Summary of Drugs Affecting Cardiovascular System (CVS) PDF

Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Lecture 1 Drugs affecting cardiovascular system (CVS) hypertension Blood pressure (hypertension): is the force of bl...

Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Lecture 1 Drugs affecting cardiovascular system (CVS) hypertension Blood pressure (hypertension): is the force of blood against your artery walls as your heart pumps blood through your body. ‫زيادة ضغط الدم علي الوعاء الدموي فبيزود الضغط‬ Hypertension occurs when the force of blood is stronger than it should be normally Hypertension: systolic >140 mmHg and/or diastolic > 90 mmHg Anti-hypertensive drugs blood pressure ‫ اللي لما هشتغل عليها هقلل ال‬receptors ‫عندنا بعض ال‬ Subtype Organ Effect (receptors) α1 Peripheral blood vessels (arterioles) Vasocontraction α2 Presynaptic (CNS) Decrease sympathetic outflow β1 Heart Increase the force and rate of contraction β2 Bronchi Bronchodilation ‫ بيحصل‬activation ‫ لما بيحصلها‬... (blood vessel) ‫ موجودة في أماكن كتير اشهرها الوعاء الدموي‬α1 ‫ال‬- blood pressure ‫ فبالتالي هتزود ال‬vasoconstriction flow of ‫ بتقلل ال‬activation ‫ لما بيحصلها‬... presynaptic neurons ‫ وبالتحديد في ال‬CNS ‫ موجودة في ال‬α2 ‫ال‬- blood pressure ‫ وبالتالي بتقلل ال‬norepinephrine ‫ وال‬epinephrine α2 ‫ بتاع ال‬activation ‫ عكس ال‬α1 ‫ بتاع ال‬activation ‫فنقدر نقول إن ال‬ ‫ يعني هيا بتعمل‬inotropic effect ‫ بتزود حاجه اسمها‬activation ‫لما بيحصلها‬... heart ‫ موجوده علي ال‬β1 ‫ال‬- ‫ يعني تزامني يعني ضربات القلب‬chrono...positive inotropic effect and positive chronotropic effect blood ‫ وبالتالي هتزود ال‬... ‫ يعني القلب ينقبض جامد‬forced contraction ‫ يعني‬ino ‫اما‬.. ‫تزيد وتضخ دم اكبر‬ pressure bronchodilatation ‫ بتاعتها بتعمل‬activation ‫ ال‬... bronchi ‫ موجوده في أماكن كتيرة اشهرها علي ال‬β2 ‫ال‬- ‫يعني بتوسع الشعب الهوائية‬ ‫ كده‬β2 ‫ وعالجلي الضغط بس قفل معاها‬β1 ‫ وقفل ال‬β2 & β1 ‫ يعني بيشتغل علي‬non-selective ‫فلو انا جبت دواء‬ ‫ يعني ضيق في الشعب الهوائية‬bronchospasm ‫المريض هيحصله‬ 1 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Anti-hypertensive drugs Centrally acting agents (CNS) peripherally acting agents (blood vessels) a- α2 agonist b- Adrenoreceptor antagonist (β1-blocker, α1 blocker and mixed α1, β1 blockers) c- Vasodilators d-Renin-angiotensin-aldosterone antagonist e- Calcium channel blockers f- Diuretics Centrally acting sympatholytic ( α2 - agonist ) Mechanism: Stimulation of α2-receptors → ↓sympathetic flow of NE, E from the brain → B.P. ‫ بتاع ال‬reuptake ‫ بتحفز ال‬presynaptic neuron ‫ اللي موجودة علي ال‬α2-receptors ‫ بتاع ال‬stimulation ‫ال‬ ‫ فعشان كده قولنا أنها‬sympathetic flow ‫ يعني يرجعوا تاني فيقلل ال‬epinephrine and norepinephrine blood pressure ‫ فتقلل ال‬sympatholytic effect ‫ بتاعته‬activation ‫ ال‬sympathetic ‫ ال‬... sympatholytic and sympathomimetic ‫عندنا حاجه اسمها‬ sympathetic ‫ يعني حاجه بتعمل تحفيز لل‬sympathomimetic ‫ فلو حاجه بتعمل‬blood pressure ‫بتزود ال‬ ‫ فتقلل‬sympatholytic ‫ يبقي دي‬sympathetic flow ‫لو احجه هتعاكس ال‬... ‫ هترفع الضغط‬nervous system sympatholytic effect ‫ فيحصل‬activation ‫ بتعمل‬α2 ‫فعندنا ف حالة ال‬... ‫الضغط‬ Classification of α2 - agonist: Cyclic guanidine: Clonidine False transmitter: Methyldopate HCl Cyclic guanidine: Clonidine SAR 2 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran guanidine ‫أول حاجة عندنا من اهم الحاجات اللي الزم تكون موجودة هيا ال‬ S Urea Thio-Urea Guanidine ‫ المهم تكون موجودة‬cyclic ‫ أو تكون محطوطة في حلقة‬opened ‫ وممكن تكون‬.. essential ‫ دي‬guanidine ‫عندنا بقي ال‬ ‫ بدل‬reaction ‫ فال‬α1 agonist ‫ ل‬α2 agonist ‫ هتتحول من‬CH2 ‫ اللي في النص لو استبدلناها ب‬NH ‫تاني حاجه عندنا ال‬ ‫ ويرفع الضغط‬sympathomimetic ‫ هيبقي‬sympatholytic ‫ما يكون‬ ortho ‫اهمية ال‬... ortho position substitution ‫ وبيكون عليها في ال‬phenyl ring ‫تالت حاجه عندي حلقة‬ non-coplanner ‫هيحصل حاجه اسمها‬... ‫ يعني يعمل زحمة‬steric hindrance ‫ انها بتعمل حاجه اسمها‬substitution ‫ اللي علي ال‬substitution ‫والزم يكون ال‬... ‫ مش علي نفس المستوي‬phenyl ring ‫ وال‬imidazole ‫يعني الحلقتين ال‬ CNS ‫ اللي موجود في ال‬α2 ‫ عشان يوصل لل‬BBB ‫ عشان يعدي ال‬lipophilic ‫ يكون‬ortho position : 3 interactions ‫ من خالل‬α2 receptor ‫عندنا ان الدواء بيمسك في ال‬ positive ‫ الن عليا‬protonation ‫ بيحصلها‬imidazole ‫ بتاعه ال‬NH2 ‫ إن ال‬ionic interaction ‫أول حاجه‬ charge and H2 hydrogen bond interaction ‫ دي بتعمل‬NH ‫ال‬.. CH2 ‫ اللي قولنا مينفعش نستبدلها ب‬NH ‫تاني حاجه في ال‬ hydrophobic interaction ‫ بتاعتها بتعمل‬lipophilicity ‫بسبب ال‬... phenyl ring ‫تالت حاجه ال‬ Cyclic Guanidine Clonidine [Catapress®] N-(2,6-Di-chlorophenyl)-4,5-dihydro-1H-imidazol-2-amine 3 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran ‫الحظ الفرق بين‬ Imidazole Imidazoline Imidazolidine 4 3 3 3 4 2 2 5 2 5 1 1 1 4,5-dihydro-1H-imidazole Prototype of this class => class ‫يعني أول دواء اكتشفوه في ال‬ Act on both α2-receptors & Imidazoline receptors [I1]. ‫ بتتميز‬sympatholytic ‫ بتاعتها بتعمل‬activation ‫عندنا بعض المستقبالت اللي بتشبهه واللي ال‬.. α2 receptor ‫غير ال‬ imidazoline receptors ‫ فعشان كده سمينها ال‬imidazoline ring ‫ان محدش يقدر يشتغل عليها اال بس المركبات الل يفها‬ [I1] Imidazoline receptors also mediate the sympatho-inhibitory actions of imidazolines to lower blood pressure. SAR of Clonidine -Clonidine is imidazole derivative. Exchange of bridging N atom for CH2 causes drop in activity. -It has lipophilic O-dichloro substituents on phenyl ring. (B.B.B)... ‫ ذي ما هيا‬NH ‫وفيه‬.. guanidine ring (cycle) ‫ هنالقي ان فيه‬... SAR ‫ حقق شروط ال‬clonidine ‫هنالقي ان ال‬ 2 substitutions on ortho positions ‫بس كمان عندنا‬.. ortho substitution ‫ ذي ما هيا وعليها‬phenyl group ‫وال‬ ‫ وبما انه‬highly active and high lipophilic ‫ وبالتالي هيبقي‬non-coplanner ‫وده كويس النه هيخلي المركب‬ CNS ‫ ويوصل لل‬BBB ‫ فيقدر يعدي ال‬lipophilic 4 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran 2- Drugs affecting peripheral sympathetic nerves b- Adrenoreceptor antagonist 1- β1-blocker => on heart 2- α1 blocker => on blood vessel 3- mixed α1, β1 blockers 1- β1-adrenergic blockers inotropic ‫ اللي قولنا علبهم ال‬force and rate of contraction ‫ ولما هقفلها هقلل ال‬heart ‫دي بتشتغل علي ال‬ ‫ وبالتالي أقلل ضغط الدم‬and chronotropic effect 2- SAR of β-adrenergic blockers β-adrenergic blocking agents are arylethanolamine or aryloxypropanolamine ‫اوال انه‬.. receptor β1 ‫ عليه لل‬affinity ‫ عشان يكون ليه‬chemical structure ‫ المطلوبة لل‬requirements ‫ال‬ arylethanolamine or aryloxypropanolamine ‫يكون حاجه من اتنين ياما‬ I- Absolute requirements: 1- Aromatic ring or it can be benzoheterocyclic such as indole or heterocyclic such as thiadiazole. 2- β-Aminoethanol ‫ وممكن‬... aryl or aryloxy ‫ يعني ياما‬aromatic ring ‫ انه يكون‬absolute requirememnts ‫يبقي عندني من ال‬ aromatic ring ‫ مثال المهم يكون‬thiazole ‫ او ال‬indole ‫ ذي ال‬hetero cycle ‫ واحط واي‬phenyl ring ‫اشيل ال‬ Thia-di-azole indole β amino-ethanol ‫ بينهم وهيا ال‬common ‫ فيه حاجه‬arylethanolamine or aryloxypropanolamine β 5 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran II-variables ‫الحاجات اللي ممكن العب فيها‬ 1-Side chain; -X = direct link (aryl) or –OCH2 (aryloxy) -R = H or CH3 H or CH3 ‫ بانها تكون‬N ‫ علي ال‬substitution ‫ممكن اعمل‬ isopropyl amine ‫ يبقي عندي‬H ‫ هو ال‬substitution ‫لو ال‬ Tertiary butyl amine ‫ يبقي عندي‬CH3 ‫ هو ال‬substitution ‫لو ال‬ 2-Aromatic substitution; Y may be another ring or substituent o-substituted derivatives show no selective β-blocking effect while p-substituted one possess β-selectivity. β1, β2 ‫ فهيقفل ال‬non-selective β blocker ‫ يبقي‬6 ‫ او‬2 ‫ سواء‬ortho position ‫ علي ال‬substitution ‫لو ال‬- bronchospasm ‫وبالتالي لألسف هيعمل‬ ‫ فميعملش‬β2 ‫وميروحش لل‬.. β1 ‫ اعلي علي ال‬selectivity ‫ هيخلي ال‬para position ‫ علي ال‬substitution ‫لو ال‬- para position ‫ وبالتالي يفضل يبقي علي ال‬bronchospasm Generally most β-blockers are non-selective competitive (inhibition) antagonists as they block both β1 and β2 receptors. However a few are only selective β1-blockers (e.g Atenolol and Metoprolol). prototype drug in this class is the: Propranolol (Inderal®) Propranolol (Inderal®) All β-adrenergic blockers have asymmetric centers at the β- carbon to which the –OH is attached. The active form is levorotatory S (-) form. 3 2 1 1-(iso-propyl-amino)-3-(1-napthyloxy)-propan-2-ol Alcohol has the priority over the amine group to be the parent Propranolol is the prototype drug in this class. 6 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Non-selective β-adrenergic blocker (contraindicated in patients with asthma). Propranolol is lipid soluble drug, known to readily pass BBB, causing CNS S.E as: Dizziness, confusion, depression 2- α1 blockers - α1-blockers recommended in hypertensive patients who also suffer from benign prostatic hyperplasia (BPH). ‫ فلو حد‬relaxation to the bladder ‫ فبتعمل‬bladder ‫غير أنها موجوده علي األوعية الدموية لقوا انها موجودة عند ال‬ hypertension ‫ ويكون عنده طبعا‬.. ‫( تعالجه‬prostatic hyperplasia) ‫عنده تضخم في البروستا‬ - α1-blockers possess a characteristic “first-dose effect”, which means that orthostatic hypotension may occurs with the first few doses. This S.E. (side effect) can be minimized by slowly increasing the dose (at bed time). ‫ يعني المريض أول ما هيقف ضغطه هينزل جامد وممكن‬orthostatic hypotension ‫مشكلتها انها ف بداية الجرعة بتبقي‬ ‫يقع وده بيبان في الجرعات األولية فعشان كده بينصح ان الدواء يتاخد قبل النوم ويبدا بجرعات قليلة وبعد كده يزودها‬ Prazosin (Minipress®) The first known selective α1-blocker Quinazoline (benzene ring + pyridine ring) antihypertensive Used alone or in combination with other drugs for long-term therapy for management of hypertension, and prostatic hyperplasia. 4 6 3 7 4-amino-6,7-dimethoxy quinazoline (benzopyrimidine) 1 7 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran 2- Drugs affecting peripheral sympathetic nerves d- Renin-angiotensin-aldosterone systems (RAAS) is a hormone system that regulates blood pressure and fluid, electrolyte balance. renin ‫ في وجود إنزيم ال‬angiotensinogen ‫عندنا ال‬ ‫ اللي‬angiotensin 1 ‫( بيديني ال‬angiotensinogenase) ACE (angiotensin converting ‫في وجود ال‬ angiotensin 2 ‫ بيديني‬enzyme) ‫ علي‬vasopressor effect ‫ عنده‬angiotensin 2 ‫ال‬ ‫ انها‬kidneys ‫الوعاء الدموي الي جانب انه ممكن يحفز ال‬ blood pressure ‫ اللي هو بيعلي ال‬aldosterone ‫تفرز ال‬ ‫ فيزود حجم الدم فيزود الضغط‬electrolytes ‫وبيحبس مايه و‬ :‫ ده‬system ‫الحاجات اللي بتشتغل علي ال‬ A- ACE inhibitors (Prils) B- Angiotensin II receptor antagonists (blockers) (ARB) C- Renin Inhibitor A- ACE inhibitors (Prils) angiotensin 1 to angiotensin 2 ‫هتمنع تحويل ال‬ SAR of ACE inhibitors ‫ ذي مثال‬metals ‫ يعني البروتين الطبيعي بتاعنا عادي بس فيه‬metallo-protein ‫أوال الزم نعرف ان عندنا حاجه اسمها‬ ‫الدواء بتاعي بقي الزم يكون فيه حاجه‬... ‫ وبيبقي فيه الزنك‬metallo-protein ‫ من امثلة ال‬ACE ‫ال‬... ‫المنجنيز او الزنك‬ hydrophobic interaction ‫ وحاجه تشبك ب‬hydrogen bond ‫ وحاجه تشبك ب‬inonic bond‫ ب‬ACE ‫تشبك مع ال‬ coordinate bond ‫وحاجه تشبك وتحديدا مع الزنك ب‬ 8 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran share of ‫ بيبقي ال‬covalent ‫ بس الفرق ان ال في ال‬covalent bond ‫ ده شكل من أشكال ال‬coordinate bond ‫ال‬ ‫ بيبقي من ذرة واحدة‬share of electrons ‫ بيقي ال‬coordinate ‫ بينما ال‬.... ‫ بين ذرة وذرة‬electrons So, the requirements for the ACE inhibitor drug is: Contain anionic site [ COO- ]. negative charge ‫ عليها‬carboxylate ‫ الزم المركب يبقي فيه‬ionic bond ‫عشان تحصل‬ Contain H-bond forming group [ C=O ]. C=O ‫ الزم المركب يبقي فيه مجموعة الكربونيل‬hydrogen bond ‫عشان تحصل ال‬ Contain SH, COO- or phosphinate group to react with Zn++. (coordinate bond) phosphinate ‫ او ال‬COO- ‫ او ال‬thiol (SH) ‫ياما‬.. ‫ حاجه من تالتة‬coordinate bond with Zn ‫اللي يقدر يعمل‬ Contain hydrophobic moiety [if methyl as in captopril → S isomer is more active than R] high hydrophilicity ‫ يعني يكون ليه‬hydrophobic moiety ‫ الزم المركب يبقي‬hydrophobic bond ‫عشان تحصل‬ propranolol ‫ ولقوا انه شبه ال‬chiral carbon ‫ فبتعمل‬chirality ‫ بيخلوها ميثيل النها بتعمل‬moiety group ‫أحيانا ال‬ S (-) more active than R ‫ان ال‬ Side effect: Dry cough ✓ ACE inhibitors prevent bradykinin breakdown and stimulate prostaglandin synthesis. The increased level of both prostaglandin and bradykinin is responsible for the cough. ‫ فبيحاولوا يعدلوه‬inflammatory prostaglandin ‫ حيث انه بيمنع تكسيره فبيزيد ال‬bradykinin ‫الكحة بتبقي بسبب ال‬ N.B: ACE inhibitors: can be subclassified into three groups based on their chemical composition not potency: 1- sulfhydryl-containing inhibitors (First generation) [captopril] ‫هنتكلم علي ده بس‬ 2-dicarboxylate-containing inhibitors (Second generation) [enalapril] coordinate with zinc ‫ والتانيه هتعمل‬ionic interaction ‫واحده هتعمل‬ 3-phosphinate-containing inhibitors (Third generation) [fosinopril] 9 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran 1- Sulfhydryl-containing inhibitors Captopril (Capoten®) (1st generation( 1-[2-Methyl-3-thiopropanoyl]-pyrrolidine-2-carboxylic acid. methyl ‫ و‬coordinate bond ‫ تعمل‬SH ‫ و‬ionic bond ‫ تعمل‬COOH ‫ فيه‬... ‫عندنا المركب محقق الشروط‬ hydrogen bond ‫ تعمل‬C=O ‫ و‬hydrophobic bond ‫ تعمل‬group Captopril is the first orally active ACEI (Prototype). Sulfhydryl (SH) group responsible for excellent inhibitory activity (coordinate bond) Sulfhydryl group responsible for the most common side effects, skin rashes and taste disturbance sulfhydryl group ‫ هنالحظ انها متشال منها ال‬second and third generations ‫عشان كده طوروه برده وعملوا‬ B- Angiotensin II receptor antagonists (blockers) (ARB) (sartans) ‫ عادي بس الدواء بقي‬angiotensin 2 ‫هنا بقي هيتكون ال‬ ‫ وبالتالي مش هيقدر يطلع‬angiotensin 2 ‫هيقفل مستقبالت ال‬ ‫ هيتحبسوا‬electrolytes ‫ وبالتالي مفيش مايه وال‬aldosterons ‫في الدم فيقل الضغط‬ Valsartan (Tareg®) -Valsartan, named for the valine portion of the compound -The tetrazole ring and carboxylic acid function will be ionized at physiological pH. -The tetrazole group is more lipophilic than carboxylic acid group. - These properties have been proposed to be responsible for the enhanced binding and bioavailability of the tetrazole-containing compounds. ‫ في األول بيتم التصور شكل ال‬.. ‫عندنا الدواء لما بيكتشف مش بيبقي علطول هو المنتج‬ structure ‫ وبشوف محتاج إيه عشان يشتغل عليه وبجمعه في‬receptor ionization with ‫ وكان بيحصلها‬tetrazole group ‫ بدل ال‬carboxylic moiety ‫في األول كانوا حاطين‬ ‫ هتقل‬lipophilicity ‫ بتاعتها اقل الن ال‬bioavailability ‫ وكانت ال‬physiological PH 10 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran inductive ‫ ليها‬N ‫ الن ال‬4N ‫ النها واقعة بين‬H ‫ بسبب ال‬carboxylic ‫ تقريبا شبه ال‬acidity ‫ عنده‬tetrazole ‫ال‬ biological activity ‫ وحافظ علي ال‬lipophilicity ‫ فكده حسن ال‬effect C- Renin Inhibitor angiotensin ‫ده بقي بيقفل العملية من األول فبيمنع تكون ال‬ from angiotensinogen by renin Ex: Aliskiren® 2- Drugs affecting peripheral sympathetic nerves e- Calcium channel blockers (CCBs) -Calcium channel blockers have been approved for the treatment of hypertension, angina pectoris, and specific types of arrhythmias. myosin light chain ‫ لل‬myosin phosphorylation ‫ بيحفز ال‬ca ‫ ال‬... intracellular ca ‫هنا بقلل نسبة ال‬ ‫ قل العملية هتتعكس‬ca ‫فلو ال‬...vascular smooth muscle contraction ‫فبيحصل‬ -Vascular smooth muscle depends on Ca2+ influx for contraction. -Inhibition of Ca2+ influx→ decrease myocardial contractions→ decrease Cardiac overload. -calcium channels are in myocardium and blood vessels Classification A) 1,4-Dihydropyridines (1,4-DHPs) ……. Vaso-selective ‫بتقفل اللي علي الوعاء الدموي بس‬ Ex: Nifedipine B) Aralkyl amine …… Selective for myocardium ‫بتقفل اللي علي عضلة القلب بس‬ Ex: Verapamil C) Benzothiazepine ……. Intermediate (heart & Bl. Vs) ‫بتقفل االتنين‬ Ex: Diltiazem 11 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran A) 1,4-DHPs Nifedipine (Adalat®) 2 Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 5 4 3 1 ‫ في اول التمية حتي لو عكس األبجدية‬alcoholic portion ‫في األستر بحط ال‬ 6 2 Nifedipine: indicated in prinzmetal angina => angina at rest Nifedipine synthesis (Hantzsch synthesis) 1,4-dihydropyridine ‫ عشان يديني‬NH3 ‫ مع جزء من ال‬2-β keto ester ‫ مع‬aldehyde ‫بفاعل‬ SAR of 1,4-DHPs 12 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran dihydropyridine ring ‫الزم يكون عندنا‬ free ‫ يعني تبقي‬substitution ‫ تكون مش مرتبطة باي‬NH ‫الزم ال‬ methyl ester ‫ يكون عندي‬3 ‫ يعني مثال ممكن عند‬identical ‫ ومش شرط يكونوا‬ester ‫ الزم يكون عندي‬5 ‫ و‬3 ‫عند رقم‬ ester ‫ المهم يكون‬propyl ester ‫ يكون عندنا‬5 ‫ورقم‬ small groups ‫ يعني يكونوا‬bulky ‫ بس ميكونوش‬6 ‫ و‬2 ‫ في رقم‬substitution ‫الزم يكون عندنا‬ ‫ عشان‬ortho position ‫ علي ال‬substitution ‫ ويفضل يكون عندها‬4 ‫ مرتبطة عند رقم‬phenyl ring ‫الزم يكون عندنا‬ electron ‫ ويفضل يكون‬... ‫ يعني مش نقس المستوي‬non-cooplanner ‫ هيحصل‬steric hindrance ‫تعمل‬ withdrawing group as NO2 f- Diuretics A diuretic is a substance that promotes diuresis, increased production of urine (excretion of water and electrolytes; Na+ & Cl-). ‫ بيستخدم في حاالت التورمات ذي ال‬... urine ‫ لل‬nephron ‫ والمايه من ال‬electrolytes especially K ‫مادة بتحفز ال‬ intra ocular ‫ النها بتقلل‬glaucoma ‫ او تقلل ال‬... ‫ او تقلل الضغط النها بتقلل حجم الدم‬liver cirrhosis ‫ او ال‬CHF pressure Use: 1-Treatment of edematous conditions resulting from (CHF, renal failure, hepatic cirrhosis). 2-Management of hypertension. 3- Treatment of glaucoma. Classification Osmotic Carbonic Loop Thiazide Potassium- diuretics anhydrase diuretic / diuretics sparing inhibitors High ceiling diuretics ‫ فبتعمل‬secretion to K ‫ فهيا بتعمل‬secretion to K and Na ‫ دي الي جانب انها بتعمل‬classes ‫كل ال‬ ‫ ومشاكل في ضربات القلب‬diarrhea ‫ فبيعمل‬hypokalemia potassium sparing diuretic ‫ هو ال‬K ‫الوحيد اللي بيحافظ علي ال‬ Potassium-sparing diuretics These are diuretics which do not promote the secretion of K + into the urine. They act by inhibit sodium reabsorption and inhibit potassium ions secretion. ‫ واالتنين مش عايزهم ال‬.. hyperkalemia ‫ بيحصل‬K ‫ ونتيجة لزيادة رجوع ال‬reaborbtion to K ‫بيعمل‬ hyperkalemia ‫ وال‬hypokalemia potassium sparing diuretic ‫ ذي مثال‬hyper and hypokalemia ‫ بين‬mix ‫فعشان يحلوا المشكلة دي بيعملوا‬ balance ‫ فيعوضوا بعض ويعملوا‬with loop diuretic 13 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Drawback: Hyperkalemia. - So, Potassium-sparing diuretics are generally used in combination with other diuretic drugs (e.g. thiazide and loop diuretics) that would otherwise tend to increase the potassium levels to potentially dangerous high levels (hyperkalemia). - The combination therefore helps maintain a normal reference range for potassium. 1 8 2 Triamterene (Dyrenium®) 7 3 6 6-phenylpteridine-2,4,7-triamine 4 5 ‫االسم التجاري مش حفظ‬ Antianginal drugs and vasodilators Angina pectoris is the sensation of chest pain, pressure, or squeezing due to shortage of blood and oxygen supply to the heart muscle as a result of obstruction or spasm of the coronary arteries. It is characterized by a sudden severe pain in the chest extending to the left shoulder then down the arm. spasm or obstruction ‫ بيبقي بسبب نقص االكسجين اللي واصل لعضلة القلب سواء بسبب‬angina pectoris ‫ال‬ Therapy of angina is directed toward alleviating and preventing anginal attacks by altering the oxygen supply/oxygen demand ratio to the cardiac muscle or dilating the coronary vessels. dilatation ‫ او اني اعمل‬oxygen supply and oxygen demand ‫ بين ال‬ratio ‫العالج بيبقي باني ياما اغير ال‬ coronary artery ‫لل‬ Antianginal drugs: 1-Organic nitrites and nitrates (Vasodilators). 2-Calcium channel blockers 3-β-adrenergic blockers Organic nitrites (NO2) and nitrates (NO3) (vasodilators) -The class of choice in treatment of acute anginal episodes. -Are esters of alcohol or polyol with nitric acid esterification with acid ‫ بيحصلها‬OH ‫ عنده كذا‬poly alcohol ‫ وال‬.. low M. wt.‫ ليه‬poly alcohol ‫بيبقي‬ volatile ‫ فهيا‬low M. wt. ‫ ونظرا النها‬... nitric acid ‫اللي هو‬ The small lipophilic ester character makes them: 1-Volatile. 2-Very efficient in emergency treatment of anginal episodes as a result of their rapid absorption through biomembranes. 14 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran acute angina ‫الي جانب انه بيمتص سريعا فبيستخدم في عالج ال‬ Administration: by inhalation, chewable or sublingual for rapid onset of action. Mechanism of action ▪ Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO cyclization ‫ يعني بيحفز عملية ال‬guanylate cyclase ‫ عن طريق انه بيحفز ال‬vasodilator effect ‫ ليه‬NO ‫ال‬ Ca channels ‫ عن طريق انه بيقفل ال‬muscle relaxation ‫ لما بيزيد بيعمل‬cGMP ‫ ال‬... cGMP ‫ ل‬GTP ‫فبيحول ال‬ ▪ Nitrates may act indirectly by stimulating guanylate cyclase enzyme, which cause increased formation of cGMP through formation of a nitrosothiol-imtermediate in vascular smooth muscles. ▪ Increasing intracellular cGMP concentrations, which in turn blocks the calcium catalyzed vascular contractions ‫ اللي‬site of action ‫ لما بيوصل ل‬... R-NO2 ‫ وبيتحول ل‬reduction ‫ لما يخش الجسم بيحصله‬organic nitrate ‫ال‬ sulfhydryl group (SH group) ‫الخلية بيبقي عليها مجموعة وظيفية اسمها‬.. coronary artery ‫هيا ال‬ ‫ وكده‬S-nitroso thiol (R-S-NO) ‫ مهم جدا اسمه‬intermediate ‫ بيديني‬R-NO2 ‫ لما يتفاعل مع ال‬SH group ‫ال‬ ‫ تاني‬reduction ‫معناها حصل‬ ‫ ويحصل‬ca channels ‫ فيقفل ال‬cGMP ‫ ل‬GTP ‫ اللي هيحول ال‬guanylate cyclase (GC) ‫ بقي تحفز ال‬NO ‫ال‬ relation to muscle relaxation Nitroglycerin (glyceryl trinitrate) It’s sublingual preparation is rapidly absorbed from the sublingual, lingual, and buccal mucosa. => ttt of acute angina Its onset of action is 2 minutes and duration of action also is 30 minutes. 15 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Free tissue sulfhydryl groups play a key role in venodilation effect of nitroglycerin (stimulate the release of NO). So, pretreatment with reagents that react with free sulfhydryl groups such as ethacrynic acid, blocked triglyceride venodilation effect. ‫فلو انا‬.. sulfhydryl group ‫ عن طريق انها بتمسك في ال‬S-nitroso thiol ‫ محتاجة تكون ال‬nitrates ‫عندنا إن كل ال‬ relaxation ‫ مش هيتكون فمش هيحصل‬NO ‫ كده ال‬sulfhydryl group ‫اديت حاجه تمسك في ال‬ nitrate ‫ فيمنع تحول ال‬sulfhydryl group ‫ بيرتبط بال‬ethacrynic acid ‫ ال‬.. ‫فالزم ناخد بالنا من االدوية اللي بتتاخد‬ nitroglycerine is contraindicated to ethacrynic acid ‫ فكده عندنا ال‬S-nitroso thiol ‫ل‬ rapid action ‫ مش‬protection ‫ بنبقي عايزين نديله حاجه تعمل‬chronic angina ‫عندنا لو حد عنده‬ Antiarrhythmic drugs Arrhythmia: (irregular heartbeat) ❖ It is an alteration in the normal sequence of electrical impulse rhythm that leads to contraction of the myocardium. dysrhythmia = arrhythmia ‫لو حصل خلل في كهربة القلب هيحصل خلل في النبضات فيحصل‬ Classification Class I: Sodium channel blockers (Membrane stabilizing drugs) Class II: β-adrenergic blockers (affect sympathetic flow to SA node) Class III: Potassium channel blockers Class IV: Calcium channel blockers (Affect SA, AV node conductibility) Class IA Procainamide (Pronestyl®) 4-amino-N-(2-diethylaminoethyl) benzamide Procainamide metabolism Procainamide is metabolized in liver by acetylation. N-acetyl-procainamide , active as antiarrhythmic drug=> active metabolite p-aminobenzoic acid (PABA), which excreted in the urine. => inactive metabolite (highly polar) 16 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran ‫ بيحصل‬action potential of the heart ‫احنا عندنا في ال‬ )‫ (انعكاس في الشحنة‬rapid depolarization in phase 0 rapid ‫ وبعدها يحصل‬slow depolarization ‫وبعدها بيحصل‬ )‫ (إعادة للشحنة‬repolarization ‫للتوضيح‬ ‫بس‬ Na ion channels ‫ فيها هو ال‬rate limiting ‫ اهم‬phase 0 ‫ال‬ sodium channel blocker ‫عشان كده عملوا‬ potassium channels ‫ فيها هو ال‬class ‫ اهم‬phase 3 ‫ال‬ blockers calcium channels blockers ‫ فعملوا‬ca ‫ فيها هو ال‬class ‫ اهم‬phase 2 ‫ال‬ β-adrenergic blockers ‫ فعملنا‬SA node ‫ عن طريق‬CNS ‫او نقفل من المصدر األساسي من ال‬ ‫ فبيبقي فيه الي حد ما انتظام في نباضات القلب (ولو ان الدوا ممكن شخصيا هو اللي‬action potential ‫كلهم بيوسعوا ال‬ )‫يلخبط نباضات القلب‬ Lecture 2 Antihyperlipidemic drugs Hyperlipidemia ‫زيادة الدهون في الدم فبيبقي فيه خطر لإلصابة بتصلب الشرايين‬ An excess plasma concentration of cholesterol, cholesterol esters, triglycerides, or phospholipids. These lipids are transported in the blood in the form of lipoproteins Lipoproteins are separated according to their density, (VLDLs), (IDLs), (LDLs), and (HDLs). LDL is the richest in cholesterol and VLDL are the richest in triglycerides. The therapy target is reducing VLDL and LDL, on the other hand, increasing level of HDL which carry small amount of lipids ‫ بيرسب ال‬VLDL, IDL, LDL ‫ من الدم ويرميه علي الكبد يكسره فيمنع ترسيبه اما ال‬cholesterol ‫ بياخد ال‬HDL ‫ال‬ artery walls ‫ علي ال‬cholesterol HDL ‫ ونزود ال‬VLDL and LDL ‫فاحنا بنحاول نقلل ال‬ triglycerides ‫ بيشيل ال‬VLDL ‫ وال‬cholesterol ‫ عادة بيشيل ال‬LDL ‫ال‬ 17  Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran HMG-CoA reductase inhibitors (Statins) These compounds effectively block the conversion of HMG-CoA (3-Hydroxy-3-methylglutaryl coenzyme A) to mevalonic acid, a precursor in the de novo synthesis of cholesterol, this result in decrease in cholesterol and LDL levels. ‫ فيحوله ل‬HMG-CoA reductase ‫ بيشتغل عليه انزيم ال‬HMG-CoA ‫ عندنا في الجسم حاجه اسمها‬.. statins ‫ال‬ mevalonic acid ‫ فلو انا‬.. ‫ يعني بيصنع من البداية‬de novo.. cholesterol ‫ مهم في عملية إزالة ال‬precursor ‫ ده‬mevalonic acid ‫ال‬ ‫ فكده هوقف تصنيع ال‬mevalonic acid ‫ وتوقفه كده همنع تكوين ال‬HMG-CoA reductase ‫جبت حاجة تشتغل علي ال‬ )‫ كان بيشيله فكد هو كمان هيقل‬LDL ‫ (وبما ان ال‬cholesterol ‫عشان نضحك علي‬HMG-CoA reductase ‫ يكون شبه ال‬HMG-CoA reductase inhibitor ‫فاحنا محتاجين ال‬ :‫ يشتغل علي الدواء بتاعي ومن األمثلة علي االدوية دي‬HMG-CoA ‫االنزيم ده فبدل ما يشتغل علي‬ Lactone ring Lovastatin and simvastatin are prodrugs, their lactone ring are converted by hepatic enzymes into 3,5-dihydroxy acid, the open chain active forms. The structural similarity between the dihydroxy acid form of lovastatin (derived in-vivo hydrolysis of lactone portion of the drug) and the upper portion of HMG-CoA complex enables statin to inhibit the reducing enzyme HMG-CoA reductase. All HMGRIs are 7-substituted-3,5-dihydroxy heptanoic acids. 18 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Anticoagulants These are agents that interfere with blood clotting to ensure proper flow of blood. Clots are formed as a result of formation of fibrin and aggregation of platelets. ▪ Anticoagulants are drugs that interfere with formation of insoluble fibrin. ▪ Antithrombotics (Antiplatelets) interfere with platelet aggregation. ▪ Thrombolytics are drugs that are capable of dissolving existing blood clots. ‫اذوب الجلطة بعد ما اتكونت‬ I. Anticoagulants A- Oral anticoagulants (vitamin K antagonists) B- Injectable anticoagulants A- Oral anticoagulants (vitamin K antagonists) Mechanism of action: Vitamin K is required for the proper production of certain proteins involved in the blood clotting process. These drugs deplete the active form of the vitamin K (Hydroquinone). ‫ بيشتغل كعامل محفز في تحويل‬vit. K.. depletion to the reduced form of vit. K ‫بتعتمد األدوية علي انها تعمل‬ ‫ ل‬fibrinogen (soluble) ‫ بيحول ال‬thrombin ‫ ال‬.. thrombin (active) ‫ ل‬prothrombin (inactive) ‫ال‬ insoluble fibrinogen (clot) Ex: Coumarin derivatives They have long duration of action because they are highly bound to plasma proteins Warfarin (Marevan®) SAR: Coumarins activity based on substitution of the lactone ring in positions 3 and 4. 19 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran B- Injectable anticoagulants Heparin, natural anti-coagulant; is composed of sulfated mucopolysaccharides isolated from bovine lung or porcine intestinal mucosa. MOA of Heparin Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. ‫ بتاعه‬affinity ‫ لكن ال‬.. factor Xa ‫ و‬thrombin ‫ ل‬inhibition ‫ بيعمل‬antithrombin ІІІ (AT) ‫عندنا انزيم اسمه‬ ‫ يمسك في‬heparin ‫ لما ال‬.. thrombin ‫ ضعيفة خصوصا ال‬thrombin and factor Xa ‫ علي ال‬antithrombin ‫ال‬ ‫ مرة‬1000 ‫ تزيد‬thrombin ‫ لل‬affinity ‫فال‬. conformational change ‫ بيحصل فيه‬AT ‫ال‬ The activated AT then inactivates thrombin, factor Xa. The rate of inactivation by AT can increase by up to 1000-fold due to the binding of heparin. Heparin Not used orally [highly ionic + it’s sugar and the polysaccharide chains are broken down by gastric acid] & not taken I.M. [irritant make edema & hematoma]. Highly ionic => low absorption Only used I.V. or S.C. [rapid onset drug]. II. Antithrombotics (Antiplatelets) Antiplatelet drugs work by inhibiting platelet activation via different mechanisms. 1- COX-1 inhibitors 2- Phosphodiesterase inhibitors (PDEI) 3-Platelet receptor antagonists 20 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Platelet receptor antagonists ADP receptor antagonist These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. (cAMP inhibits platelets aggregation) This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. Ticlopidine and clopidogrel are thienopyridines that are potent and long acting platelet aggregation inhibitors. P2Y12 ‫ اسمه‬receptor ‫ الصفائح الدموية دي بيبقي عليه‬... ‫ في الصفائح الدموية بيمنع تجمعها‬cyclic AMP ‫زيادة ال‬ Gi protein ‫ بيبقي ماسك في ال‬P2Y12 ‫ وفي نفس الوقت ال‬ADP ‫بيمسك فيها ال‬ ‫ ل‬ATP ‫ اللي بيحول ال‬adenylate cyclase ‫ ل حاجه اسمها‬inhibition ‫ هيعمل‬P2Y12 ‫ لما يمسك في ال‬ADP ‫ال‬ ‫ ل‬ATP ‫ اللي بيحول ال‬adenylate cyclase ‫ ل‬inhibition ‫ هيعمل‬P2Y12 ‫ يمسك في ال‬ADP ‫ فلما ال‬... cAMP ‫ هتزيد‬aggregates ‫ يقل كمية الصفائح اللي هيكون ليها القدرة انها تكون‬cAMP ‫ في ال‬... cAMP ‫ فيقل ال‬cAMP platelets ‫ يقل ال‬cAMP ‫ فلما ال‬platelet aggregation ‫ وبتمنع ال‬vasodilatation ‫ بتعمل‬cAMP ‫حيث ان ال‬ ‫ هيزيد‬aggregation ‫ هتقل‬platelets aggregation ‫ هيزيد فال‬cAMP ‫ ده كله فال‬pathway ‫لو عكسنا ال‬ Clopidogrel Ticlopidine was replaced with clopidogrel to avoid its induced neutropenia. Clopidogrel is a prodrug, it has a chiral center and the S-isomer is the active one. The thienopyridines specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, their action still for 7 to 10 days after discontinuation of the medication. 21 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran The thienopyridines are prodrugs, require hepatic activation by CYP450. III. Thrombolytics (Fibrinolytics) These are enzymes or proteins that act on plasminogen to generate plasmin that dissolves the fibrin component of the clot. Examples: Streptokinase, Urokinase Anti neoplastic agents (Anticancer agents or anti tumor agents) 1)Alkylating agents I) N-mustard. (Mustine HCl ) II) Aziridines (Ethylene imines) (Thiotepa) III) Sulphonic acid esters. (Busulfan) IV) Nitroso urea derivatives. (Carmustine, Lomustine) 2)Antimetabolites I)Folic acid analogues. (Methotrexate) II)Purine analogues. (6-Mercapto purine, azathioprine) III)Pyrimidine analogues. (5-Fluro uracil, Floxuridine) 3)Anticancer antibiotics. D-actinomycin 4) Vinca plant alkaloids Vinblastine, Vincristine 5) Immunotherapy Tilorone 22 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran 1)Alkylating agents that treat cancer by alkylation which is (irreversible covalent bond) of DNA, so inhibit DNA replication by cross linking. Usually alkylation occurs by formation of covalent bond between alkyl gp (R⁺) and N7 of (GUANINE BASE) of DNA. Non specific drugs. intrastrand cross linking ‫ بعد ما تتحول‬DNA ‫ ل‬alkylation ‫ بسبب انه بيعمل‬bone marrow depression ‫ بيسبب‬mustard gas ‫لقينا ان ال‬ DNA ‫ ويبدا يشبك علي ال‬free radical ‫ او‬cabanion ‫ او‬carbocation ‫ ياما بتبقي في شكل‬interactive ‫لحاجة‬ bifunctional ‫ لو شبك من الناحيتين هنسميه‬.. mono alkylation ‫لو شبك مم ناحية واحدة هنقول عليه‬ intercalation ‫ هنسميه‬DNA nycleotides ‫ وحشر نفسه بين ال‬bifunctional ‫لو هو‬ interstrand cross ‫ يبقي‬2 strands ‫ من‬nuclei base ‫ و‬nuclei base ‫ من بره علي‬DNA ‫لكن لو مسك في ال‬ ‫ من غير ما يحشر نفسه‬linking intrastrand cross linking ‫ هنسميه‬strand ‫ من نفس ال‬nuclei base ‫ و‬nuclei base ‫لو شبك علي‬ ‫ جديد‬DNA ‫ مبيقدرش يفك ويعمل‬DNA ‫ بنحجم ال‬alkylation ‫لما بنعمل‬ I) N-mustard: Nitrogen mustards are cytotoxic chemotherapy agents derived from mustard gas. They are nonspecific DNA alkylating agents. The nitrogen mustard first chemotherapy drug (mustine). 23 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran MOA ‫ هيا‬lone pair of electron ‫ اللي عليه‬.. + charge ‫ فبتخرج وتسيب‬good leaving group ‫ تعتبر‬Cl ‫احنا عندنا ال‬ ‫ الحلقات الثالثسة والرباعية‬... aziridinium cation ‫ وتقفل بحلقة ثالثية اللي هيا‬nucleophilic attack ‫ فتعمل‬N ‫ال‬ electrophilic ‫ فتعمل‬+ charge ‫ هيبقي عليها‬C ‫ وال‬N ‫فالحلقة هتتكسر وترجع الشحنة تاني ل‬.. ‫سهل اوي تتكسر‬ N-7 of guanine ‫ علي ال‬attack Nitrogen mustards forms aziridinium rings. This aziridinium group then alkylates DNA once it is attacked by the N-7 nucleophilic center on the guanine base. A second attack after the displacement of the second chlorine forms the second alkylation step that results in the formation of interstrand cross- links. N.B: Rate limiting step of alkylation reaction is (Formation of Aziridinium cation). SAR of N-mustard alkylating agents: 1) (R) (Aliphatic) eg: CH3 gp. It is considered Electron donating gp (ED gp) that make stabilization and fixation of lone pair of Nitrogen, so increase Aziridinium cation formation, so increase anticancer activity. ‫ هتزيد‬activity ‫ فال‬aziridinium cation ‫ فهيبقي سهل تكوين ال‬donating activity ‫ ليها‬aliphatic ‫ال‬ 1) ® (Aromatic) eg: Benzene ring. -Make participation of lone pair of Nitrogen in RESONANCE with the ring, so decrease aziridinium ion formation, so decrease anticancer activity. 24 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Substitution of benzene ring by (ED) gp →it will increase anticancer activity. Substitution of benzene ring by (EWD) gp →it will decrease anticancer activity. Generally: [ED on aromatic > Aliphatic > Aromatic > EWD on aromatic]. ‫ في حلقة البنزين فتقلل قدرتها علي تكوين‬resonance ‫ هتخش في‬lone pair of nitrogen ‫ هنا هتقل الن ال‬activity ‫ال‬ aziridinium cation ‫ال‬ N ‫ تروح ناحية ال‬electron density ‫ فال‬electron donating ‫ ب‬aromatic ring ‫ علي ال‬substitution ‫لو عملنا‬- aziridinium cation ‫فنقدر نكون ال‬ N ‫ من ال‬electrons ‫ فهتسحب ال‬electron withdrawing ‫ ب‬aromatic ring ‫ علي ال‬substitution ‫لو عملنا‬- aziridinium cation ‫فتقلل قدرتها علي تكوين ال‬ 2)Nitrogen: May be present as 1°ry , 2°ry or 3°ry amine. If present as 4°ry it will not contain unshared lone pair ,so it will not form aziridinium cation under physiological PH. 3)Halogen: Replacement of Cl¯ by Br¯ that make formation of aziridinium cation is more rapid so it is more toxic than Cl¯, so we use Cl¯ as halogen not Br¯ although its lower activity toxicity ‫ بس مشكلته في ال‬leaving group ‫ هو احسن‬I ‫ال‬ 4) Amino acids and DNA bases: May be used as carrier for N-mustard, so increase selectivity cancer cells ‫ الن الدواء يروح لل‬selectivity ‫ فكده انا بزود ال‬amino groups ‫ ليها شراهه ناحية ال‬cancer ‫خاليا ال‬ 25 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran lecture 3 Example of alkylating N- mustard drugs Mustine HCl (mustargen®) 1 Trade and chemical name: Mustine HCl (mustargen®) 2 2 IUPAC name: Bis (2-chloroethyl) methylamine HCl 1 - It is one of most active drugs in N-mustard but also the most toxic. - Used in Hodgkin lymphoma disease. IІ) Aziridines: Thiotepa Trade and chemical name: Thiotepa IUPAC name: Thio triethylene phosphoramide aziridine molecule ‫ انه منه فيه‬N-mustard ‫بيتميز عن ال‬ - Is a tertiary aziridine - Used in Treatment for Breast and Ovarian cancer Aziridine ring ‫للتوضيح فقط‬ It is possible for the nitrogen atoms to protonate before reacting with DNA. (A more attractive target for DNA nucleophiles) ‫اتشرح المحاضرة اللي فاتت‬ Thiotepa undergoes oxidative desulfuration, forming an active cytotoxic metabolite known as TEPA (triethylene phosphoramide). Both thiotepa and TEPA have been proposed to alkylate DNA through the hydrolytic release of aziridine. => both are active oxidative desulfuration thiotepa TEPA 26 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran III) Sulphonic acid esters Busulfan (Busulfex®) Trade and chemical name: Busulfan (Busulfex®) synthesis: Esterification 2 sulphonic acid ‫ بيبقي‬O=S(OH)=O... sulfonyl ‫ اسمها‬O=S=O ‫ ال‬... sulfinyl ‫ اسمها‬S=O ‫ال‬ busulfan ‫ والتفاعل يفضل نشط ف اتجاه تكوين ال‬acid ‫ بحيث تتفاعل مع ال‬base ‫ اللي طالع بنحط‬HCl ‫بسبب ال‬ MOA (mechanism of action): It is a bifunctional alkylating agent that forms DNA – DNA intrastrand linking between the DNA bases guanine and adenine and between guanine and guanine. This occurs through nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. DNA crosslinking prevents DNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis ‫ يخش الجسم ال‬busulfan ‫ أول ما ال‬good leaving group ‫ دي‬methyl sulfonate group ( = mesylate) ‫ال‬- ‫ واحده بتخرج وتسيب‬... ‫ مش بيخرجوا سوا‬mesylate group ‫ (االثنين‬positive charge ‫ تخرج وتسيب‬mesylate )‫ الثانية‬mesylate group ‫ يليها خروج ال‬positive charge N-7 of guanine ‫ علي ال‬electrophilic attack ‫ تعمل‬positive charge ‫ال‬- ‫ يعني‬intrastrand crosslinking ‫ يقدر يعمل‬busulfan ‫ فال‬mesylate group ‫ وبما ان الموضوع ده بيحصل لالتنين‬- ‫ مش هيعرف‬DNA ‫ للخلية الن ال‬apoptosis ‫ فبيحصل‬strand ‫ علي نفس ال‬2 guanine nucleobases ‫تقدر تشبك علي‬ ‫ فخاليا الكانسر تموت‬replication ‫يعمل‬ 27 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran IV) Nitrosourea derivatives General structure If R is CH3-CH2-Cl => carmustine If R is phenyl group => lomustine MOA: Act by Alkylation of DNA and carbamoylate glutathione reductase. This lead to cell death. ‫ يحصله‬moiety ‫ الجزء األسود اللي هو ال‬DNA ‫ لل‬alkylation ‫ أول طريقة العادية اللي هو ال‬... ‫بتشتغل بطريقتين‬ N-7 of guanine ‫ علي ال علي ال‬electrophilic attack ‫ تعمل‬positive charge ‫ يخرج ويسيب‬Cl ‫ وال‬alkylation )) bifunctional ‫ الن طلع جروب واحد بس (مش‬monoalkylation ‫ نوعه‬alkylation ‫(هنا ال‬ ‫ بإنزيم اسمه‬reduction ‫ بتعمل‬carbamoylation ‫ بتعمل‬carbamoyl group ‫ اللي هو ال‬pink ‫أما الجزء ال‬ ‫ في ال‬glutathione ‫ وطالما ال‬reduced form ‫ في ال‬glutathione ‫ وده بيحافظ علي ال‬glutathione reductase ‫ هيزيد ال‬carbamoylation ‫ فانا لما بقفل اإلنزيم ده بال‬... free radicals ‫ فهو بيحافظ علي الخاليا من ال‬reduced form DNA ‫ بسبب حدوث قصور في ال‬cell death ‫ وبالتالي‬free radicals 2)Anti-metabolites: Def: They are compounds similar in chemical structure to normal essential metabolites e.g: (Folic acid, Purine bases, Pyrimidine bases), so they can replace these normal metabolites in biological system. - Thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as stopping cell growth and cell division, so these compounds are used as chemotherapy for cancer. 28 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran cancer cells ‫ نتيجة لشراهة ال‬cancer ‫ في حالة ال‬... ‫ للجسم‬essential ‫ بتبقي‬normal metabolites ‫بيبقي عندنا‬ structure ‫ من بره ليه‬drug ‫ فلو انا جبت‬... normal metabolites ‫بسبب االنقسامات اللي بتعملها بتحتاج لل‬ ‫ وتحولها‬normal metabolites ‫ فبالتالي اإلنزيمات اللي كانت بتشبك علي ال‬similarity with normal metabolites drug ‫ هتشبك علي ال‬active form ‫لل‬ structure similarity ‫ الن ليها‬competitive inhibitors ‫عشان كده ده يعتبر األدوية دي‬ active ‫ مش هتالقي‬cancer cells ‫ فكده ال‬active metabolites ‫ لل‬normal metabolites ‫وطالما مش هتتحول ال‬ cytotoxicity ‫ اللي محتاجاها وبالتالي يحصل‬metabolites Classification of antimetabolites: I) Folic acid analogues. II) Purine analogues. III) Pyrimidine analogues. Folic acid analogue (Folic acid antagonists) : chemical structure ‫ عشان نعرف نعمل دواء قريب ليه في ل‬folic acid ‫الزم نعرف شكل ال‬ Methotrexate Trade and chemical name: Methotrexate IUPAC name: 4-amino-N-methyl folic acid So, methotrexate can prevent neoplastic cells from dividing. 29 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran MOA: inhibit DHF reductase enzyme (is an enzyme that reduces dihydro folic acid to tetrahydro folic acid). Dihydrofolate Dihydro folic acid tetrahydro folic acid reductase (DHF) Methotrexate Folate is needed by rapidly dividing cells to make thymine. So, antifolates can prevent neoplastic cells from dividing. Antifolates are drugs of choice in ttt of Acute leukemia in children. Methotrexate is a chemotherapy agent and immune system suppressant. Besides its use as anti-cancer, It is also used to treat autoimmune diseases (rheumatoid arthritis). Antiviral drugs Virus: it is an obligatory intracellular parasite , as it enter the host cells and direct its biochemical machinery to serve his own replication. It is not a cell but a particle on the borderline between living (ability to reproduce) and non living (not a cell). ‫ هو يصنف انه عنده القدرة علي االنقسام بس في‬.. ‫ يعني متقدرش تعيش بره الخلية وال تتكاثر‬Obligatory intracellular cytoplasm or cell membrane ‫نفس الوقت مش خلية النه معندهوش‬ Virus is composed of 1) The envelope (have glycoprotein (the eye of virus cells)) 2) Capsid (protect DNA or RNA of virus) 3) Nucleic acid The development of antiviral agents is confronted with 2 major obstacles: 1)Lack of selectivity: due to *The intimate relationship between the virus and the host cell, so any drug will be toxic on both. 2)Too late diagnosis of viral diseases: the symptoms appear at the final stage of viral replication. 30 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Nucleobases: Purine vs pyrimidine Nucleoside Nucleotide Base + sugar Base + sugar + phosphate sugar can be: ‫للتذكير‬ DNA Viral polymerase: ▪ DNA polymerase is an enzyme that synthesizes DNA molecules from deoxyribonucleotides, the building blocks of DNA. These enzymes are essential for DNA replication ▪ DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. ▪ The polymerase finger tips pick nucleoside triphosphate only ▪ When the nucleoside analogue drug molecule is mistakenly incorporated in the growing strand one of 2 things may happen: 1)The polymerase continues its action resulting in fake nucleic acid. 2)The polymerase stops its action resulting in premature (Chain termination). ‫ يشتغل عليها‬DNA polymerase ‫ بتاعه الجسم فال‬nucleosides ‫ يعني بعمل دواء شبه ال‬Nucleoside analogue chain termination ‫ أو يوقف شغله ويحصل‬fake nucleic acids ‫وبالتالي فيه حلين يا يكمل ويكون‬ 31  Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Classification of Anti viral agents Against DNA viruses Against RNA viruses 1- Inhibitors of viral DNA polymerase 1- Antiflu agents a- Purine nucleoside analogues a- Ion channel disruptors (M2 inhibitor) (Acyclovir and its prodrugs) (Amantadine , Rimantadine) b- Pyrimidine nucleoside analogue b- Neuraminidase inhibitors (Oseltamivir) (Cidofovir) c- Non nucleosides drugs (Foscarnet) 2- Antisense therapy (Fomivirsen) 2- Anti HIV agents a- Reverse transcription inhibitors a. Nucleoside RT inhibitor (Zidovudine) b. Non nucleotide RT inhibitors (Nevirapine) b- Integrase inhibitor (Raltegravir) c- Protease inhibitor (Ritonavir) d- CCR5 entry inhibitor (Maraviroc) 2- Anti HCV agents ----- a- Broad spectrum antivirals (interferon , Ribavirin) b- Direct acting antivirals (sofosbuvir) Against DNA viruses 1- Inhibitors of viral DNA polymerase a- Purine nucleoside analogues Acyclovir (Zovirax®) Trade and chemical name: Acyclovir (Zovirax) Acyclic analogue of deoxyguanosine Structure similarity to Normal nucleoside Deoxy guanosine The (Gold standard) for HSV. 32 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Acyclovir is a prodrug (needs bioactivation before acting). ‫ علي ال‬pick ‫ عشان يقدر يعمل‬triphosphate ‫ ويبقي‬phosphorylation ‫ بسبب انه محتاج يتعمله‬active ‫هو مش‬ DNA polymerase Viral thymidine Cellular kinase Acyclovir Acyclovir mono phosphate Acyclovir triphosphate kinase Chain termonation Incorporated in place of Binds to DNA polymerase (as it deoxyguanosine in the has structural similarity to due to absence of deoxyguanosine triphosphate) 3`OH synsthesis of nuclei acid Inhibation of nuclei Inactivation of acid synthesis DNA polymerase viral ‫ نفسه اسمه‬virus ‫ بتاعه انه بيحصل بإنزيم من ال‬activation ‫ انه أول خطوة ف ال‬acyclovir ‫ميزة ال‬ phosphorylation ‫ ) وبعدها بيحصله‬activation ‫ مش هيحصله‬virus ‫ (لو مفيش‬safe ‫ فكده هو‬thymidine kinase ‫ مش هيعمل حاجة‬virus ‫ جدا لو راح لخلية مفهاش‬safe ‫ فهو‬... ‫ بتاع جسمنا عادي‬cellular kinase ‫ب‬ Acyclovir is one of the safest antiviral agents -Acyclovir has 100 fold selectivity for viral cell versus host cell (Viral thymidine kinase). -Acyclovir has 50 fold selectivity for viral cell versus host cell (Viral DNA polymerase). -Selective uptake of Acyclovir by infected cells. (Acyclovir is the most selective antiviral). 33 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Acyclovir mono phosphorylation occurs faster within cells infected by herpes virus than in normal cells because acyclovir is a poor substrate for the normal cell thymidine kinase. Problem (1) : Acyclovir oral bioavailability is only 15-30 %. *Reason: Due to poor transport through membranes due to high hydrophilicity (high polarity) *Solution: Development of (Prodrugs) with improved transport and hence improved pharmacokinetics (esterification with amino acid so increase lipophilicity) Valciclovir: (valtrex®) Trade and chemical name: Valciclovir (valtrex®) Oral bioavailability 54% as it passes by active transport and passive diffusion. Acyclovir is a prodrug while Valciclovir is a pro pro drug generally (but a pro drug for acyclovir) as Valciclovir as it gives firstly acyclovir which is then converted to acyclovir triphosphate Problem (2): Acyclovir is not effective against some herpes virus such as cytomegalovirus (CMV). *Reason: the virus produces different (Thymidine kinase) which fail to phosphorylate Acyclovir. *Solution: Development of analogue more structure similar to (Deoxy guanosine) so as to bind viral (Thymidine kinase) eg: Gancyclovir. 34 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Ganciclovir: (cymevene®) Trade and chemical name: Ganciclovir (cymevene®) *Used orally but it has low oral bioavailability (8.5%), intravitreally *Used IV as drug of choice for treatment of CMV retinitis. - It is more similar to deoxy guanosine *S/E: it is nearly equally monophosphorylated by CMV Kinase as well as by cellular kinase →lower selectivity and higher toxicity. Due to higher similarity to deoxy guanosine, so cause bone marrow suppression. Besides, it is cytotoxic drug Problem (3): Ganciclovir has low oral bioavailability (only 8.5%). *Reason: too hydrophilic to cross membranes by passive diffusion. *Solution: assist transport through L-valyl ester prodrug formation. Valganciclovir (Valcyte®): Trade and chemical name: Valganciclovir (Valcyte®) Oral bioavailability 65 % as it passes by active transport and passive diffusion. (Valganciclovir is prodrug of ganciclovir) Ganciclovir is a prodrug while valganciclovir is a pro pro drug generally (but a pro drug for Ganciclovir) as Valganciclovir as it gives firstly ganciclovir which is then converted to ganciclovir triphosphate Valganciclovir and ganciclovir => make fake nucleic acids as it contains OH Acyclovir and valciclovir => cause chain termination 35 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Against RNA virus: The Flu virus: ✓ The nucleocapsid of the virus contains (-)-ssRNA and a viral enzyme called “RNA polymerase”. ✓ The viral envelope contain 2 viral glycoproteins hemagglutinin (H) , and neuraminidase (N). ▪ Hemagglutinin binds to sialic acid terminals in the surface of host cells there by facilitating virus entry. ▪ Neuraminidase cleaves sialic acid–hemagglutinin complex from the surface of host cell thereby facilitating virus release. Sialic acid (nine-carbon sugar neuraminic acid derivative) is a terminal sugar of glycoproteins and glycolipids in cell surface. ‫ يشوفه يرتبط بيه عن طريق ال‬virus ‫ موجود في جسمنا أول ما ال‬sialic acid ‫ال‬ Just explaining ‫ بعد ما الفيرس يتكاثر داخل‬.. endocytosis ‫ وبعدها الفيرس يخش بال‬Hemagglutinin ‫ للفيرس‬release ‫ فيحصل‬hemagglutinin ‫ وال‬sialic acid ‫ يكسر الرابطة بين ال‬neuraminidase ‫الخلية بيجي ال‬ Anti-flu agents 1) M2 inhibitors Trade and chemical name: Trade and chemical name: Amantadine (Adamine®) Rimantadine (Flumadine®) Cage structure: Diamondoids (Adamantane nucleus) 36 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran -M2 channels allows acidification of virus -Initiates uncoating of viral RNA -Allows viral replication -M2 inhibitors block this action nucleic acid ‫ فيحصل‬virus ‫ من الخاليا بتاعتنا لل‬protons ‫ أول ما الفيرس يخش الخلية بتسمح بمرور ال‬M2 ‫ال‬ ‫ وبالتالي‬acidification to the interior of the virus ‫ لما بنقفلها فمش هيحصل‬... replication ‫ ويحصل‬uncoating replication ‫ وبالتالي مش هيحصل‬uncoating ‫مش هيصحل‬ MOA Interference with the viral protein, M2, a proton channel on viral envelope. After entry of the virus into cells via endocytosis, the M2 channel functions in transporting protons with the gradient into the interior of the virus. Acidification of the interior results in disassociation of ribonucleoproteins, and the initiation of viral replication. Amantadine and rimantadine block pore function of M2 ion channels. Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, preventing both amantadine and rimantadine from inhibiting the channel in their usual way. Amantadine and rimantadine are ineffective towards all circulating Influenza B strains. 2) Neuraminidase (NA) inhibitors: Trade and chemical name: Oseltamivir (Tamiflu®) IUPAC name: ethyl -4-acetamido-5-amino-3-(pentan-3-yloxy)- cyclohex -1-ene-carboxylate 1-carboxylate Sialic acid analogue. The first orally active NA inhibitor. Uses: for prevention of Influenza A, B. 37 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran MOA Oseltamivir (sialic acid analogue) is, a competitive inhibitor of influenza's neuraminidase enzyme. (competitive due to structural similarity) The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell. Thus oseltamivir prevents new viral particles from being released. Anti HIV agents HIV = Human Immunodeficiency Virus. * A unique type of viruses (a retrovirus). * AIDS patients die of opportunistic infections and cancers. * HIV cannot replicate on its own, so in order to make new copies of itself, it must infect cells of the human immune system, called CD4 cells (T-cells or Helper cells). * CD4 cells are white blood cells that play a central role in responding to infections in the body. An example of retroviruses is HIV. When these viruses enter a host cell, they must first convert their RNA into DNA. This process, called reverse transcription. Often, retroviruses use an enzyme, called integrase, to insert the retroviral DNA into the genome of the host cell. The ability of retroviruses to integrate this DNA into the host cell’s DNA increases the chances of causing cancer or other diseases. 1) Reverse transcriptase inhibitors: - Reverse transcriptase (RT) → It is unique to HIV and it is primarily DNA polymerase, it catalyzes the synthesis of DNA strand using viral RNA as a template. 38 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran A) Nucleoside RT inhibitors: (NRTIs) Trade and chemical name: Zidovudine (Retrovir®) Azido group -chain termination group Structral similarity Deoxy thymidine -Normal nucleoside MOA Bind to RT Cellular kinase Drug triphosphate Being structure similar to Drug corresponding normal nucleoside Chain termination Incorporation in place due to absence of of corresponding normal nucleoside Inactivation of RT 3`OH N.B: HIV Does Not produce viral kinase. Common side effect of NRTIs is : (Hepatomegaly and lactic acidosis). cellular ‫ بال‬phosphorylation ‫ غير انه يحصله‬option ‫ فمفيش قدام‬viral thymidine kinase ‫ مفهوش‬HIV ‫ال‬ hepatomegaly and lactic acidosis ‫ ذي مثال‬toxicity ‫ فده بيسبب‬kinase 39 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran b) Non-nucleoside RT inhibitors : (NNRTIs) Trade and chemical name: Nevirapine (Viramune XR®) IUPAC name: Dipyrido diazepinone MOA: ✓ These compounds act as Allosteric inhibitors of RT. ✓ Non nucleoside RT inhibitor, so non competitive with nucleosides. => no structural similarity ✓ They are hydrophobic compounds have no structure similarity to normal nucleosides. ✓ Less toxic than NRTIs due to higher selectivity to viral RT RT ‫ فمكان ارتباط ال‬changes ‫ وبيعمل‬RT ‫بيشتغل عن طريق انه بيمسك في مكان جنب مكان اللي بيمسك فيه ال‬ active site of RT ‫ ألنه بيشتغل علي ال‬phosphorylation ‫فميعرفش يرتبط فهو مش محتاج يحصله‬ Hepatitis C virus (HCV) Types of HCV genomes: Genotype 1 (Difficult treatment) , 2 , 3 , 4 (Wide in Egypt) , 5 , 6. (Anti Hepatitis C agents) I) Broad spectrum antivirals with anti HCV activity: *Interferon *Ribavirin II) Direct acting antivirals: NS3/4A Protease inhibitors (Telaprevir). NS5A polymerase inhibitors (Daclatasvir). NS5B Polymerase inhibitors (Sofosbuvir). NS (Non-Structural) 40 Dr Ayman Abo Elmaaty... medicinal 1... By: Reem Badran Trade and chemical name: Sofosbuvir (Sovaldi®) -(NS5B polymerase inhibitors) *Sofosbuvir is a turning point in hepatitis C treatment Sofosbuvir inhibits the hepatitis C NS5B polymerase protein. Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis C virus (HCV). It is an RNA polymerase, having the key function of replicating HCV's viral RNA by using the viral positive RNA strand as a template. Sofosbuvir appears to have a high barrier to the development of resistance. ‫بيقاوم التغيرات‬ it acts by (Chain termination) as F atom not at right side so make steric effect with polymerase enzyme. 1) The phosphonamidite prodrug will survive in GIT. 2)The terminal ester will be hydrolyzed by carboxy esterase 1 (CES1) during first pass metabolism in the liver followed by a cascade of enzymatic reactions to release (The active uridine triphosphate in high concentration in liver). Sofosbuvir metabolic pathway ‫تم بحمد هللا‬ 41