Systems Pharmacology and Chemotherapeutics PDF

Systems Pharmacology and Chemotherapeutics SCPCB3-B44 Eduvos (Pty) Ltd (formerly Pearson Institute of Higher Education) is registered with the Department of Higher Education and Training as a...

Systems Pharmacology and Chemotherapeutics SCPCB3-B44 Eduvos (Pty) Ltd (formerly Pearson Institute of Higher Education) is registered with the Department of Higher Education and Training as a private higher education institution under the Higher Education Act, 101, of 1997. Registration Certificate number: 2001/HE07/008 Antihistamines Lesson 1 Autacoids Prostaglandins H1 Antihistamines H2 antihistamines Mifepristone Acrivastine Cimetidine Misoprostol Cetirizine Ranitidine Chlorpheniramine Cyclizine Desloratidine Diphenhydramine Dimenhydrinate Doxepin Doxylamine Fexofenadine Hydroxyzine Loratidine Meclizine Promethazine H1 antihistamines Antihistamine pharmacology Antihistamine pharmacology Visual Mnemonic Visual Mnemonic Introduction Autocoids: Prostaglandins Histamine Serotonin Are all formed by the tissues upon which they act Differ from local hormones as: They are produced by many tissues Rather than in specific endocrine glands Prostaglandins Prostaglandins Abortion Abortifacients Oral administration: mifepristone followed by Vaginal administration of misoprostol (24 hours later) AE’s: infection, haemorrhage & retained tissue Therapeutic uses Peptic ulcers Inhibit secretion of gastric acid Also enhances mucosal resistance to injury in patients with gastric ulcers using NSAIDs Histamine Anaphylaxis “markedly improved susceptibility to a specific protein after a suitable incubation period” -- Charles Richert, 1902 Current definition: sudden, severe, potentially fatal, systemic allergic reaction that can involve various areas of the body (such as the skin, respiratory tract, gastrointestinal tract, and cardiovascular system). Common cause: Food, Insect stings, Medicines, Latex Histamine NH2 5 4 1 3 N N H Sir Henry Dale, 2 discovered histamine Histamine Experiments: - Guinea pigs - Dogs Histamine Location: Lungs, skin, GIT, ↑ [] in mast cells & basophils Synthesis Decarboxylation of the amino acid histidine By histidine decarboxylase Enzyme expressed by the following cells: Neurons Gastric mucosa parietal cells Mast cells: histamine stored in granules Inactive complex composed of histamine & heparin If histamine is not stored, it is rapidly inactivated by enzymes Basophils Biosynthesis of histamine Histamine Release of histamine Released in response to certain stimuli In conjunction with other mediators Stimuli examples: Destruction of cells as a result of: Bacterial toxins Bee sting venoms Trauma Allergies Anaphylaxis Histamine Mechanism of action Histamine binds to: H1, H2, H3 & H4 receptors H1 and H2 receptors: Widely expressed Targets for certain drugs H3 and H4 receptors: Expressed in only a few cell types Histamine Receptors Contain seven transmembrane helical domains G protein-mediated second messenger systems H1 receptors Smooth muscle contraction Increasing capillary permeability H2 receptors Gastric acid secretion Actions of histamine Role in allergy & anaphylaxis IV histamine: produces actions similar to anaphylactic shock Resulting from release of certain mediators from storage sites: Histamine, serotonin, leukotrienes, eosinophilic chemotactic factor Differences in severity: Sites of release Rates of release Does it allow inactivation? Actions Contraction of smooth muscle Stimulation of secretions Dilation & increased permeability of the capillaries Antihistamines Actions of H1 antihistamines Inhibition of release of mediators from mast cells & basophils Down-regulation of certain transcription factors Decreased production of pro-inflammatory cytokines Histamine H1 Receptor Blockers H1 Antihistamines Mechanism of action Does not inhibit formation or release of histamine! Instead, it blocks receptor-mediated response of target tissue Whereas cromolyn inhibits release of histamine from mast cells First generation Older Inexpensive Penetrate CNS: sedation Interact with a variety of other receptors Causing a variety of AE’s Cholinergic, adrenergic or serotonin receptors Low specificity H1 Antihistamines Second generation Specific for H1 receptors Do not penetrate BBB Least sedation: Desloratidine Fexofenadine Loratidine Relative potential for sedation H1 Antihistamines Therapeutic uses: Allergic and inflammatory conditions Allergic rhinitis & urticaria Ineffective in bronchial asthma Systemic anaphylaxis: epinephrine Motion sickness and nausea Examples: diphenhydramine, dimenhydrinate, cyclizine, meclizine, hydroxyzine Independent of their antihistaminic actions Somnifacients Examples: diphenhydramine & doxylamine Therapeutic advantages & disadvantages of H blockers 1 Pharmacokinetics Oral adminstration: well absorbed Half life: 4-6 hours Meclizine: longer t1/2 (12-24 hours) More effective: prophylactically Effects of H Antihistamines at 1 various receptors Adverse effects CNS effects Sedation, tinnitis, dizziness, lassitude, incoordination, blurred vision, tremors Dry mouth Anticholinergic effects Drug interactions Potentiation of the effects of other CNS depressants Alcohol May not be used together with MAOI’s: exacerbate anticholinergic activity Overdoses Acute poisoning: CNS Hallucinations, excitement, ataxia, convulsions, cardiorespiratory collapse Adverse effects Histamine H2 Receptor Blockers H receptor blockers 2 Therapeutic use Inhibitors of gastric acid secretion In the treatment of ulcers Mechanism of action: Reduce intracellular levels of cAMP Thereby reducing secretion of gastric acid Examples: Cimetidine, ranitidine, famotidine & nizatidine  Immuno- Lesson 2 pharmacology Organ transplant rejection prevention Induction drugs: Powerful antirejection medicine used at the time of transplant (just before) Maintenance drugs: Antirejection medications used for the long term Rejection agents: Medications which are used for the treatment for rejection episodes Immunosuppressive drugs Selective inhibitors of cytokine Immunosuppressive production & function antimetabolites Cyclosporine Azathioprine Everolimus Mycophenolate mofetil Sirolimus Mycophenolate sodium Tacrolimus Antibodies Adrenocorticoids Alemtuzumab Methylprednisolone Antithymocyte globulins Prednisolone Basiliximab Prednisone Dacilzumab Muromonab-CD3 Introduction Earlier immunosuppressants Non-selective Suppression of both parts of the immune system Humoral Cell-mediated Introduction Rx Autoimmune diseases Organ & tissue transplantation Severely toxic drugs Used in combination At low doses Selective Inhibitors of Cytokine Function & Production CD (clusters of differentiation) Ability to act as receptors Expressed by lymphocytes and antigen presenting cells Antigen presenting cells: CD80 CD86 T Cells: CD3 CD28 CD25 (IL receptor) Mechanism of action: Cyclosporine- CsA (IV or PO) CsA diffuses into T Thus nFATc cannot And cytokines are cells enter the nucleus not produced No IL-2 to stimulate Binds to cyclophilin But now calcineurin proliferation of T (a immunophilin) to cannot perform this cells or activate NK form a complex function cells, macrophages & cytotoxic T cells Calcineurin (a type CYP3A4 of phosphatase) This complex binds Extensive drug interactions function: to calcineurin dephosphorylates nFATc Cyclosporine (CsA) Cyclic peptide Extracted from a soil fungus More effective when administered with a glucocorticoid Rx: Prevention of organ transplant rejection RA: alternative to methotrexate Psoriasis Mechanism of action Preferentially suppresses cell-mediated immunity Effect of cyclosporine on liver transplant survival Adverse effects: Cyclosporine Nephrotoxicity Avoid coadministration of drugs that can cause kidney dysfunction: E.g. Aminoglycosides, anti-inflammatories (diclofenac, naproxen), cimetidine Hepatotoxicity Development of life-threatening infections Herpes & cytomegalovirus Lymphoma Adverse effects: Cyclosporine Anaphylactic reactions on parenteral administration Hypertension Hyperkalemia Do not use potassium sparing diuretics Tremor, Hirsutism, Gum hyperplasia Tacrolimus (TAC) Rx: Rejection of liver & kidney transplants Given in conjunction with a glucocorticoids Preferred over cyclosporine Less episodes of rejection More potent Lower doses of glucocorticoid necessary? Mechanism of action Similar to cyclosporine Binds to a different immunophilin FKBP-12 Mechanism of action: Cyclosporine & Tacrolimus Tacrolimus Pharmacokinetics IV or oral Absorption decreased when taken with high fat meals Potency: 10 – 100 times more potent than CsA Highly plasma protein bound Concentrated in erythrocytes (like CsA) Interpersonal variation: oral absorption incomplete & variable Requires dosage adjustment CYP3A4 Extensive drug interactions Tacrolimus Adverse effects More severe than CsA Nephrotoxicity Neurotoxicity Tremors Seizures Hallucinations Development of insulin-dependent Diabetes mellitus Black & hispanic patients Anaphylaxis Does not cause Gingival hyperplasia or Hirsutism Five year renal allograft survival in patients treated with tacrolimus or cyclosporine Sirolimus (SRL) Macrolide From fermentations of a soil fungus Equipotent to CsA Rx: After renal transplantation In conjunction with glucocorticoids & CsA (synergism) Sirolimus coated stents in cardiac vasculature Antiproliferative effect : reduces proliferation of endothelial cells Prevents restenosis  Mechanism of action: Sirolimus SRL binds to FK-BP But does not form a complex with calcineurin Instead SRL binds to mTOR = mammalian target of rapamycin mTOR function: cell cycle progression, DNA repair, protein translation Thus by binding to mTOR, T cells arrest in the G1 phase Sirolimus Pharmacokinetics High fat meals decrease SRL’s absorption Highly plasma protein bound Metabolism: CYP3A4 Same drug interactions as CsA & TAC Elimination: faeces Its immunosuppression lasts 6 months after cessation of therapy Adverse effects: Sirolimus Combination of CsA & SRL is more nephrotoxic (Combination of TAC & SRL is less toxic) Hyperlipidaemia Headache Nausea Diarrhoea Hypertension Leukopaenia & thrombocytopaenia Immunosuppressive Antimetabolites Used in combination with CsA, TAC & glucocorticoids Azathioprine Azathioprine is converted to 6- Thus require de mercaptopurine novo synthesis (6-MP) 6-MP is converted Majorly affects to thioinosinic lymphocytes: lack acid (nucleotide purine salvage analogue) pathway Thioinosinic acid Lymphocytes = (rapidly dividing) immunosuppressi require PURINES! ve Mechanism of action: Azathioprine Azathioprine Pharmacokinetics Erratic absorption from oral route Does not cross the BBB Decrease the dose of azathioprine in Hyperuricaemic patients receiving allopurinol Azathioprine Adverse effects Bone marrow suppression Nausea & vomiting Mutagenic and carcinogenic Concomittant use with ACE-I’s or cotrimoxazole In renal transplant patients > leukopaenic response Mycophenolate mofetil Replacing azathioprine Rx: Heart, liver & kidney transplants Pharmacokinetics Mycophenolate mofetill & mycophenolic acid are both highly plasma protein bound Coadministration with the following drugs decreases absorption: Magnesium/aluminium antacids Cholestyramine  Mechanism of action: Mycophenolate Mycophenolate mofetil is rapidly Thus T & B cells hydrolysed to cannot synthesize mycophenolic acid nucleic acids (MPA) Causes inhibition Blocking the de of ionosine novo synthesis of monophosphate guanosine dehydrogenase phosphate (GP) (IMPDH) Mycophenolate mofetil Adverse effects Pain Diarrhoea Leukopaenia Opportunistic infections Lymphoma Sepsis MPA is less mutagenic & carcinogenic than azathioprine Antibodies Immunization of rabbits & horses With lymphoid cells Producing polyclonal antibodies Hybridoma technology Fusing mouse Ab-producing cells with Immortal, malignant plasma cells Producing monoclonal antibodies Recombinant DNA technology Humanizing mouse genes Naming conventions: monoclonal antibodies (-mab) Antithymocyte globulins Thymocytes: T-cell precursors Polyclonal antibodies Rx: Hyperacute phase of allograft rejection Antithymocyte globulins bind to T-cells Which are destroyed by: Complement-mediated destruction Antibody-dependent cytotoxicity Apoptosis Opsonization Antibody-bound T-cells are phagocytosed in the liver & spleen Result: lymphopaenia & impaired T-cell responses Antithymocyte globulins Does not affect the humoral part of the immune system So antibodies can still be formed against foreign antigens Adverse effects Chills & fever Leukopaenia & thrombocytopaenia Anaphylaxis Skin rashes infections Muromonab-CD3 (OKT3) Therapeutic applications: Acute rejection of renal allografts Steroid-resistant acute allograft rejection In cardiac & hepatic transplant patients Deplete T cells from donor bone marrow prior to transplantation Mechanism of action Muromonab-CD3 binds to CD3 protein (monoclonal) This blocks the access of the antigen to the recognition site Which disrupts T-cell function Which depletes T-cells Which decreases the immune response Muromonab-CD3 Pharmacokinetics IV Extensive metabolism First administration: cytokine storm Premedication: methylprednisolone, diphenhydramine & acetaminophen Adverse effects: Muromonab-CD3 Anaphylactic reactions Cytokine storm symptoms Ranges from a mild flu-like illness to a life-threatening, shock-like reaction High fever CNS effects: seizures, encephalopathy, cerebral oedema, aseptic meningitis, headache Contraindications Pregnant & breastfeeding women Heart failure patients Seizure patients IL-2 receptor antagonists Humanised antibody = Daclizumab 90% human protein Chimerized antibody = mBasiliximab 25% mouse & 75% human protein Therapeutic applications Prophylaxis of acute rejection in renal transplantation Used in conjunction with CsA & corticosteroids IL-2 receptor antagonists Mechanism of action: Bind to the IL-2 receptor Thus interfering with the proliferation of T-cells Also prevents antigens from activating the T-cell immune response Basiliximab is 10x more potent than daclizumab Pharmacokinetics IV Daclizumab > t1/2 Adverse effects Both are well tolerated GIT effects Glucocorticoids Adrenocorticoids Transplantation Prednisone & methylprednisolone Used in combination with other immunosuppressants Autoimmune conditions E.g. RA, SLE Prednisone & prednisolone Mechanism of action: Reduce T-cell populations Mechanism of action Glucocorticosteroids bind to intracellular cytoplasmic receptors in target tissues Dimerise and then the receptor-hormone complex translocates to the nucleus Where it attaches to gene promotor elements Acts as a transcription factor to turn genes off (in all macrophage-like/immune cells) Produces effects  AEs: Long term corticosteroid therapy  Anti- Lesson 3 Hypertensives Introduction Systolic: >140mmHg Diastolic: > 90mmHg Can lead to: Myocardial infarctions Congestive heart failure Renal damage Cerebrovascular incidents Frequency of concomitant diseases in hypertensive patients Introduction Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure Classifies hypertension Risk factors Stressful lifestyle High dietary intake of sodium Obesity Smoking Introduction Aetiology of hypertension Essential hypertension More common form of hypertension Black people more prone to hypertension than whites Males are more prone than females Secondary hypertension Caused due to other diseases Antihypertensive drugs Is it B1 B2 receptors that play a role is vasoconstriction of arteriole smooth muscle? or Angiotensin II Diuretics β-blocker ACE Inhibitors receptor antagonist Amiloride Atenolol Benazepril Azilsartan Bumetanide Carvedilol Captopril medoxomil Chlorthalidone Labetalol Enalapril Candesartan Eplerenone Metoprolol Fosinopril Eprosartan Furosemide Nadolol Lisinopril Irbesartan Hydrochlorothi Nebivolol Moexipril Losartan azide Propranolol Quinapril Olmesartan Metolazone Timolol Ramipril Telmisartan Spironolactone Valsartan Triamterene Antihypertensive drugs Sodium nitroprusside- a derivative of nitric oxide, which acts as a? Calcium channel α-blockers Renin inhibitors Other blockers Amlodipine Doxazosin Aliskiren Clonidine Diltiazem Prazosin Diazoxide Felodipine Terazosin Hydralazine Isradipine α-methyldopa Nicardipine Minoxidil Nifedipine Sodium Nisoldipine nitroprusside Verapamil You will be asked the following: What are the target(s) for the following three drugs: 1)Ramipril 2)Losartan 3)Hydrochlorothiazide Major factors affecting blood pressure What effect does binding of epinephrine to A1 receptors in arteriolar smooth muscle have? Mechanisms for controlling blood pressure Short term control Sympathetic nervous system Baroreceptors in the aortic arch & carotid sinuses Long term control Renin-angiotensin-aldosterone system Baroreceptors in the kidney Treatment strategies Reduce cardiovascular and renal morbidity & mortality First line therapy: Thiazide diuretics Inadequately controlled hypertension Add a β-blocker If still uncontrolled Add a vasodilator Individualised treatment Different patients respond better to certain drugs Black patients: Respond well to diuretics & CCB’s Respond less effectively to β-blockers & ACE-I’s Elderly patients: Favoured: CCB’s, ACE-I’s, diuretics Less effective: β-blockers & α-antagonists Patient‘s comorbidities may be aggravated by antihypertensive drugs Patient compliance Lack of compliance: main reason for failure of therapy Asymptomatic patients Diagnosed before complications Adverse effects E.g. β-blockers decrease libido & can induce impotence Poor compliance Not “worth it” to experience AE’s NOW to prevent diseases in the FUTURE Careful consideration of drug class for individual patients thus necessary! Thiazide Diuretics Thiazide diuretics First line treatment Useful in combination therapy Actions: Short-term: increases water & sodium excretion Which decrease plasma volume Which decreases CO & renal blood flow Long-term: plasma volume approaches normal, But peripheral vascular resistance is decreased Spironolactone can be administered simultaneously Potassium-sparing diuretic NB: Prevents heart remodelling Actions of thiazide diuretics Thiazide diuretics Pharmacokinetics Oral administration Ineffective in patients with poor kidney function Creatinine clearance = 150mmHg & SBP > 210mmHg OR DBP >130mmHg in an individual with pre-existing complications: Encephalopathy Cerebral haemorrhage Sodium nitroprusside Aortic stenosis Labetalol Fenoldopam Nicardipine Hypertensive emergency treatments: Sodium nitroprusside IV administration Rapidly metabolised Requires constant infusion Prompt vasodilation Arteries: decreases BP Veins: decreases preload Adverse effects: Cyanide toxicity Due to production of cyanide ions Administration of sodium thiosulphate Produces thiocyanate Hypertensive emergency treatments Labetalol IV α and β blocker Does not cause reflex tachycardia Long t1/2 Fenoldopam IV Dopamine 1 receptor agonist Increases renal perfusion: renal insufficiency Nicardipine IV Calcium channel blocker Comparison