Drugs for Special Patient Groups: Elderly PDF

Drugs for Special Patient Groups III – Elderly Pharmacology II Self-Directed Learning Introduction Providing safe, effective drug therapy is one of the greatest challenges in geriatrics :- Use more drugs than any other age group and have many chronic disorders that affect drug r...

Drugs for Special Patient Groups III – Elderly Pharmacology II Self-Directed Learning Introduction Providing safe, effective drug therapy is one of the greatest challenges in geriatrics :- Use more drugs than any other age group and have many chronic disorders that affect drug response Acute or chronic disorders can further deplete the already diminished physiologic reserves of the elderly, increasing their risk of adverse drug effects Altered pharmacodynamics and pharmacokinetics and thus affects the choice, dose, and frequency of use of many drugs May be unable to obtain or afford drugs or adhere to complex drug regimens Disease symptoms tend to appear atypical in elderly. Physiological changes with aging Organ System Manifestation Body composition ↓ Total body water ↓ Lean body mass, ↑ Body fat Cardiovascular ↓ Cardiovascular response to stress ↑ orthostatic hypotension ↓ Cardiac output ↑ Systemic vascular resistance with loss of arterial elasticity ↓ Resting and maximal heart rate Central nervous ↓ Number of receptors of all types and ↑ sensitivity of system remaining receptors Gastrointestinal ↓ Motility of the large intestine Hepatic ↓ Hepatic size ↓ Hepatic blood flow Renal ↓ GFR ↓ Renal blood flow Altered Pharmacokinetics with Aging ↓ Active transport and ↓ bioavailability for some drugs Absorption ↓ First-pass metabolism, ↑ bioavailability for some drugs, and ↓ bioavailability for some prodrugs Body's fat compartment increases, and the water compartment decreases with ageing :- ↓Volume of distribution and ↑ plasma concentration of Distribution water-soluble drugs ↑ Volume of distribution and ↑ terminal disposition half- life (t1/2) for lipid-soluble drugs Cytochrome P-450 enzyme system decreases with ageing Hepatic ↓ Clearance and ↑ t1/2 for some drugs metabolism Phase 1 affected more than phase 2 Renal ↓ Clearance and ↑ t1/2 for renally eliminated drugs and excretion active metabolites Altered Pharmacokinetics with Aging Creatinine clearance decreases an average of 8 mL/min/1.73 m2/decade at 30yo Serum creatinine levels often remain within normal limits despite a decrease in glomerular filtration rate (GFR) Due to reduced muscle mass and thus produce less creatinine Decreases in tubular function parallel those in glomerular function Altered Pharmacodynamics with Aging There is a general trend of altered drug response or increased “sensitivity” in older adults. Older adults are particularly sensitive to the CNS effects of drugs. Increased sensitivity to the CNS effects of medications in older adults has been demonstrated for benzodiazepines, anesthetic agents, opioid analgesics, antipsychotics, lithium, and anticholinergic medications. Patientd with dementia, are particularly prone to CNS adverse effects of such drugs Drug Category of Concern NSAIDs NSAIDs may cause peptic ulceration and upper GI bleeding It may increase risk of cardiovascular events and can cause fluid retention Use cautiously in elderly. Drug Category of Concern Anticoagulants Aging does not alter the pharmacokinetics of warfarin May increase sensitivity to its anticoagulant effect Careful dosing and scrupulous monitoring required to overcome the increased risk of bleeding in the elderly Drug Category of Concern Antihypertensives Elderlys have lesser cardiovascular response to stress and are prone to orthostatic hypotension. Lower starting doses of antihypertensives may be necessary to reduce risk of adverse effects Drug Category of Concern Antiparkinsonian Drugs Levodopa clearance is reduced in elderly patients Also more susceptible to orthostatic hypotension and confusion Therefore a lower starting dose should be given and careful monitoring of adverse effects is required. Patients who become confused while taking levodopa may also not tolerate newer dopamine agonists (eg, bromocriptine, pergolide, pramipexole, ropinirole) More to be discussed during lecture on Parkinson’s disease  Drugs Category of Concern Digoxin Digoxin clearance decreases about 50% in elderly patients with normal serum creatinine levels Maintenance doses should be started low (0.125 mg/day) Adjusted according to response and serum digoxin levels Drug Category of Concern Antihyperglyemics Doses of antihyperglycemics should be titrated carefully in patients with diabetes mellitus Risk of hypoglycemia due to sulphonylureas may increase with aging. Choose short-acting ones.  Elderlies are prone to the following DRPs:- Polypharmacy Inappropriate prescribing Underuse Drug-Related Problems (DRPs) in Elderly Polypharmacy Polypharmacy can be defined as either the concomitant use of multiple drugs or the administration of more medications than are indicated clinically Inappropriate prescribing Inappropriate prescribing can be defined as prescribing medications outside the bounds of accepted medical standards. Prescribing cascade begins when an adverse drug effect is misinterpreted as a new disorder Another drug is prescribed, and patients may develop additional adverse effects related to the second, unnecessary drug Additional adverse effects may also be misinterpreted as a new disorder and treated unnecessarily A new symptom or sign is due to drug therapy should always be considered a possibility Underuse Underuse - omission of drug therapy that is indicated for treatment or prevention of a disease Tools to prevent DRPS in Elderlys Several tools have been developed to assess Elderlies for potential DRPs :- Beers Criteria STOPP/START Criteria Beers Criteria Aka Beers List (U.S) Provide a list of medications that are generally considered inappropriate when given to elderly people Medications listed tend to cause side effects in the elderly due to the physiologic changes of aging Beers Criteria (Sample) STOPP/START Criteria UK STOPP: Provide a list of drug prescriptions that are generally considered inappropriate when given to elderly people START: Provide a list of medications that should be prescribed to elderly with appropriate indications STOPP Criteria (Sample) START Criteria (Sample)  Definitions Age ranges Born at less than 37 weeks Preterm newborn infants gestation Term newborn infants 0-27 days Infants and toddlers 28 days to 23 months Children 2-11 years Adolescents 12-16 or 18 yrs Pharmacology II Self-Directed Learning Part I  Introduction  FDA Categories of Drug Safety During Pregnancy  Effects of drugs on fetus  Drug of interest:  Vaccines  Vitamin A  Cigarettes  Alcohol  Caffeine  Most commonly used drugs in pregnancy include antiemetics, antacids, antihistamines, analgesics, antimicrobials.  Some of these used can have adverse effects on the fetal development  Classic example was Thalidomide, responsible for over 10,000 human birth deformities  Thalidomide was found to act as an effective tranquiliser ,painkiller and was proclaimed as a "wonder drug" for insomnia, coughs, colds and headaches.  It was an effective antiemetic which had an inhibitory effect on morning sickness  Thousands of pregnant women took the drug to relieve their symptoms  Known as "the biggest medical tragedy of modern times"  Few well-controlled studies of therapeutic drugs have been conducted in pregnant women  Most information about drug safety during pregnancy is derived from animal studies and uncontrolled studies in humans (eg. post-marketing reports)  Drug exposure (excluding alcohol) accounts for only 2 to 3% of all fetal congenital malformations  Most malformations result from genetic, environmental, or unknown causes Category Description A Controlled human studies show no fetal risks; these drugs are the safest B Animal studies show no risk to the fetus and no controlled human studies have been conducted, or animal studies show a risk to the fetus but well- controlled human studies do not C No adequate animal or human studies have been conducted, or adverse fetal effects have been shown in animals but no human data are available D Evidence of human fetal risk exists, but benefits may outweigh risks in certain situations (eg, life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineffective) X Proven fetal risks outweigh any possible benefit  Not all maternal drugs cross the placenta to the fetus  Those that do can have a direct toxic or teratogenic effect (causing development malformation of the embryo/fetus) Known or Suspected Teratogens ACE inhibitors Carbamazepine Etretinate Phenytoin Alcohol Coumarins Isotretinoin Radioactive iodine Aminopterin Danazol Lithium Tetracycline Androgens Diethylstilbestrol Methimazole Valproate  Those that do not cross the placenta may still harm the fetus by:  Constricting placental vessels and thus impairing gas and nutrient exchange or  Producing severe uterine hypertonia resulting in anoxic injury or  Altering maternal physiology (eg. causing hypotension)  Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers  Factors that determine if or the extent of a drug crosses the placenta:  Molecular weight  Lipid solubility  Affinity to another substance e.g. Carrier proteins  Area available for exchange across the villi  Amount of drug metabolized by the placenta  Drugs with a mol wt < 500 daltons readily cross the placenta and enter fetal circulation  Substances with a high mol wt (eg, protein-bound drugs) usually do not cross the placenta  Except IgG used to treat disorders such as fetal alloimmune thrombocytopenia  Effect on the fetus is determined largely by:  Fetal age at exposure  Drug potency  Drug dosage.  Drugs given before the 20th day after fertilization may have an all-or-nothing effect  Teratogenesis is not likely during this stage  Teratogenesis - more likely during organogenesis (between 14 and 56 days after fertilization)  Drugs reaching the embryo at this stage may result in abortion, a sublethal gross anatomic defect (true teratogenic effect), or covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life),  Drugs may have no measurable effect  Drugs given after organogenesis (in the 2nd and 3rd trimesters) are unlikely to be teratogenic  May alter growth and function of normally formed fetal organs and tissues.  Immunization is as effective in women who are pregnant as in those who are not  Influenza vaccine is recommended for all pregnant women in the 2nd or 3rd trimester during influenza season  Other vaccine reserved for significant exposure risk situations e.g. cholera, hepatitis A and B, measles, mumps, plague, poliomyelitis, rabies, tetanus-diphtheria, typhoid, and yellow fever  Live-virus vaccines should not be given to women who are or may be pregnant e.g. Rubella and Varicella  May cause subclinical placental and fetal infection  Inadvertent vaccination in early pregnancy does not require termination  Typically present in prenatal vitamins (5000 IU/day), no teratogenic risk  Doses > 10,000 IU/day during early pregnancy may increase risk of congenital malformations  Retinoids such as Retinol, Isotretinoin known to cause birth defects  Carbon monoxide and nicotine in cigarettes cause:  Hypoxia and vasoconstriction  Increasing risk of spontaneous abortion (fetal loss or delivery < 20 wk)  Fetal growth restriction (birth weight averaging 170 g less than that of neonates whose mothers do not smoke)  Premature rupture of the membranes  Preterm birth and stillbirth  Neonates whose mother smoke are more likely to have:  Anencephaly  Congenital heart defects  Orofacial clefts  Sudden infant death syndrome  Deficiencies in physical growth and intelligence, and behavioural problems  Increases risk of spontaneous abortion  probably related to amount of alcohol consumed, but no amount is known to be risk-free  Regular drinking decreases birth weight by about 1 to 1.3 kg  Binge drinking in particular, possibly as little as 45 mL of pure alcohol (equivalent to about 3 drinks) a day, can cause fetal alcohol syndrome  Syndrome occurs in 2.2/1000 live births  Fetal growth restriction  Facial and cardiovascular defects  Neurologic dysfunction  It is a leading cause of mental retardation and can cause neonatal death due to failure to thrive  Whether it increase risk of perinatal complications is unclear  small amounts (eg, 1 cup of coffee/day) appear to pose little or no risk to the fetus  consuming large amounts (> 7 cups of coffee/day) increases risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions Part II  Breastfeeding mothers should avoid taking drugs if possible  If drug is necessary then:  Nursing mother should avoid contraindicated drugs and take the safest known alternative immediately after nursing or before the infant's longest sleep period  less helpful with neonates who nurse frequently and exclusively.  Knowledge of the adverse effects of most drugs comes from case reports and small studies  Safety of some has been determined by extensive research, but others are considered safe only on the basis of the absence of case reports of adverse effects  Drugs with a long history of use are generally safer than newer drugs for which few data exist Anti-thrombotic Agents I Candice Chang [email protected] Ext 1594  Understand the mechanisms of hemostasis (primary and secondary)  Explain the mechanism of actions and adverse effects of the different antiplatelet agents.  Thrombosis vs Embolism  Hemostasis & Coagulation  Fibrinolysis  Anti-thrombotics  Anti-platelets  Anti-coagulants  Fibrinolytic WHAT’S THE DIFFERENCE??? Formation of a thrombus (blood clot) inside a blood vessel, obstructing blood flow  Can occur in any blood vessel  Venous thrombosis: o venous stasis in lower extremities o most common = DVT  Arterial thrombosis: o Atherosclerosis, arrhythmias (eg. AF)  Embolus = travelling blood clot  Embolism = embolus lodged within a blood vessel & block blood flow  Example: o Thrombus detach from vessel wall carried in bloodstream as embolus a) obstruct pulmonary vessel  pulmonary embolism b) obstruct coronary artery 3 broad categories of factors that are thought to contribute to thrombosis Eg: immobility, s atrial fibrillation eg: trauma, major surgery, hypertension eg: cancer, obesity, smoking Let’s recap… 1. Vascular spasm-damaged blood vessels constrict. 2. Platelet plug formation (Primary Hemostasis) 3. Coagulation/Clot formation (Secondary Hemostasis) 3 stages: i. Prothrombin activator (Intrinsic/Extrinsic) ii. Prothrombin  Thrombin iii. Fibrinogen  Fibrin 4. Clot retraction  Cutting a vessel will cause vascular constriction to slow or stop bleeding, lasts for 30 mins.  Endothelial cells release factors such as ADP, tissue factor and prostacyclin, endothelins  Limits blood loss Vessel Injury Localised vasoconstriction Primary Hemostasis Platelet adhesion & Secondary Hemostasis activation (Coagulation Cascade)  Extrinsic Pathway + Intrinsic Pathway Platelet aggregation   Common Pathway Formation of primary  hemostatic plug Stable, Permanent Plug  Platelets circulate through vessels with intact endothelium (inactive)  Upon contact with damaged tissue inside a blood vessel wall and to Von Willebrand factor (vWF), platelet aggregation occurs :-  Platelet changes shapes (with projecting fingers)  Release thromboxanes (TX's),prostaglandins (PG's) and serotonin (5- HT) and thrombopoietin and ADP o TX & PG: chemotaxis & activation of more platelets; vascular spasm o 5-HT: vascular spasm o Thrombopoietin: stimulate production of more platelets o ADP: stimulates platelet aggregation Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation. Vessel Injury Localised vasoconstriction Primary Hemostasis Platelet adhesion & Secondary Hemostasis activation (Coagulation Cascade)  Extrinsic Pathway + Intrinsic Pathway Platelet aggregation   Common Pathway Formation of primary  hemostatic plug Stable, Permanent Plug 3 stages of clot formation: initiated by factors within the blood initiated by factors from the blood vessel not the blood itself (Factor IV) (Factor II) (Factor I)  Process where a fibrin clot (the product of coagulation) is broken down  Plasmin, breaks down the fibrin mesh at various places  Leading to the production of circulating fragments that are cleared by other proteinases or by the kidney and liver.  Plasminogen  t-PA (tissue-type plasminogen activator) Activation t-PA  Enzyme synthesised by the endothelium and released into the Plasmin circulation Thrombin Fibrinogen Fibrin Breakdown of Fibrin Vessel Injury Localised vasoconstriction Secondary Hemostasis Primary Hemostasis (Coagulation Cascade) Fibrinolysis Blood Clot Degradation Products  Three main types Acting at the  Antiplatelet agents different stages of  Anticoagulant agents the thrombotic  Fibrinolytic agents process  Vessel Injury Localised vasoconstriction Secondary Hemostasis Primary Hemostasis (Coagulation Cascade) Anticoagulants Antiplatelets Blood Clot Degradation Products Fibrinolysis Fibrinolytics  Prevents platelet aggregation Recall: Platelets initiate the formation of blood clots by clumping together (platelet aggregation)  Prophylaxis only No effect on existing clots Used in patients at risk of clot formation  Uses Prophylaxis against stroke, MI Secondary prevention of occlusive ischemic events (cerebral & CV) o Previous stroke, MI o Recurrent/Previous TIA o Unstable angina  Classified based on their  Examples: MOA  Aspirin (Cardiprin®) 1. Cyclo-oxygenase  Dypiridamole (Persantin®) inhibitors  Ticlopidine (Ticlid®) 2. Phosphodiesterase  Clopidogrel (Plavix®) (PDE) inhibitors  Abciximab (Reopro®) 3. P2y12 inhibitors  Tirofiban (Aggrastat®)  Eptifibatide (Integrilin 4. GPIIb-IIIa Antagonists  2 Dipyridamole 1 3 4  Aspirin (Acetylsalicylic acid)  Dose for inhibition of platelet aggregation: 75-325mg/day  Compared to Dose for analgesic, anti-inflammatory, antipyretic properties: 300-900 4-6x daily (Max 4g/day)  Irreversibly inhibits cyclooxygenase   formation of thromboxane A2 in the platelets  Inhibits platelet aggregation and coagulation  Adverse Effects:  Bronchospasm  GI haemorrhage  Other haemorrhage (e.g. subconjunctival) Aspirin  Example: Dipyridamole  Mechanism of Action  Inhibit phosphodiesterase in platelet Inhibit the breakdown of cAMP Increase in concentration of cAMP Inhibits platelet activation and aggregation  Has weak anti-platelet properties by itself  Seldom used alone  Usually administered in combination with aspirin or warfarin  Dosing:  Dipyridamole: 1 hr BEFORE FOOD  Adverse reactions:  Bleeding: GI, nose bleeds, bruising/hematoma, hematuria, ocular hemorrhage, intracranial bleeds  Throbbing headache  Hypotension (due to vasodilatory actions)  Precautions:  As with anticoagulants   Ticlopidine  Clopidogrel Thienopyridines  Prasugrel  Mechanism of action  irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation P2y12 inhibitors  Given twice daily  Adverse reactions:  Haemorrhage  Leucopenia, Thrombocytopenia GI discomfort (TAKE AFTER FOOD!)  Precautions:  Stop 7-10 days before surgery!  Neutropenia  Thrombocytopenia  Abnormal hemostasis  Concurrent anticoagulants & antiplatelets  Contraindications:  Active bleeding  Leucopenia, Thrombocytopenia  Hemorrhagic stroke  Look out for:  Sore throat , fever, mouth ulcers  Prolonged/unusual bleeding  Hematomas, bruising, black tarry stools  Jaundice, dark urine Twice daily + poor side effect profile = no longer popular !  Given once daily  Prodrug  Requires CYP2C19 activation (some individuals may be poor metabolizer of clopidogrel  increase CVS risk!)  Precautions:  As with ticlopidine  Adverse effects:  Bleeding: GI, nose bleeds, bruising/hematoma, hematuria, ocular hemorrhage, intracranial bleeds  Rashes  Neutropenia (rare, unlike ticlopidine)  Similar to Clopidogrel  Given once daily  Also a prodrug that needs to metabolized to active form but not affected by genotype  Faster onset than Clopidogrel  Also a P2Y12 inhibitor but is reversible o Faster recovery of platelet function  Given twice daily  Faster onset than Clopdiogrel  Not a prodrug  supposedly works faster !  Examples:  Abciximab (Reopro®- monoclonal antibody)  Eptifibatide (Integrilin®)  Tirofiban (Aggrastat®)  Mechanism of Action  Binds to Glycoprotein IIb/IIIa Receptor  Prevents fibrinogen from binding to the receptor  Prevents platelet aggregation gp2A/3B inhibitors  Administration:  I/V – bolus or infusion  Side Effects  Bleeding  Thrombocytopenia  Contraindications:  Active internal bleeding  History of intracranial bleeding  Aneurysm  Pre-existing thrombocytopenia  Precautions:  Recent bleeding  Aggrastat: < 1yr  Integrilin: < 30 days  History of GI or GU bleeding  History of thrombocytopenia  Recent stroke, major surgical procedure or trauma within 1mth  Severe uncontrolled hypertension, retinopathy  D/C if thromobcytopenia develops!  Thrombosis is the formation of blood clot in blood vessel.  Embolism occurs when thrombus detach from vessel wall and get carried in bloodstream. Embolus can obstruct blood flow when it lodges in blood vessel.  3 catergories of factors that contribute to thrombosis are flow/stasis, endothelial damage and hypercoagulable state.  Haemostasis occurs in the following manner: vascular spasm, platelet plug formation, coagulation and finally fibrinolysis.  There are 4 different classes of antiplatelets. Candice Chang [email protected] Ext 1594  Understand the mechanisms of hemostasis (primary and secondary)  Explain the mechanism of actions and adverse effects of the anticoagulants and fibrinolytic agents. Vessel Injury Localised vasoconstriction Primary Hemostasis Platelet adhesion & Secondary Hemostasis activation (Coagulation Cascade)  Extrinsic Pathway + Intrinsic Pathway Platelet aggregation   Common Pathway Formation of primary  hemostatic plug Stable, Permanent Plug  Vessel Injury Localised vasoconstriction Secondary Hemostasis Primary Hemostasis (Coagulation Cascade) Anticoagulants Antiplatelets Blood Clot Degradation Products Fibrinolysis Fibrinolytics  Interfere with clotting mechanisms  Prophylaxis only (formation & extension of thrombus)  Do not have effect on existing thrombi  Used in patients at high risk of clot formation  Can be classified into 2 catergories :-  Oral – eg: warfarin, NOACs  IV – eg: Heparin, LMWH  Most commonly prescribed oral anticoagulant  Interferes with synthesis of vit K-dependent clotting factors  For patients who require long-term anticoagulant Tx  Drug names:  Coumarin (1, 2, 5mg)  Marevan (1, 3, 5mg)  Antagonist of vitamin K  Vitamin K is needed for the carboxylation of the following to active form  coagulation factors 2,7,9,10  protein C, protein S 3 stages of clot formation: initiated by factors within the blood initiated by factors from the blood vessel not the blood itself (Factor IV) (Factor II) (Factor I) 9 1. Prophylaxis & treatment of thromboembolic disorder like :-  Deep Vein Thrombosis (DVT)  Pulmonary Embolism (PE) 2. Prevent embolic complications that can occur in patients with:  Postoperative patents eg: Hip replacement, Knee replacement surgery  Atrial Fibrillation  Heart valve replacement  Bleeding : bladder, bowel, stomach, uterus, mucous membranes  Alopecia  Urticaria  Abdominal cramping  Diarrhea  Rash  Hepatitis  Jaundice  Prothrombin time (PT)  test that measures the time it takes for blood (plasma) to clot  measures the time it takes prothrombin to turn into thrombin  How is done?  Blood is collected with citrate (which stops coagulation)  Calcium (to reverse the effect of the citrate)  Tissue factors are mixed with plasma sample  Time is measured until a clot forms  International Normalised Ratio (INR)  INR was devised to standardise results of prothrombin time tests  even when they come from different labs and different test methods.  To counteract batch to batch variations of tissue factors  Normal range for the INR is 0.8-1.2 “ the higher the INR, the ‘thinner’ the blood”  Narrow therapeutic range!  Blood too thick – increase risk of thromboembolism  Blood too thin – increase risk of bleed !  INR target for most indications around 2-3.  For high risk conditions like valve replacement, INR target may be higher like 2.5 to 3.5  All patients who are newly started on warfarin should be counselled on the following :-  Purpose of therapy o DVT? AF? PE? Valve?  Expected duration of therapy o 3/12? 6/12? 12/12? Lifelong?  Dosing and administration o once a day at same time everyday  What to do if a dose is missed o If miss for 8 hours, skip dose. Resume usual timing on next day.  Importance of regular INR monitoring o frequent blood-taking? Target INR?  Recognition of signs and symptoms of bleeding  Recognition of signs and symptoms of new thrombus formation o Heart attack? Stroke? DVT?  Potential for drug (including OTC)/food interactions  Significance of informing other healthcare providers o dental treatment? Interaction with meds from GP or retail pharmacy External Internal  Excessive bleeding  Blood in stools (black tarry from cuts/grazes stool)  Excessive menstrual  Blood in urine (tea-coloured) bleeding  Petechiae (small red spot caused by a minor hemorrhage)  Bruising without trauma  Bloody vomitus Stop warfarin and see a doctor immediately! May require reversal therapy like vitamin K or plasma transfusion in severe cases.  Dietary consistency is the key to maintaining a sustained, stable response during warfarin therapy.  Food rich in vitamin K decreases efficacy of warfarin  Patients should be aware of vitamin K content in common foods  Foods high in vitamin K - a consistent amount of these foods should be maintained  VITAMIN K CONTENT LOW MODERATE HIGH coffee fruit juice green tea Chrysanthe BEVERAGES cola milk herbal tea mum tea CEREALS AND GRAIN bread pasta PRODUCTS cereals rice margarine butter DAIRY AND EGG cheese PRODUCTS egg corn oil olive oil OIL AND DRESSINGS peanut oil mayonnaise (to limit to not more than 3 sesame oil salad dressing tablespoons a day ) sunflower oil soybean oil beef pork Meat chicken seafood carrot pumpkin broccoli asparagus seaweed VEGETABLES cauliflower potato brussel cabbage spinach dark green, leafy vegetables corn snap beans sprouts celery spring are generally rich in vitamin cucumber sweet potato dou miao lentils onion K garlic turnip kailan Lettuce watercress Iceberg lettuce Tomato parsley (butterhead, romaine, cos) mushroom Onion FRUITS Apple pear removal of fruit peels reduce banana plum vitamin K content grapes strawberry avocado mango watermelon orange pear cake jam DESSERTS AND SNACKS chocolate peanut pistachio nut honey yoghurt ice-cream Alcohol  Increase effect of warfarin  Best to avoid. If unavoidable, maximum 1 drink per day.  Herbal Products that can affect bleeding time  Coenzyme Q10 (similar chemical structure to Vit K)  Danshen  Dong quai  Garlic  Ginkgo biloba  Ginseng; or  St. John's wort.  Feverfew  Herbal teas: green tea, buckeye, horsechestnut, tonka, bean, meliot, and woodruff.  Herbal medications should either be avoided while on warfarin therapy. If unable to avoid, always consult a doctor/pharmacist before starting.  Warfarin has many drug-drug interactions !  NSAIDs  Antibiotics e.g. Ciprofloxacin, Clarithromycin Erythromycin, Metronidazole, Trimethoprim- sulfamethoxazole  Cimetidine  Antidepressants  Antiepileptics  Injection ONLY: inactivated by gastric acid  Never I/M (can cause hematoma) – given I/V or S/C  Available as:  Unfractionated Heparin sodium (UFH)  S/C or I/V  Fractionated heparins -more commonly known as Low- molecular weight heparin (LMWH)  S/C  Eg of LMWH : Enoxaparin, Fondaparinux, Dalteparin  UFH  Binds to antithrombin III (AT3)   activity of AT3 at least 1000 fold  AT3 ability to inhibits factor IIa (thrombin), Xa more  Note that AT3 also inhibits VIIa, IXa, Xia, XIIa  LMWH  Binds to AT3 to increase AT3 ability to inactivate Factor Xa 3 stages of clot formation: initiated by factors within the blood initiated by factors from the blood vessel not the blood itself (Factor IV) (Factor II) 2 4 (Factor I) 1. Prophylaxis & treatment of thromboembolic disorder like :-  Deep Vein Thrombosis (DVT)  Pulmonary Embolism (PE) 2. Prevent embolic complications that can occur in patients with:  Postoperative patents eg: Hip replacement, Knee replacement surgery  Atrial Fibrillation 3. Anticoagulation for angioplasty 4. Anticoagulant for dialysis procedures  UFH  Monitoring is done frequently to prevent bleeding due to over- coagulation (prolonged PT time)  Monitored using aPTT assay  Dose adjusted accordingly using strict monitoring protocol  LMWH  Anticoagulant effect is not accurately reflected by aPTT assay  Requires specialised assay for antifactor Xa activity  Not necessary to monitor in most clinical situations due to its greater therapeutic index  aPTT (Activated Partial Thromboplastin Time)  Measures intrinsic and common pathways of coagulation  How is it done?  Blood is collected with citrate (which stops coagulation)  To activate the intrinsic pathway, phospholipids, silica (an activator) and calcium (to reverse the effect of the citrate) are mixed with plasma sample.  Time is measured until a clot forms.  Results  Normal Value – 25 to 39 sec (vary from lab to lab)  Heparin dosage - usually adjusted so that the aPTT is about 1.5 to 2.5 x the normal value.  Bleeding  Heparin-induced Thromobocytopenia (HIT)  More common in UFH than LMWH  Local irritation (S/C)  Increased liver enzymes  Alopecia  Hypersensitivity rxn: fever, chills, urticaria  Patients with severe thrombocytopenia  Active Bleeding  Recent surgery (except LMWH used after surgery to prevent thromboembolic complications)  Pregnancy  Elderly (bleeding more common > 60yo, esp women)  Severe renal disease, diabetes, diabetic retinopathy, ulcer disease  Uncontrolled hypertension  All patients with potential site for bleeding  Concomitant use of: Aspirin, NSAIDs, thrombolytics Renal dose adjustment not needed for UFH UFH can be reversed using protamine.  New class of anticoagulants that can be used orally  Xa inhibitors : Rivaroxaban, Apixaban  IIa inhibitors (a.k.a direct thrombin inhibitor): Dabigatran  Similar to Warfarin 1. Prophylaxis & treatment of thromboembolic disorder like :-  Deep Vein Thrombosis (DVT)  Pulmonary Embolism (PE) 2. Prevent embolic complications that can occur in patients with:  Postoperative patents eg: Hip replacement, Knee replacement surgery  Atrial Fibrillation  NOACs Warfarin  More effective than Less effective than Noacs Warfarin Requires frequent INR  Do not require frequent taking INR taking More food-drug, drug-  Less food-drug, drug-drug interactions drug Interaction No antidote to reverse  Over-coagulation can be over-coagulation (except reversed using vitamin K dabigatran)  Cheap! Expensive  NEW!! Reversal agent for Dabigatran: IDARUCIZUMAB (Praxbind®)  Humanized monoclonal antibody fragment  Potently and rapidly binds to dabigatran, with a high affinity (350-fold more potent than the binding affinity of dabigatran for thrombin)  Reversal effect of Praxbind is immediate.  A.k.a thrombolytic agents. Breaks down pre-existing blood clots & hence re-open occluded blood vessels  Anticoagulants and antiplatelets are not effective against pre-existing clots. Effective only for prevention of thrombus  Usually given bolus followed by infusion  Examples:  Urokinase (Abbokinase®)  Alteplase(Actilyse®)  Streptokinase (Streptase®)  Tenectaplase (Metalyse®)  Plasminogen  Breaks down fibrin hence thrombus Activation t-PA  Used to treat:  Acute MI, DVT, PE, ischemic stroke Plasmin  Each fibrinolytic differ slightly in their Thrombin selectivity for fibrin Fibrinogen Fibrin clots Breakdown of Fibrin  Hemorrhage  GI tract, genitourinary tract, brain, respiratory tract, venipuncture sites, recent surgical wounds  Increase risk with high blood pressure or concurrent use of blood- thinning agents  monitor bp ! Withhold any antiplatelet or anticoagulant !  Nausea and vomiting  Hypotension  Allergic reactions (including rash, flushing) and anaphylaxis has been reported with streptokinase  Contraindications:  Recent stroke  Aneurysm  Recent intracranial surgery  Active bleeding  Hypersensitivity  known bleeding diathesis (conditions that increase bleeding risk)  Precautions:  Recent major surgery (< 10days; eg. CABG)  Birth (vaginal or C-section)  GI bleed or trauma within past 10 days  Hypertension, diabetes, retinopathy  Concurrent anticoagulants/antiplatelets tx  Warfarin is a vitamin K antagonist that inhibits the activation of coagulation factor 2,7,9,10.  Warfarin has many interactions with food and drug.  Patients should be educated on proper use of warfarin, especially on the side effects. They should also be reminded to go for regular INR check.  UFH works by increasing the ability of AT3 to inhibit factor 2 and 10 (for LMWH, factor 10 only)  There are some differences between UFH and LMWH.  Fibrinolytics are the only agents that break down pre- existing blood clots. Cancer Chemotherapy Candice Chang [email protected] Ext 1594 Cancer Chemotherapy  Overview  Alkylating agents  Antitumor Antibiotics  Antracyclines  Others  Anti‐metabolites  Antineoplastic enzyme  Hydroxyurea Alkylating Agents Cancer Chemotherapy  Alkylating Agents  6 classes of alkylators  They share a common molecular mechanism of action, but differ greatly in their pharmacokinetics, lipid solubility and chemical reactivity  Used to treat a wide spectrum of malignancies including solid tumours and haematological malignancies  Alkylation: Process of substitution of an alkyl group for a hydrogen atom in an organic compound  Alkylating Agents MOA: Alkylates DNA at any phase of cell cycle resulting in:‐  Inhibition of DNA replication and transcription  Mispairing of DNA  Strand breakage  Cell death !  Greatest cytotoxic effect is on rapidly dividing cells (less time to repair damage before entering vulnerable DNA synthesis phase)  Alkylating Agents 6 classes  Nitrogen mustards [cyclophosphamide, ifosphamide, melphalan, chlorambucil]  Nitrosureas [carmustine]  Alkyl sulfonates [busulphan]  Ethylenimines [thiotepa]  Triazenes [dacarbazine, temozolamide]  Platinum analogues [cisplatin, carboplatin, oxaliplatin] General Toxicities of Alkylating Agents  Myelosuppression (dose‐limiting)  Mucosal toxicity  Nausea & vomiting  Alopecia  Infertility  Secondary leukaemia  Cyclophosphamide Most widely used alkylating agent Prodrug Can be used for chemotherapy for lymphomas & many solid tumours (breast, ovarian & lung) and treatment of auto‐immune such as rheumatoid arthritis Specific Toxicities Haemorrhagic cystitis Due to acrolein, a byproduct of metabolism, especially at high dose. Vigorous hydration & MESNA can be used to prevent damage to bladder Syndrome of inappropriate antidiuretic hormone secretion (SIADH)  Ifosphamide  Structural analogue of cyclophosphamide  Produces more acrolein than cyclophosphamide) Specific Toxicities  Haemorrhagic cystitis  SIADH  CNS toxicity (change in mental status, lethargy & coma)  MESNA  2‐mercaptoethane sulfonate Na  Given to patients receiving ifosphamide or high dose cyclophosphamide to prevent haemorrhagic cystitis  Dose is usually during, as well as 4 & 8 hours after ifosphamide infusion  Chlorambucil  Uses:‐  Chronic lymphocytic leukaemia  Oral  Myelosuppression is most common toxicity Specific Toxicities  Pulmonary Fibrosis  Carmustine  lipid soluble – penetrate in CNS  usually used for malignancy of the brain  Toxcities:  Myelosuppression (leukopenia) major dose limiting toxicity  Nausea and vomiting  Platinum Analogues  Similar MOA as alkylating agents even though they do NOT alkylate DNA but instead, they covalently bind to DNA  Cisplatin  Uses: Head and neck cancer, stomach cancer, cervical cancer and lymphoma. Specific Toxicities: Nephrotoxicity is the major dose‐limiting toxicity (reversible renal tubular damage) o Must be administered with aggressive hydration Severe delayed nausea and vomiting Ototoxicity Peripheral neuropathy  Carboplatin  Analogue of cisplatin  Uses: gynecological cancers Specific toxicities (similar to Cisplatin but occurrence is less) Nephrotoxicity Severe delayed nausea and vomiting Ototoxicity Peripheral neuropathy  Oxaliplatin  Uses: colorectal cancer  Specific toxicities (similar to Cisplatin but occurrence is less except for ***) Nephrotoxicity Severe delayed nausea and vomiting Ototoxicity Peripheral neuropathy***  dose‐limiting factor Antitumor Antibiotics Cancer Chemotherapy  Antitumor Antibiotics  Fermentation products of Streptomyces species 1.Anthracyclines Doxorubicin Daunorubicin Epirubicin Idarubicin 2.Others Bleomycin Dactinomycin Mitomycin  Antitumor Antibiotics General Toxicities Myelosuppression (except bleomycin) Mucositis Nausea and vomiting (except bleomycin) Alopecia  Anthracyclines MOA:  Induce formation of covalent topoisomerase II DNA complexes – this inhibition prevents the relegation of DNA during DNA replication causing DNA strand breaks  Intercalations between base pairs in the DNA are formed causing DNA breaks  Metabolized in the liver to form oxygen free radicals which adds onto cytotoxicity  Topoisomerase Enzymes  Enzymes that facilitate the process of unwinding, separation & rejoining of DNA strands  2 classes: type 1 & 2  Type 1 : produces transient single‐stranded break in DNA. Does not require ATP for energy  Type 2: produces transient double‐stranded breaks in DNA. Requires ATP for energy.  Anthracyclines  Specific Toxicities: red discoloration of urine Cardiac toxicity ‐ Cumulative dose‐dependent Vesicant (require immediate medical attention if extravasation occurs)  Bleomycin MOA  Generates free radicals that cause DNA strand breaks  Inhibits DNA and RNA synthesis  Acts primarily in G2 phase of cell cycle  Uses: Testicular cancer, lymphomas, head & neck tumours  Rarely causes myelosuppression, nausea or vomiting   Bleomycin Specific Toxicities:  cumulative dose‐dependent pulmonary toxicity  Hypersensitivity – premedicate with paracetamol & steroids  Mitomycin MOA: Cross‐link DNA resulting in:‐  Inhibition of DNA synthesis  Strand breakage  Given by intravenous injection. Can also be directly instilled into the bladder (superficial bladder tumours)  Specific Toxicities: pulmonary toxicity Haemolytic uremic syndrome (Haemolytic anaemia, thrombocytopenia, irreversible renal failure) Antimetabolites Cancer Chemotherapy  Antimetabolites MOA  Structurally analogues of naturally occurring substances required for specific biochemical rxns  Interfere with normal synthesis of nucleic acids  substitute themselves for purines or pyrimidines  Inhibit enzymes involved in nucleic acid synthesis  (affect DNA, RNA, protein synthesis)  Cell cycle specific. Exert most of their cytotoxic effects during the S phase  Antimetabolites Folate Antagonist Pyrimidine Antagonists Methotrexate Cytarabine Fludarabine Fluorouracil Purine Antagonists Gemcitabine Cladribine Mercaptopurine Thioguanine  Antimetabolites  General Toxicities  Myelosuppression  Mucositis  Mild nausea and vomiting (except high dose cytarabine and methotrexate  Methotrexate Folate antagonist MOA: inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid  inhibition of DNA synthesis  Cell death  Specific Toxicities: Nephrotoxicity o Can be prevented by alkalinising urine, maintaining good urine output, avoiding medications that can hinder MTX excretion eg: probenecid pulmonary pneumonitis  Methotrexate Routes Oral Intrathecally Intramuscular Intraventricularly Intravenous Leucovorin Rescue Methotrexate cytotoxicity may be reversed Renal function must be assessed before Mtx is used (Creatinine clearance > 60 ml / min)  Fluorouracil A.k.a 5‐FU Pyrimidine Antagonists Inhibits synthesis of thymidine nucleotide inhibition of DNA synthesis  Cell death Active predominantly in S phase of cell cycle  Specific Toxicities: hand‐foot syndrome (Palmar Plantar Erythrodysethesias) diarrhea  Mercaptopurine (6‐MP) A.k.a 6‐Mercaptopurine Structural analogues of guanine which undergo conversion to substrates incorporated into DNA and prevent purine synthesis Active predominantly in S phase of cell cycle  6‐MP is converted to an inactive by an oxidation reaction catalyzed by xanthine oxidase  Allopurinol is a xanthine oxidase inhibitor  When given together, allopurinol can increase blood level of 6‐MP  toxicity Antineoplastic Enzymes Cancer Chemotherapy  Asparaginase Derived from Escherichia coli breakdown asparagine  deplete the supply of the amino acid to cancer cells (lead cancer cells to starvation and die) Targets G1 of cell cycle  Specific Toxicities: Hypersensitivity reaction pancreatitis Hydroxyurea Cancer Chemotherapy  Hydroxyurea MOA Acts by inhibiting ribo‐nucleoside diphosphate reductase (converts ribonucleotides to deoxyribonucleotides)  impairs DNA synthesis (S phase) Capable of rapidly killing circulating leukemic cells Myelosuppression most common toxicity Nausea, vomiting, diarrhoea, skin rashes Summary Some specific toxicities covered today…. Specific Toxicity Agents Haemorrhagic cystitis Cyclophosphamide, Ifosphamide SIADH Cyclophosphamide, Ifosphamide CNS Toxicity Ifosphamide Peripheral Neuropathy Platinum especially oxaliplatin Nephrotoxicity Platinum, MTX Otoxicity Platinum Pulmonary toxicity Chlorambucil, mitomycin, MTX Cardiotoxicity anthracyclines Vesicant anthracyclines Haemolytic uremic syndrome mitomycin Hand‐Foot syndrome 5FU THANK YOU ! Introduction to Chemotherapy Candice Chang [email protected] Ext 1594  Cancer  Uncontrolled growth or division of cells that are genetically dysfunctional  Lack growth control mechanism  Malignant cells  invade surrounding tissues & spread throughout body How Cancer Starts  Etiology  Environmental exposure  Lifestyle  Diet  Drugs  Heredity  Viruses  Benign vs Malignant Tumors Characteristics Benign Tumors Malignant Tumors Yes. May invade surrounding tissues or Potential to metastasize No spread to distant sites via blood, lymph or both Encapsulated Yes No Morphologically typical of tissue Yes No origin Unpredictable & Rate of growth Slow unrestrained Recurrence after Rare Common surgical removal Benign vs Malignant Tumors  Tumour Growth  Usually cannot be detected by physical exam or radiological studies  Tumours of deep internal organs (eg. colon) detected only until much larger  Tumour growth depends on:  rate of cell death  rate of cell division within tumour mass  Tumour Growth Doubling time: time it takes a tumour mass to double in size Doubling time of most solid tumours ~ 2 – 3 mths A tumour mass usually cannot be detected until≥ 1 cm diameter A 1 cm mass weighs ~ 1 g & contains ~1 billion  Tumour Growth  Chemotherapy is most successful in killing tumour cells when:  the total number of tumour cells burden is low  growth fraction percentage of actively dividing cells is high  Occurs in early part of growth curve  How Cancer Spreads  Metastasis  Through the blood  Through the lymphatic system  Complex, multi-step process  May begin very early in the life of a tumour How Cancer Spreads  Cancer Treatment  Treatment Goals Cure Extend Life Relieve Symptoms  Treatment Modalities Surgery Radiation Therapy Chemotherapy Immunotherapy  Surgery  Oldest cancer treatment  Best chance of cure for most patients with solid tumours  Most invasive treatment method  Radiation Therapy  destruction of cancer cells by ionisation radiation  Component of treatment for 1/2to 2/3 of patients with cancer  Can be curative or used as a supplement to surgery  Patient may develop serious radiation toxicities such as pneumonitis  Immunotherapy  Refers to anticancer treatment that attempts to influence patient’s own immune response to tumour  Include treatments to help bone marrow recover from chemotherapy  Eg. interferons, interleukins, tumour vaccines and antibodies & gene therapy  Chemotherapy  Use of conventional cytotoxic drugs includes hormonal & endocrine drug therapy  Can reach widely disseminated cancers  Cytotoxic Drugs Damage cancer cells by: – Interfering with synthesis of precursors of DNA – Chemically interacting with DNA itself and so interfere with cellular division  Aims of Chemotherapy 1. Primary Chemotherapy  chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists.  Goals of therapy are to relieve tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression 2. Neoadjuvant chemotherapy  Treatment with drugs before surgery/ radiation to debulk tumour & reduce extent of tumour  reduce the size of the primary tumor so that surgical resection can be made easier and more effective  Aims of Chemotherapy 3. Adjuvant chemotherapy  Chemotherapy given after surgery  To eradicate any residual micro-metastases and prevent them from growing into clinically evident disease  To reduce the incidence of both local and systemic recurrence and to improve the overall survival of patients  Role of Cell Cycle Kinetics & Anti-cancer Effect S Phase DNA synthesis chromosomes are duplicated G0 (Resting phase) cells not committed to division inactive metabolically G2 (Pre-mitotic phase) Preparation for mitosis protein and RNA synthesis manufacture of G1 (Post mitotic phase) mitotic spindle cells increase in size & apparatus prepares to copy DNA synthesis of many enzymes necessary for DNA synthesis can re-enter S or G0 M (Mitosis cell division) phase prophase, metaphase, anaphase, telophase Role of Cell Cycle Kinetics & Anti-cancer Effect Cell cycle-specific drugs  Drugs exert their action on cells traversing the cell cycle Cell cycle-nonspecific drugs  Exert cytotoxic effect throughout cell cycle Both Cell cycle-specific & Cell cycle-nonspecific drugs preferentially kill proliferating cells regardless of whether they are malignant or normal cells. Role of Cell Cycle Kinetics & Anti-cancer Effect  Chemotherapy Combinations  Chemotherapy often used in combination of cytotoxic drugs rather than a single drug. Advantages 1. Provides maximal cell kill within the range of toxicity tolerable by patients. 2. Broad coverage against multiple cancer cell lines 3. may prevent and/or slow the subsequent development of cellular drug resistance  Protocol Concept Different tumours respond to different “cocktails” of chemotherapy Efficacy established through clinical trials Numerous combination encountered in practice, important to understand the rationale behind the combination Different centres have different protocols for treatment  Evaluation of Treatment Response Complete remission : complete disappearance of all evidence of tumour ( for at least 1 mth) Partial response: > 50% decrease of measurable tumour, no evidence of progression Disease progression: treatment failure Increase of measurable tumour by >25% Appearance of new lesions Stable disease: Measurable tumour that does not meet criteria for the other definitions  Tumour does not increase or decrease in size by >25%  Classification of Cytotoxic Drugs Drug chemistry Mechanism of action Cell cycle effect Classification by Drug Chemistry Drug Chemistry Example Purine analogues 6-Thioguanine Pyrimidine analogues Methotrexate Nitrogen mustard analogues Cyclophosphamide Nitrosureas Carmustine Ethylenimines Thiotepa Methanesulfonate analogues Busulfan Organometallic Cisplatin Triazene analogs Dacarbazine Natural antibiotics Doxorubicin Vinca Alkaloids Vincristine Hormonal agents Tamoxifen  Classification by Mechanism of Actions Mechanism Example Nitrogen mustards, Alkylating Agents damage DNA via alklyation Nitrosoureas interfere with enzymes involved in Anthracyclines Doxorubicin DNA replication interfere with DNA and RNA growth by Antimetabolites substituting for the normal building Methotrexate blocks of RNA and DNA. Topoisomerase interfere with topoisomerases, which Epotoside, Irinotecan inhibitors help separate the strands of DNA Mitotics Inhibitors Stops mitosis Taxanes, Vincristine Antitumor Bioreduction and free radical Doxorubicin, antibiotic formation Mitomycin C Others Inhibition of protein synthesis L-Asparaginase Questions ?