.g. cerebral stroke, encephalopathy, heart failure, aortic dissection, edema of the optic disc (papilledema). Management:

Hypertensive encephalopathy Is a clinical presentation consists of severe headache, mental confusion, blurred vision, and focal neurologic signs. If untreated it may progress over a period of 12– 48 hours to convulsions, coma, and even death.

– Hospitalization

and start parenteral therapy to lower BP rapidly (within a few hours not minutes).

– Chronic hypertension is associated with autoregulatory changes in cerebral, myocardial, and renal blood flow; so if sudden lowering of BP is done, cerebral, renal, and myocardial ischemic events can develop.

– The initial target in the first 1-2 hrs is to lower systolic BP by no more than 25%, maintaining diastolic BP at no less than 100 mmHg.

– Drugs commonly used: sodium nitroprusside, labetalol, fenoldopam, all are given by slow i.v. infusion.

– Recent guidelines state that the following drugs are not recommended: 

Nifedipine, nitroglycerin, and hydralazine: because these agents can cause sudden, uncontrolled, and severe reductions in BP that may precipitate cerebral, renal, and myocardial ischemic events with fatal outcomes.



Furosemide can lead to significant volume depletion and should be used only if there is associated volume overload as in case of pulmonary edema and acute heart failure.

163

Part 2 2:

The erapy off periph heral vas scular disease d ((PVD)

It is a narrowing of the arteries o other than n coronary y and cerrebral ves ssels. It commo only affectss arteries of o lower lim mbs, but also renal and mesentteric arteries. Risk fa actors  Diab betes and smoking are a the mo ost importa ant risk factors.  Age e > 65 yearrs, hyperch holesterole emia, hype ertension and obesityy. Manife estations  Inte ermittent cllaudication n: pain in m muscles wh hen walkin ng  Resst pain in th he soles off the feet, p particularly y when the e feet are eelevated.  Skin n: cool, blu uish, ischemic ulcerss. gement Manag ▌Life-s style:

 Stop smoking: the most important factor  Con ntrol of risk k factors:  S Statins for hypercho olesterolem mia.  T Treatment of hyperte ension and d DM. ▌Drug therapy: Pentox xifylline

 It in ncreases RBC R deform mability byy inhibition n of PDE enzyme; e thhis effect reduces r



bloo od viscositty and facilitates passsage of RBCs through narrow wed capillarries and isch hemic sitess. It iss the 1st drrug approv ved to imp prove micrrovascular circulationn in patien nts with inte ermittent claudicati c ion, diabettic angiop pathy, and chronic leeg ulcers. Typical dosse is 400 mg m twice a day.

azol Cilosta

   

It is the 2nd drug recently y approved d for treatm ment of inttermittentt claudicattion. It in nhibits PDE E enzyme (type 3) le eading to VD V and ↓ platelet agg gregation. Hea adache is the most common c sside effect. Clio ostazol is contraind dicated in patients with CHF F because recent ev vidence sho owed that inhibitors of o PDE enzzyme type 3 increase e mortality in those patients. p

Clopid dogrel Antipla atelet agen nts such clopidogr el (75 mg g/d) have additionaal benefits s when compa ared with aspirin in diabetic pattients with PVD. 164

Part 3 3:

Isc chemic heart h dis sease and a antia anginal drugs

█ Bas sic inform mation ▌Ische emic hea art diseas se include es: ■ Chrronic sta able ang gina (Cl assic; exe ertional an ngina): - It is due to atheromatous naarrowing of the coronary artery. - Pain is induced by effortt and disappearrs with rest. ■ Acu ute corona ary syndro omes (ACS S):

- Unstable e angina: It is du ue to rupture of o atheromatous p plaque and form mation of thrombuss. The patient ex xperiences s accelerattion in the frequency or severity s of chest pain, or ne ew-onset angina a pain n. des the - Myocardiial infarcttion: An inntraluminall thrombuss complettely occlud epicardial coronary artery at the site of plaque rup pture leadiing to irrev versible coagulativve necrosis s. ■ Prin nzmetal’s angina (V Variant ang gina; angin na of rest; α-mediatted angina): The e coronary artery und dergoes se evere spas sm due to overactivitty of α1 rec ceptors. The e patient de evelops pa ain at rest.

▌Chro onic stablle angina a Definittion: retrosternal pa ain due to o ischemia a of the myocardium m m as a re esult of imbalan nce betwe een heart work w (O2 de emand) and d coronary y blood flow w (O2 supp ply). 165

Clinica al picture: Centra al chest pa ain is the cardinal c syymptom:    

Site e and radiiation: retrrosternal, radiating to t the left should der and the e left arm. Cha aracter: an ny character (usuallly sense of che est tightnesss). Precipitated by b 3E: exertion, emo otion, eating, and d relieved by b rest and d nitrates. Durration: usu ually < 10-15 min. If longer tha an 15 m min → susp pect ACS.

Diagno osis: 

ECG G: - R Resting 12 2-lead ECG G: this is o often norm mal a and doess not exc clude isch hemic hea art d disease. - D During atttack: the ere is S ST segme ent d depression n and T-wa ave inversiion. - IIn myocardial infarcttion: ST ellevation an nd d deep Q-wa ave.

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Exe ercise ECG: reco ording E ECG und der con ntrolled physical effo ort to reco ord ischem mic cha anges.

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Nuc clear isoto ope stress s imaging..

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Corronary ang giography y.

█ Man nagemen nt of stab ble angin na

n-drug the erapy = life e style mo odification n: ■ Non

 T The same as hyperte ension (see e before). ■ Pha armacolog gical thera apy:

 Immediate treatme ent of acutte chest pain: p – Glyceryyl trinitrate e (GTN): su ublingual or spray. – Aspirin n 300 mg lo oading dosse as soon n as possib ble. It reduce es the risk of progresssion to MI. – Refer the patient to hospitaal if an ACS S is suspec cted.

 Long-term m therapy:

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– – – – – – –

Beta-blockers: the first-line agents for chronic stable (exertional) angina. CCBs: the second-line agents for chronic stable angina Long and intermediate acting nitrates. pFOX inhibitors: trimetazidine Newer antianginal drugs: ranolazine and nicorandil Lipid lowering drugs: statins (see chapter 6). Antiplatelet drugs: e.g. aspirin, clopidogrel (see pharmacology of blood).

■ Surgical treatment (myocardial revascularization). Organic nitrates and nitrites Classification

Short-acting nitrates: Amyl nitrite crushable ampoules Glyceryl trinitrate tablets or spray Isosorbide dinitrate Glyceryl trinitrate (Tridil®) Intermediate-acting nitrates: Isosorbide dinitrate Long-acting nitrates: Isosorbide mononitrate Transdermal patches

Dose

Onset

Duration

0.3 ml inhalation 0.5 mg SL 5 mg SL 5 μg/min i.v.i.

1-2 min 1-5 min 3-5 min

5-10 min 10-20 min 60 min

10 mg oral 40 mg oral SR

15 min 30 min

3-6 hrs 6-10 hrs

20 mg oral 60 mg oral SR

30 min 30 min

6-8 hrs 6-10 hrs

30 min

12-18 hrs

Pharmacokinetics Absorption: nitrates are rapidly absorbed from all sites of administration. Metabolism: in the liver: – If given oral → extensive first-pass metabolism (oral bioavailability 100 mm mHg. m starrt IV dopam mine or – If the SBP is 40% (> 2000 ml)

Coma …….. death

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Treatment

  

I.v. fluids (Ringer solution is more superior to normal saline for use in massive hemorrhage). Blood transfusion Dopamine: to ↑ COP.

█ Cardiogenic shock Causes   

Acute MI Blunt cardiac trauma Myocardial depression due to any cause (drugs, infection, etc.).

Treatment

  

All measures of treatment of acute MI (see before). Dobutamine i.v.i. (usually at 5 - 20 μg/kg/min). Lidocaine i.v. for control of ventricular arrhythmia.

█ Septic shock Cause: severe infection → release of inflammatory cytokines from the inflammatory cells → venodilatation (↓ venous return) and progressive tissue hypoxia. Treatment

   

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Antibiotics according to the type of pathogen. Dopamine or dobutamine to ↑ COP. Low dose steroids to minimize toxemia. Oxygen if O2 saturation is