Pharmacotherapy I PDF

 refers to the process by which a drug is metabolized in the liver after being absorbed from the gastrointestinal tract and before it enters systemic circulation. A prodrug is an inactive compound that is converted into an...

 refers to the process by which a drug is metabolized in the liver after being absorbed from the gastrointestinal tract and before it enters systemic circulation. A prodrug is an inactive compound that is converted into an active drug (metabolite) in the body after administration. Prodrugs are designed to improve the pharmacokinetic properties of the active drug.  PHAM 322 (Pharmacotherapy I) Introduction to Pharmacotherapy Prepared By: Ph. Omar Alsamani, PharmB, Rph, CPHQ, CSSYB, BLS, mDip Pharmacoeconomic, TeamSTEPPS Master Trainer  Objectives 1. Define pharmacotherapy, clinical pharmacy and pharmaceutical care and their interrelationship 2. Address the requirements of pharmacotherapy 3. Justify the pharmacist being responsible for the process of pharmacotherapy 4. Outline the principles of pharmacotherapy 5. List some of the roles of the clinical pharmacist 6. Mention elements of each of the principles of pharmacotherapy 7. Describe the key functional and operational elements of Drug Use (Patient care) Process 8. Outline the practical steps of patient care  Clinical Pharmacy/Pharmacotherapy. Clinical Pharmacy: Comprises a set of functions that promote: Safe. Effective. Economic. Clinical pharmacy encourages pharmacists to shift their focus from solely product-oriented to more direct engagement with patients and the problems they encounter with medicines. Development of Clinical Practice in Pharmacy The emergence of clinical pharmacy as a practice has been attributed to poor hospital medicine control systems in the early 1960s. Medication safety may have been the spur, but clinical pharmacy in the 1980s grew because of its ability to promote cost-effective medicines used in hospitals.  In Qatar, they found that Cost savings and cost avoidance through clinical pharmacists interventions resulted in -11,536 QAR (-3169 USD) and 1,607,484 Development of QAR (441,616 USD), respectively. Clinical Practice in Pharmacy Total benefit of 1,595,948 QAR (438,447 USD) per 3 months and 6,383,792 QAR (1,753,789 USD) per a year. Aims of pharmacotherapy / Clinical Pharmacy: Maximize drug efficacy. Minimize drug toxicity (Maximize drug safety). Promote cost-effectiveness. Johnson's Mild Combination How can pharmaceutical care guarantee maximum benefit & minimum toxicity? 1. Ensure safe and appropriate choice of medicines and therapeutic regimens 2. Ensure structured discussion with the patient on specified aspects of the medicines (i.e. Counselling) & patient compliance /adherence. 3. Ensure systematic collaboration with the prescriber and other healthcare team members in addressing patient needs.  Principles of Pharmacotherapy 1. Pharmaceutical/Patient Care Process (Medicines Management process). 2. Pharmaceutical Considerations. 3. Patient Factors.  1. Pharmaceutical Care. Pharmaceutical care: It’s a cooperative, patient-centered system for achieving specific and positive patient outcomes. Patient-centered care: focuses on the patient and the individual's particular health care needs. Its goal is to empower patients to actively participate in their care. The practice of clinical pharmacy is an essential component in the delivery of pharmaceutical care.  1. Pharmaceutical Care. The delivery of pharmaceutical care is dependent on the practice of clinical pharmacy but the key feature is taking the responsibility for a patient’s drug- related needs Why the pharmacists? Drug experts (Knowledge and skills of the profession). Ethics & professionalism of the pharmacists: e.g. Pharmacists are accountable for the services they provide, service-oriented, and committed to self-improvement.  1. Benefits of Pharmaceutical Care In the USA, pharmacists’ participation in physician ward A study covering 1029 US rounds has been shown to hospitals indicates that patient- reduce adverse drug events by specific clinical pharmacy 78% and 66% in general medical services are associated with and intensive care settings reduced mortality rates. respectively. Key Elements of the Pharmaceutical Care Process. The main goal is to establish a full Assessment medication history and highlight actual and potential drug-related problems This should clearly state the goals to optimise care and the responsibilities of Care plan both the pharmacist and the patient in obtaining the stated goals This reviews progress against the stated Evaluation patient outcomes  Drug Use Process (DUP) Steps To ensure that all medications provide their maximum benefit, it is essential to follow the DUP protocol.  2. Pharmaceutical Considerations Many factors influence the effect that a medicine has at its site of action. These include the:  Rate and extent of absorption.  Plasma protein binding.  Volume of distribution.  Routes of metabolism or excretion. 2. Pharmaceutical Considerations  3. Patient Factors Without background information on the patient's health and social circumstances, it is difficult to establish the existence of, or potential for, Medication-Related Problems (MRPs). 3. Patient Factors  Some Roles of the Clinical Pharmacist 1. Prevent / Reduce unnecessary Drug Therapy 2. Detect Ineffective Drug Therapy e.g. Dose adjustment 3. Actual or Potential Adverse Drug Reactions 4. Patient Counselling Services during admission and on Discharge 5. Adherence / Compliance issues 6. Miscellaneous e.g. Monitoring, Administration errors.  When can clinical pharmacy services be implemented? Trained clinical pharmacist Clear & implemented roles & regulations Documentation (Patient Drug Profile / Clinical Pharmacy Profile / Medication Reconciliation form)  Case Study Mr JB, a 67-year-old retired plumber, has recently moved to your area and has come to the pharmacy to collect his first prescription. He has coronary heart disease (CHD) and has recently had a coronary artery stent inserted. He has a long history of asthma which is well controlled with inhaled medicines. Drug Use Process (DUP) Steps Step 1. Establishing the need for drug therapy. Does this patient have an active complaint that requires medication establishment? Yes, the patient has been recently diagnosed with (CHD) and has recently had a coronary artery stent inserted. In addition, the patient has a history of asthma.  Step 2. Selecting the medicine Medical Condition CHD Asthma Anti-platelet aggregation β2-Agonist inhalers HMG-CoA reductase Steroid inhalers Recommended drug Inhibiter Organic Nitrate Antimuscarinic inhalers B-Blocker Calcium Channel Blocker ACE Inhibitor Steps 3 and 4. Administering and providing medicines Medical Condition CHD Asthma Aspirin 75 mg OD Oral Tab Salbutamol Inhaler 100mcg PRN Clopidogrel 75 mg OD Oral Budesonide Inhaler Tab 200mcg BD Simvastatin 20 mg HS OD Tiotropium Evo Inhaler Recommended drug Oral Tab 5mg OD Nitrates 0.5mg Sublingual Tab PRN Bisoprolol 5mg PM OD Oral Tab Diltiazem 60mg BD OD Oral Tab Ramipril 10mg OD Steps 5, 6, and 7. Monitoring therapy, patient education, and evaluation Thank You  PHAM 322 (Pharmacotherapy I) Clinical Pharmacokinetics, Biopharmaceutics, & Therapeutic Drug Monitoring (TDM). Prepared By: Dr. S. Mahmood Alqallaf. Modify By: Ph.Omar Alsamani  Objectives Define pharmacokinetics and describe how pharmacokinetics is related to pharmacodynamics and Therapeutic drug monitoring (TDM). Define each pharmacokinetic parameter and describe how they would affect the drug dosing and dosage regimen Define biopharmaceutics and describe how it affects drug product performance. Address the need of the pharmacokinetics parameters in calculation of the drug doses and dosage regimen Explain the difference between bioavailability and bioequivalence Illustrate the difference between linear and non-linear pharmacokinetics Explain the reason for the non-linear pharmacokinetics Describe the Michaelis-Menten kinetics and give examples of drugs that follow it Give examples on each type of the pharmacokinetics drug-drug interaction Define biopharmaceutics and pharmacogenetics Justify the need for therapeutic monitoring and when it is to be done Give examples of drugs which concentration monitoring is helpful PK & PD  Practical/Clinical Pharmacokinetics. Clinical pharmacokinetics: The study of the time course of the absorption, distribution, metabolism, and excretion of drugs and their corresponding pharmacological response. The discipline that applies pharmacokinetic concepts and principles in humans to Design Individualized Dosage Regimens that enhance the therapeutic response of medication while minimizing the incidence of ADR. Relationship between PK & PD  Why Study clinical PK? Individualize patient drug therapy Maximize efficacy and minimize ADR & toxicity of medications Monitor medications with a narrow therapeutic index Evaluate drug PK/PD as a diagnostic tool for some underlying diseases  General Applications Time to maximal response: By Knowing the half-life of a drug, the time to reach a steady state may be estimated (3-5 half- life). Need for a loading dose: By Knowing the half-life of a drug, whether a loading dose is necessary can be determined. Drugs with longer half-lives are more likely to require loading doses for acute treatment.  General Applications Dosage Alterations: Clinical pharmacokinetics can be useful in determining dosage alteration if the route of elimination is impaired through end-organ failure or drug interaction. Choosing a Formulation: Understanding of absorption may be useful in evaluating the appropriateness of a particular formulation of a drug in patient.  Clinical Pharmacokinetics Definitions and Terminologies Therapeutic level: Is the dosage range or blood plasma or serum concentration usually expected to achieve the desired therapeutic effect. This does not mean that patients may not achieve benefit at concentrations below the minimum threshold or may not experience adverse effects if kept within the range.  Clinical Pharmacokinetics Definitions and Terminologies Therapeutic index: is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refers to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side effects or toxicity.  Clinical Pharmacokinetics Definitions and Terminologies Loading Dose (LD): an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. Maintenance dose (MD): the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state. Steady State Concentration(Css): Occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly. Steady-state concentration is the time during which the concentration of the drug in the body stays consistent.  Important of the Loading Dose. Suppose a patient just started taking 100 mg of X drug every day. On the first day, they'd have 100 mg in their system; their body would clear 10 mg (10%), leaving 90 mg. On the second day, the patient would have 190 mg in total; their body would clear 19 mg, leaving 171 mg. On the third day, they'd be up to 271 mg total; their body would clear 27 mg, leaving 244 mg. it would take many days for the total amount of drug within the body to come close to 1 gram (1000 mg) and achieve its full therapeutic effect. For a drug such as this, a loading dose of one gram to be taken on the first day. That immediately gets the drug's concentration in the body up to the therapeutic level.  Effect of single IV Effect of single & repeated oral administration on plasma administration on plasma concentration concentration Impact of LD on Css  Clinical Pharmacokinetics Definitions and Terminologies Clearance (CL): Is the volume of plasma completely emptied of drug per unit of time. Example: if the drug concentration is 1g/L and CL is 1L/h, then the rate of elimination will be 1g/h. It may alter in cases of drug interactions, changing the end-organ function or autoinduction. Clearance is the most important pharmacokinetic parameter because it determines the steady-state concentration for a given dosage rate. Physiologically, clearance is determined by blood flow to the organ that metabolizes or eliminates the drug and the efficiency of the organ in extracting the drug from the bloodstream.  Clinical Pharmacokinetics Definitions and Terminologies Elimination Rate Constant (k): is the fraction of the amount of drug in the body eliminated per unit time. Example: if the body contains 100mg of a drug and 10% is eliminated per unit time, then k=0.1.  Movement of the drug from the site of Absorption administration into the general circulation Affected by factors such as: – Route of Administration – pH – Blood flow to the absorption site – Total surface area available for absorption – Contact time at the absorption surface Bioavailability (F): The proportion of administered drug that reaches the systemic circulation in unchanged form  Bioavailability (F) The fraction of the administered dose that reaches the systemic circulation as parent drug (unchanged form). Determination of bioavailability is by comparison of plasma levels of a drug obtained after administration (e.g. oral) with plasma levels following IV administration. Bioavailability determines dose required by different routes of administration. First Pass Metabolism  Bioavailability (F) F = Fractional availability Quote as percentage of 25% or as a decimal 0.25 Has no units For IV: 100% (or 1) Non IV: 0 - 100% (0 – 1)  Distribution The movement of drug from the general circulation into different parts of the body. Affected by factors such as: – Blood flow – Capillary permeability (Esp. BBB) – Binding of drugs to plasma proteins Drug distribution in Pediatrics & Elderly is different than in adults due to differences in Body Composition and Protein Binding  Volume of Distribution (Vd) Volume of distribution (Vd): is a pharmacokinetic parameter representing an individual drug's propensity to either remain in the plasma or redistribute to other tissue compartments. Vd equal to total amount of drug in entire body/drug plasma concentration. Vd is used to determine the Loading Dose (LD) that is required to achieve a particular steady-state concentration (Css) immediately after the dose is administered  Volume of Distribution (Vd) Most patients will not reach the Css after the LD, but serum drug concentrations will be high enough to experience pharmacological response. Higher doses will be needed to reach certain drug concentrations of drugs with larger Vd. Lower dose will be needed to reach a certain drug concentration of drugs with smaller Vd.  Metabolism Process of converting drugs to another form by the action of enzymes Affected by factors such: – Age – Disease – Genetics – Enzyme inducers – Enzyme inhibitors Questions related to metabolism: – What are the reactions involved in metabolism? – What is the 1st pass metabolism? – What is the prodrug?  Excretion / Clearance The volume of blood completely cleared of the drug per unit time. Expressed as volume per unit time (e.g. L/h or mL/min.) Affected by factors such: Age, Disease and pH What are the organs responsible for excretion? Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age Neonates have decreased renal blood flow i.e. glomerular filtration & tubular function produces delayed elimination of medications Clearance is used to determine the Maintenance dose (MD) that is required to maintain Css  Creatinine Clearance Creatinine is the end product of muscle catabolism It is produced endogenously and readily measured in serum or plasma It is renally excreted entirely unchanged and offers a clinically convenient measure of the renal function The most commonly used equation for calculation is Crockcroft-Gault. In Males: IBW = 50 + 2.3 x (Ht - 60in) In Females: IBW = 45.5 + 2.3 x (Ht - 60in) Use IBW if the patient is obese (ABW>30% over IBW) Age in years, IBW (Ideal Body Weight) in kg, SCr (Serum Creatinine) in mg/dL  Exercise Calculate the creatinine clearance for a 65-year-old female whose Scr is 0.6 mg/dl. the patient’s weight is 80 kg and his height is 6 feet.  Answer 1. Should we use the IBW or ABW? IBW = 45.5 + 2.3 x (Ht - 60in) = 45.5 + 2.3 ((6*12)-60) = 73.1 Kg ABW * 30% = 80 * 30% = 24 kg. 73.1 𝑘𝑔 Add the answer to the ABW = 80 + 24 % 𝐼𝐵 𝑊 Τ𝐴 𝐵𝑊 = × 100 80 𝑘𝑔 = 104 kg. = 91.4% If ABW (80 kg) is less than 104 kg, The difference is 8.6% (less than then use ABW (80 kg). 30%), so we use the ABW If ABW (80 kg) is more than 104 kg, then use IBW (73.1 kg).  Answer 𝐹𝑒𝑚𝑎𝑙𝑒 𝐶𝑟𝐶𝑙= ((140−𝐴𝑔𝑒)×𝐼𝐵𝑊)/(72 ×𝑆𝐶𝑟)) ×0.85 𝐶𝑟𝐶𝑙= ((140−65)×80)/(72 ×0.6)) ×0.85 𝐶𝑟𝐶𝑙= ((75x80)/43.2) x 0.85 𝐶𝑟𝐶𝑙= 138.89 x 0.85 = 118.06 𝑚𝐿/𝑚𝑖𝑛  Half Life & Dosage Regimen The dosage interval for a drug is determined by its half-life. If a drug half-life is 8 hours, and its therapeutic range is 10-20 mg/L. In order to ensure that maximum serum concentrations never go above and minimum serum concentrations never go below the therapeutic range, it is necessary to give the drug every 8 hours (τ = dosage interval). Pharmacokinetic Equations F  Exercises Exercise 1: Drug A has a Vd of 50 L. What IV LD is required to give a plasma concentration of 10 mg/L in a patient of 80 Kg? Exercise 2: Drug B has a Vd of 0.25 L/kg. what IV LD is required to give a plasma concentration of 10 mg/L in a patient of 80 Kg? Exercise 3: Calculate the maintenance dose for a drug to be given to a patient weighing 70 kg, required to give a Css of 10 mg/L. The drug’s clearance is 0.5 L/hr/kg  Exercises Exercise 4: Calculate the t½ of a drug that has a Cl of 0.5 L/hr/kg and Vd of 0.25 L/kg in a patient who weighs 80 kg. Exercise 5: Calculate the creatinine clearance for a 65 years old female whose Scr is 0.6 mg/dl. the patient weight is 80 kg and height is 6 feet. Exercise 6: LM is a 59-year-old, 85-kg male needing treatment with oral quinidine for an arrhythmia. Assuming F = 0.7, Vd = 200 L, and t1/2 = 8 h, Css=2 mg/L. compute dose of oral quinidine 6 hourly.  Bioequivalence Bioequivalence: is the biochemical similarity of two (or more) drugs that share the same active ingredient(s) and desired outcome(s) for patients. Pharmacokinetic studies must be done to determine whether a commercially available brand and a potential generic version share core attributes.  Biopharmaceutics Biopharmaceutics: The study of the physical and chemical properties of drugs and their proper dosage as related to the onset, duration, and intensity of drug action. The study of the effects of physicochemical properties of the drug and the drug product, in vitro, on the bioavailability of the drug, in vivo, to produce a desired therapeutic effect. Drug biological fate Physicochemical Pharmacological in the body after its properties administration action  Pharmacogenetics Pharmacogenomics (also known as pharmacogenetics): is the study of how our genes affect the way we respond to medications. Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs.  Linear vs Non-Linear Pharmacokinetics Models When drugs are given on a constant basis such as a continuous IV infusion or an oral medication given every 12 hours Serum drug concentrations increase until the rate of drug administration equals the rate of drug metabolism & excretion (Css). However, this is not the case always.  Linear Pharmacokinetics In Linear kinetics: the rate of elimination is proportional to the amount of drug present 120 Dosage increases result in proportional 100 increase in plasma drug levels 80 concentration 60 This is also called one compartment or 40 1st order model 20 0 dose  Non-linear Pharmacokinetics 50 45 In Non-linear kinetics: rate of elimination is 40 constant regardless of amount of drug present 35 concentration 30 25 When steady-state concentrations is 20 15 different than expected after dosage 10 change, there are two typical explanations. 5 – Saturated plasma protein binding sites 0 e.g. Valproic acid dose – Autoinduction of drug metabolism: e.g. Carbamazepine Drugs that exhibit non-linear pharmacokinetics are often very difficult to dose correctly.  Michaelis-Menten Kinetics Follows linear kinetics until enzymes become saturated Enzymes responsible for metabolism become saturated resulting in non- proportional increase in drug levels This phenomenon is also known as “Saturable pharmacokinetics”. Example of drugs that follow this model: Phenytoin and salicylic acid.  Important Concepts Vd is a theoretical Volume and determines the LD Cl is a constant and determines the MD CL = k * Vd CL and Vd are independent variables k is a dependent variable In Css, Rate in = Rate Out & Reached in 4 – 5 half-lives (linear kinetics) Css is important when interpreting drug concentrations in TDM or assessing clinical response Two new antibiotics have the following dose – concentration relationship. What type of pharmacokinetics does each of these drugs follow?  Answer A plot of steady-state concentration versus doses is a straight line for Curacillin, but a curved line for Bettermycin. Because this relationship is a straight line for Curacillin, it follows linear or first-order pharmacokinetics. Because the steady-state concentration versus dose plot is curved upward indicating disproportionally large increases in concentration after a dosage increase, Bettermycin follows nonlinear pharmacokinetics (Michaelis-Menten or saturable pharmacokinetics)  Pharmacokinetics Drug-Drug Interaction Absorption: Distribution: Metabolism: Excretion: e.g. drugs e.g. e.g. drugs with e.g. enzyme Ketoconazole competing to difference in induction & and gastric same protein enzyme acid excretion binding inhibition suppressants mechanism affinity Therapeutic Drug Monitoring  Therapeutic Drug Monitoring Therapeutic drug monitoring (TDM): Tests that measure the amount of certain medicines in your blood. It checks whether the amount of medicine you take is safe and effective. Drug Concentrations May Therapeutic Index Be Useful When There Is:  An established relationship between TI = toxic dose / effective concentration & response (desirable dose & undesirable) TI is a measure of a drug’s  A sensitive and specific assay is needed safety  An assay that is relatively easy A large number = a wide to perform margin of safety  A narrow therapeutic index drugs A small number = a small  A need to enhance response / prevent margin of safety toxicity  Why Measure Drug Concentrations? To individualize therapy To diagnose toxicity (including addiction) To guide withdrawal of therapy To assess adherence to therapy To determine whether a patient is already taking a drug before starting therapy (e.g. theophylline in an unconscious patient with asthma) In research (e.g. to monitor for drug interactions in post-marketing surveillance Using population pharmacokinetics).  Potential for Error When Using TDM Assuming patient is at steady-state Assuming patient is receiving / actually taking the drug as prescribed Not knowing when the drug concentration was measured in relation to dose administration Assuming the patient is static and that changes in condition don’t affect clearance Not considering drug interactions Drug concentration monitoring is helpful for the following drugs: Aminoglycoside antibiotics (plasma or serum) Cyclosporin (whole blood) Digoxin and digitoxin (plasma or serum) Lithium (serum) Phenytoin (plasma or serum) Theophylline (plasma or serum) Paracetamol and salicylate (overdose) (plasma or serum). Other drugs are sometimes measured: Anticonvulsants other than phenytoin (e.g. carbamazepine, valproate) Tricyclic antidepressants (especially nortriptyline) Anti-arrhythmic drugs (e.g. amiodarone). Thank You  PHAM 322 (Pharmacotherapy I) Issues on Crushing, Opening or Splitting Oral Dosage Forms Prepared By:Dr. S. Mahmood Alqallaf Modify By: Ph.Omar Alsamani  Objectives 1. Identify oral pharmaceutical dosage forms that must not be split, crushed, or opened 2. Explain the reasons for not splitting, crushing, or opening some oral dosage forms 3. Recognize the potential consequences of manipulating a medicinal product 4. Mention the questions need to be asked before splitting or crushing tablets 5. Describe solutions to the situations where an oral dosage form has to be manipulated 6. Give examples of drugs that must not be split, crushing, or opened & the reasons  Introduction The need for this topic has been highlighted within the British Pharmaceutical Nutrition Group (BPNG) and the British Association of Parenteral and Enteral Nutrition (BAPEN). Healthcare professionals are challenged daily by complex patients. Whose need for medicines does not fit neatly into the categories used by the pharmaceutical industry as part of their process for licensing medicines.  Introduction To provide the right level of care for these patients, professionals have to make complex and rational decisions concerning medication. This may mean stepping outside the product license for the medication needed.  This has implications for the professionals responsible for prescribing, supplying and administering the drug. As they become liable for any adverse event that the patient may experience. Legal Risks When a drug is administered outside of the terms of its product license (for e.g. by crushing tablets before administration), the manufacturer is no longer responsible for any adverse event or treatment failure. CD: Controlled CR: Controlled LA: Long delivery release acting PA: Prolonged SR: Slow SR: Sustained action release release XL: Extended XR: Extended release release  Drug Therapy Review Reduce drug therapy to the minimum necessary. Transfer the patient onto once- daily formulations with a long half-life where possible(not modified- slow-release formulations). Determine alternative formulations and routes available where possible. Make any therapy changes in an environment in which the patient can be effectively monitored.  Choice of Medication Formulation Solutions or soluble tablets are the formulations of choice. Do not assume that liquid formulation will be suitable. Do not crush tablets or open capsules unless an alternative formulation or drug is unavailable. Parenteral administration can be used and often guarantees 100% absorption, repeated injections are associated with complications and are not suitable for continuous long- term use.  Case 1 Answer The patient was prescribed a tablet that she was unable to swallow whole because of dysphagia. Because of a lack of knowledge of the characteristics of the product, the tablet was crushed for ease of administration. Oxycodone is a potent opioid, and the sustained-release formulation is designed to deliver the drug gradually over 12 hours. Crushing the tablet destroyed the drug’s sustained-release properties and led to rapid absorption of the entire 12-hour dose, which resulted in sedation and respiratory depression.  Case 2 Answer The desired benefit of the drug therapy was not obtained because the tablet was crushed. Omeprazole is formulated as an enteric-coated tablet to avoid inactivation of the drug by gastric acid. Crushing the tablet compromised the protective coating, which resulted in loss of efficacy. Thank You  PHAM 322 (Pharmacotherapy I) Interpretation of Lab. Data Dr. S. Mahmood Alqallaf Email: [email protected]  Objectives Justify the use of Lab. tests for different purposes Describe the most common errors in lab tests. Outline the main divisions of the Clinical Lab and the role of each. Outline the most important tests in hematology, nephrology, hepatology, cardiology, oncology and inflammation. Identify the characteristics and function of each type of lab. test. Identify the significance of each type of lab. tests. Identify common causes for increases and decreases in each type of lab. tests.  Introduction A drug (or any medical treatment) should be used only when it’ll benefit a patient. Benefit takes into account both the drug's ability to produce the desired result (efficacy) and the type and likelihood of adverse effects (safety). Laboratory findings, both normal and abnormal, can be helpful in assessing clinical disorders, establishing a diagnosis, assessing drug therapy, or evaluating disease progression In addition, baseline laboratory tests are often necessary to evaluate disease progression and response to therapy or to monitor the development of toxicities associated with therapy.  General Principles Generally, laboratory tests should be ordered only: 1. If the results of the test will affect decisions about the patient care. 2. The serum, urine, and other body fluids can be analyzed routinely. The economic cost of obtaining these data must always be balanced by benefits to patient outcomes. Remember that some results might be falsely increased (or false +ve) or decreased (or false –ve), so be careful of errors.  Remember Normal values may vary: From laboratory to laboratory, depending on techniques and reagents used. Depending on the patient's age, gender, weight, height, and other factors.  Some Medical Terminology 1.Aden/o Gland 11.Carcin/o Cancer 2.Cardi/o Heart 12.Chem/o Chemical 3.Cis/o To Cut 13.Dermat/o Skin 4.Enter/o Small Intestines 14.Gastr/o Stomach 5.Gynec/o Female 15.Hemat/o Blood 6.Hydr/o Water 16.Hepat/o Liver 7.Laryng/o Voice Box 17.Morph/o Shape 8.Nephr/o Kidney 18.Neur/o Nerve 9.Ophthalm/o Eye 19.Ot/o Ear 10.Path/o Disease 20.Pulmon/o Lung  Divisions of the Clinical Lab. Clinical Has several different sciences: bacteriology, virology, Microbiology parasitology, immunology, and mycology. Clinical This area includes analysis of blood specimens, including tests related to Chemistry enzymology, toxicology and endocrinology Hematology This area includes analysis of blood cells. It also often includes coagulation. Blood Bank Involves the testing of blood specimens in order to provide blood transfusion and related services. Molecular DNA testing may be done here, along with a subspecialty known diagnostics as cytogenetics. Laboratory tests Complete blood count (CBC) Most common laboratory tests used in clinical practice Electrolytes are: Blood chemistries Urinalysis (UA) Diseases specific tests  Laboratory Errors Laboratory Error Fairly uncommon occurrence However, it can happen. Potential causes : Technical error, improper calculation, inadequate specimen, incorrect sampling timing, improper sample preservation, food substances affecting specimen, or medication interference with laboratory tests. If laboratory error is suspected, the test must be repeated. Remember: Always treat the patient, Not the laboratory value!  Laboratory Error 1- Patient-related factors e.g. age, gender, weight, height, time since last meal. 2- Laboratory-based issues can also influence the accuracy of laboratory values. A. Improper handling or processing e.g. hyperkalemia due to hydrolysis of blood specimen B. Incorrect sampling timing e.g. fasting BG level taken shortly after a meal C. Incomplete Collection e.g. 24 hrs urine collection that does not span a full 24 hrs 3- Faulty poor quality reagents e.g. improperly prepared, expired 4-Technical errors e.g. human error in reading result, computer-entering error 5- Interference from medical procedures e.g. cardioversion increases CK level 6-Dietary effects e.g. meat ingestion can cause a false-positive guaiac test 7- Medications usage e.g. thiazides can increase serum uric acid concentration. 8-Clinicians might not be aware of when laboratory-related issues arise.  Complete Blood Count (CBC) Hemoglobin (Hgb) Hematocrit (Hct) WBCs and WBCs differential RBCs RBCs indices Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Platelet count  Hemoglobin (Hgb) Hemoglobin level indicates: Oxygen- carrying capacity of the blood. Limitations: variations in hemoglobin values might occur in: Adaptation to high altitudes, Extreme exercise Pulmonary conditions Male 14–18 g/dL SI 8.7–11.2 mmol/L Normal Range Female 12–16 g/dL SI 7.4–9.9 mmol/L Clinical Significance Increased Hemoglobin Decreased Hemoglobin  Polycythemia Vera Anemias  COPD. Blood loss  Chronic smokers Hemolysis  Regular vigorous exercise Pregnancy  Residents at high altitudes Fluid replacement  Hematocrit (Hct) Normal Range Male 39%-50% SI 0.39–0.50 Also called packed cell volume Female 33%-45% SI 0.33–0.45 (PCV). Volume of blood that is occupied by RBCs. It is expressed as a percentage of total blood volume. The Hct value is generally about three times the value of hemoglobin Clinical Significance Anemias Effects are similar to increases in Hgb e.g. Blood loss Polycythemia vera Hemolysis COPD Pregnancy High altitudes Cirrhosis Dehydration and shock. Hyperthyroidism Leukemia 33%-45% 39%-50% RBCs (Erythrocytes) Count Amount of RBCs per unit of blood. All blood cells including RBCs are produced in the bone marrow and then, they are released into the systemic circulation RBCs are produced further to stimulation of the bone marrow by the erythropoietin produced from the kidney. RBCs Serve to transport oxygen from the lungs to the body tissues. A life span of approximately 120 days  Normal Range Clinical Significance Male 4.2–5.9 × 106 cells/mm3 SI 4.2–5.9 × 1012 cells/L Female 3.5–5.5 × 106 cells/mm3 SI 3.5–5.5 × 1012 cells/L Increased RBCs Decreased RBCs Polycythemia vera Anemias Lymphomas High altitudes Leukemia Blood loss: after puberty, Strenuous exercise females have lower RBC’s and HB due to menstrual bleeding. Blood hemolysis  Mean Corpuscular Volume (MCV) Range An estimate of the average volume of RBCs. 76–100 μm3/cell SI 76–100 fL The higher the MCV, the larger the average size of the RBC. Cells with an abnormally large MCV are classified as macrocytic. Cells with a low MCV are referred to as microcytic. Normocytic RBCs have an MCV that falls within the normal range.  Clinical Significance Increased MCV Decreased MCV Folate deficiency, vitamin B12 Iron deficiency deficiency anemia Alcoholism Hemolytic anemia Chronic liver disease Hypothyroidism Lead poisoning Anorexia Medications e.g. valproic acid, Thalassemia zidovudine and anti-metabolites (Methotrexate)  MCH & MCHC Measure of the concentration of hemoglobin in an average RBC Range Decrease in MCH & MCHC is known as Hypochromic anemia MCH SI 26 – 34 pg Normal is known as Normochromic anemia. MCHC SI 20-360 g/L  Red Blood Cell Indices Normochromic Hypochromic Normochromic Normocytic anemias Microcytic anemias Macrocytic anemias Blood loss Iron deficiency Folic acid deficiency Hemolytic anemia Vitamin B12 deficiency  Iron Deficiency Anemia vs Anemia of Chronic Disease Lab Index Iron-Deficiency Anemia of Interpretation (Normal Values) Anemia Chronic Disease MCV Decreased Usually normal Normal in early iron deficiency, then falls (80-95 fL) as anemia progresses. But reduced levels seen in 15%-25% of patients with Anemia of Chronic Disease Serum iron Decreased Decreased Serum iron is the amount of iron in the (Men 80-180 ug/dL blood bound to transferrin and available for Women 60-160 RBC production ug/dL) Serum Ferritin Decreased Normal or Serum ferritin reflects total-body iron (Men 12-300 ng/mL increased stores. Low ferritin is diagnostic of iron Women 10-150 deficiency ng/mL)  Reticulocytes Normal 0.1%-2.5% SI 0.001– Range of RBC 0.025 RBC Immature RBCs formed in the bone marrow. An increase in reticulocytes usually indicates an increase in RBCs production Indicative of a decrease in the circulating number of mature erythrocytes.  Clinical Significance Increased Reticulocytes Decreased Reticulocytes Hemolytic anemia Infection Hemorrhage Alcoholism Sickle cell disease. Renal disease (from decreased erythropoietin) Toxins Indicative of response to treatment of anemias secondary to iron, vitamin b12, or folate deficiency. Untreated iron deficiency anemia Drug-induced bone marrow suppression.  WBCs (Leukocytes) Normal 3,200–11,300 SI 3.2–11.3 × Range cells/mm3 109 cells/L The total number of WBCs in a given volume of blood. Mature white blood cells exist in many forms, including eosinophils, neutrophils, basophils, lymphocytes, and monocytes. A WBC count with differential provides a breakdown of the percentage of each type of WBC.  Clinical Significance Increased WBCs Decreased WBCs (leukopenia) (leukocytosis) Viral infection, aplastic anemia Infection, leukemia, trauma, thyroid storm, and corticosteroid use. Emotion, Bone marrow suppression due stress, and seizures to chemotherapy or immunosuppressants When WBC >50,000 cells/mm3, false elevations in Hgb and MCH can occur.  Neutrophils The most common type of WBCs. Fight bacterial and fungal infections. May also be involved in the pathogenesis of some inflammatory disorders e.g. RA & IBD. Bands are immature neutrophils. An increase in bands, often referred to as a "shift to the left" or "left shift" may occur during infection or leukemia.  Clinical Significance Increased Neutrophils Decreased neutrophils (Neutrocytosis or Neutrophilia) (Neutropenia) Infection, Metabolic disorders (e.g. diabetic ketoacidosis), Uremia, Viral infections (eg, Response to stress, emotional mononucleosis, hepatitis), disturbances, burns, acute Septicemia inflammation, Use of medications Use of chemotherapy such as corticosteroids drugs. Absolute neutrophil count (ANC) The total number of circulating segments and bands The risk of infection increases dramatically as the ANC decreases.  Normal Range 20%-40% SI 0.20–0.40 Lymphocytes The second most common type of circulating WBCs. Main function is antigen recognition and immune response May mature into B or T cells B cells are produced in the bone marrow & mature there. The precursors of T cells leave the bone marrow & mature in the thymus B cells are most effective against bacteria & their toxins & few viruses T cells recognize & destroy body cells gone abnormal including virus-infected cells & cancer cells T cells come in two types: helper cells and suppressor cells; normally the helper cells predominate.  Clinical Significance Increased Lymphocytes Decreased Lymphocytes (Lymphocytosis) (Lymphopenia) Influenza Acute infections Pertussis Burns Tuberculosis AIDS Mumps Bone Marrow suppression Cytomegalovirus Infection Aplastic Anemia Infectious Mononucleosis Steroids Neurologic Disorders Infectious Hepatitis Multiple Sclerosis Viral pneumonia Myasthenia Gravis Guillian Barre Syndrome  Normal Range 0 % - 4 % SI 0.0 – 0.04 Eosinophils Phagocytic WBC’s that assist in the killing of bacteria and fungi. They reside predominantly in the intestinal mucosa and lungs. They are also involved in allergic reactions and in the immune response to parasites. Eosinophil count must be taken at the same time daily due to diurnal variation. Clinical Significance Increased Eosinophils Decreased Eosinophils (eosinophilia) (eosinopenia) Allergic disorders Collagen vascular disease Commonly attributed to Parasitic infections an increase in adrenal steroid production Iimmunodeficiency disorders Some malignancies. Monocytes Normal Range 2 % - 8 % SI 0.02 – 0.08 Monocytes are synthesized in the bone marrow, released into the circulation, and then migrate into lymph nodes, spleen, liver, lung, and bone marrow. In these tissues, monocytes mature into macrophages and serve as scavengers for foreign substances. Increased Monocytes Decreased Monocytes (monocytosis) (monocytopenia) May be observed in the recovery Usually not associated with a phase of some infections e.g. specific disease, but may be subacute bacterial endocarditis, seen with use of bone TB, Syphilis, Malaria marrow suppressive agents or severe stress Leukemia & lymphoma.  Basophils Normal Range Basophils are phagocytic WBCs. Less than 1% Less than 0.01 They contain histamine, and leukotrienes and are probably Clinical Significance associated with hypersensitivity Increased basophils reactions. (basophilia) May be seen in hypersensitivity reactions to food or medications Certain leukemias Polycythemia Vera.  Exercise: Interpreting the WBCs What is total WBCs count? Normal % Absolute Values If elevated (>11,000), what type of WBC is the culprit? Is it the Neutrophils 40 – 70 1800 – 7500 neutrophils, eosinophils, lymphocytes, basophils, or Eosinophils 0–6 0 – 600 monocytes? Basophils 0–1 0 – 100 WBCs: 3,200–11,300 cells/mm3 Lymphocytes 20 – 45 900 – 4500 Marked leukocytosis (Increased Monocytes 2–6 90 - 1000 WBCs) is usually due to neutrophils or lymphocytes.  Interpreting the WBCs If the neutrophils are causing the leukocytosis, compare the neutrophil % to total WBC. The total WBCs reflects the quality of the immune system The % neutrophils indicates the severity of the infection Case # 1 Case # 2 85 yrs old female with pneumonia 25 yrs old male with pneumonia WBCs: 11,500. Neutrophil % = 80% WBCs: 18,000, Neutrophils = (9200), bands = 5% 60% (10,800) This indicates that a severe infection is Marked leukocytosis and normal present (high neutrophils) but the range for neutrophils indicates immune system is unable to respond moderate infection but excellent appropriately (Normal WBCs). immune system response. Prognosis poor. Excellent prognosis  Platelets Normal Range 150,000–450,000/μL SI 150–450 × 109/L Platelets are a critical element in blood coagulation process. Low platelets could result in bleeding, but this risk is low unless platelets fall below 50,000/μL. Case 1: You are rounding on an internal medicine advanced pharmacy practice experience with the ICU team. When preparing for rounds, you noted that there was a new admission last night—an Olympic bicyclist who was struck by a car. Begin reviewing the patient's laboratory data in preparation for rounds. WBC differential RBC: 4.2 × 106 cells/mm3 -Segs: 65% Hgb: 14 g/dL -Bands: 10% Hct: 42% -Lymphocytes: 17% MCV: 90 μm3/cell -Monocytes: 5% MCH: 31 pg/cell -Eosinophils: 2% MCHC: 36 g/dL -Basophils: 0.5 % 1- What do the given abbreviations represent? 2- Which of the laboratory values are abnormal? Cardiac Tests: Creatine Kinase (CK) CK is an enzyme that is found primarily in skeletal and cardiac muscle and in smaller fractions in the brain. 3 isoenzymes available: CK-MM: available in skeletal muscles CK-BB: in brain CK-MB: in cardiac tissue. CK-MB is an important marker in the diagnosis of acute myocardial infarction (AMI).  Clinical significance: Total CK An elevation of total CK may be seen with: Trauma Surgery Shock Seizures Muscular dystrophy Cerebrovascular accident Polymyositis Dermatomyositis Chronic alcoholism Reye’s syndrome Malignant hyperthermia.  Clinical Significance (CK-MB) Less than 12 IU/L or less than 4% of total CK. Serial CK-MB tests are useful in the diagnosis of AMI. An elevated CK-MB level greater than 4% - 5% of total CK is suggestive of acute MI. Levels begin to rise 4 - 6 hours after onset of acute MI. Peaks between 12 - 24 hours Levels return to normal 2 - 3 days after acute MI. Troponin Troponins are a family of proteins found in skeletal & cardiac muscle fibers that produce muscular contraction. Troponin test measure the level of cardiac-specific troponin in the blood to help detect heart injury. 2 types of troponin are available: Troponin I is found solely in the cardiac muscle. Troponin T is found in both cardiac & skeletal muscle. Troponin I and T & sensitive markers of cardiac injury.  Troponin Normal Range Rise within 4 hours of onset of chest pain. Troponin I (cTnI) < 1.5 ng/mL (varies with assay) Levels should be drawn on admission and 8 - 12 hours thereafter. Troponin T (cTnT) < 0.2 ng/mL Patients with elevated troponin levels are considered at high risk for a significant cardiac event. This is because troponin is more sensitive and can detect smaller or more subtle injuries to the heart muscle that CK-MB might miss. Elevated troponin, even with normal CK-MB, can help identify non-Q- wave MI that might otherwise go undiagnosed. Approximately 30% of patients with no elevation in CK-MB may demonstrate elevated troponin and thus may be diagnosed with a non-Q-wave MI.  Coagulation Tests: Prothrombin Time (PT) PT is a blood test that measures how long it takes for the blood to clot PT is the time needed to convert prothrombin to thrombin. Prothrombin is a protein produced by the liver for the clotting of blood PT can be used to check for bleeding problems. PT is also used to monitor anticoagulants drugs (warfarin, heparin). Its action depends on adequate Vitamin K intake and absorption  Prothrombin Time (PT) 10–13 seconds (varies Normal with thromboplastin and Range test method used). PT is sensitive to changes in the levels of clotting factors prothrombin (factor II), factor Clinical Significance VII & factor X. Because the PT may vary according to the thromboplastin used to test the sample, INR is a better monitoring tool. PT test is performed by adding thromboplastin and calcium to a plasma sample. The normal PT range (10-13 sec.) is for a person not on anticoagulation therapy. After addition of these reagents, the time it takes for PT may be increased with the blood to clot is anticoagulation therapy, liver disease, measured. vit. K deficiency & clotting factors deficiencies.  International Normalized Ratio (INR) INR is a standardized measurement of the PT( time the blood takes to clot) Because the PT may vary due to the thromboplastin used, the INR is used to standardize the PT. INR is a ratio of the patient’s PT to that of International Reference Thromboplastin INR is used to regularly monitor WARFARIN treatment, so: High INR: blood is too thin, risk of excessive bleeding (due to high warfarin dose) Low INR: blood is too thick, risk of clotting or thrombosis (dues to low warfarin dose) INR target is usually 2.0 - 3.0 depending on patient condition Clinical significance INR below the desired range indicates suboptimal anticoagulation and a need to increase warfarin dosage. Conversely, INR above the desired range indicates a need to omit and / or reduce the warfarin dosage. Patients with elevated INRs and / or bleeding may require the administration of vitamin K, fresh frozen plasma, or clotting factors.  Factors that Interfere with INR Ingestion of excessive vitamin K rich foods (e.g. green leafy vegetables, tomatoes, etc.), promoting more rapid blood clotting (low INR) Alcoholism prolongs clotting (high INR) Diarrhea and vomiting prolongs clotting (high INR) Technique of blood draw Medications: Some antibiotics (e.g. cephalosporins & metronidazole), aspirin, cimetidine, phenytoin Activated Partial Thromboplastin Time (aPTT) Normal Range: 20 - 35 seconds. (Varies per reagent used in the Lab.) aPTT is useful for detecting bleeding disorders caused by either deficient or defective coagulation factors (I, II, V, VIII, IX, X, XI & XII). Normal aPTT may reflect normal clotting function (though moderate single factor deficiencies may still exist) PT is done by adding thromboplastin and calcium to plasma sample. PTT is done by adding Partial thromboplastin & calcium to plasma sample. Additional chemicals are added to standardize and accelerate the test, the result is reported as aPTT It is used to monitor HEPARIN therapy. Usually, No need to monitor aPTT in case of LMWH.  Clinical significance Patients on heparin therapy will have an elevated aPTT. Much like the PT, the aPTT can vary depending on the reagent (partial thromboplastin) used to test the sample. Therefore, a therapeutic range should be established for each institution based on the partial thromboplastin used at that laboratory. Low aPTT: indicates the need to increase the heparin infusion rate. High aPTT: indicates the need to hold or reduce the dose of heparin. Patients with clinically significant bleeding may require reversal with Protamine sulfate  Kidney Function Tests Blood Urea Nitrogen (BUN) Creatinine Electrolytes Blood Urea Nitrogen (BUN) Normal Range: 6–20 mg/dl (SI 2.1–7.1 mmol/L) UREA nitrogen is an end Increased BUN Decreased product of protein (Azotemia) BUN catabolism. Acute or chronic RF It is produced in the liver, HF liver failure transported in the blood, because of and cleared by the GI bleeding inability of the kidneys. High-protein diet liver to BUN concentration Shock synthesize serves as a marker of Dehydration urea renal function. SIADH Anti-anabolic & nephrotoxic drugs. Acromegaly Creatinine Normal Range: 0.7-1.2 mg/dL (SI 53–106 mmol/L) Breakdown product of creatine, an important component of muscles Production depends on muscle mass, which varies very little. Excreted fully by the kidneys Level in the blood is proportional to the GFR. It is a more sensitive test of kidney function than BUN because kidney impairment is almost the only cause of elevated creatinine. Creatinine Increased Creatinine CrCl Renal dysfunction An estimate of the Dehydration creatinine cleared of the Urinary tract obstruction body using age and Vigorous exercise weight at time of Hyperthyroidism calculation. Myasthenia gravis Used for assessing Increased protein intake kidney function in Nephrotoxic drugs e.g. Cisplatin & Amphotericin B. patients with renal impairment. CrCl can be used to Decreased Creatinine monitor patients on Cachexia nephrotoxic medications Inactive elderly or comatose patients and to assess need for Spinal cord injury patients. renal dose adjustment Blood Chemistry Tests Electrolytes: related to fluid balance Sodium Potassium Chloride Caclium Phosphorus  Normal Range Potassium (K+) 3.4-5.3 mEq/L K+ is the major component of ICF. SI 3.4-5.3 mmol/L K+ participates in enzyme activity, regulation of tissue osmolality and glycogen. K+ is also essential for cardiac & CNS function and regulating muscle and nerve excitability Renal failure, Metabolic acidosis, DKA, Addison's disease, Hyperkalemia Excessive potassium supplements, Blood transfusion Diarrhea, vomiting, GI impairment, Diuretics, Cushing Hypokalemia syndrome, Malnutrition, Restrictive diet, alcoholism  Normal Range Chloride (Cl-) 99-108 mEq/L Cl- is another component of ECF SI 99-108 mmol/L Cl- participates in tissue and cell osmolality, and passively follows sodium and water. Cl- is necessary for K+ retention, transport of CO2, and formation of HCl in the GIT. If needed, Cl- is usually provided in the form of NaCl or KCl Hyperchloremia High-salt, low-water diet, Hypertonic IV fluids use, Metabolic Acidosis, Renal failure Hypochloremia Low salt diet, Water intoxication, Diuresis, Excessive vomiting, diarrhea  Normal Range Magnesium (Mg2+) 1.5-2.4 mEq/L SI 0.75-1.2 mmol/L Mg2+ is found in the bone (50%), the ICF (45%), and the ECF (5%). Mg2+ affects enzymes activity, cardiac and neuromuscular function. Deficits of Mg2+ are usually seen with deficits in Ca2+ and/or K+ Increased intake of Mg2+ containing antacids Hypermagnesemia / salts, Renal failure, Leukemia, Dehydration Alcoholism, Eating disorders, Diuresis, DKA, Hypomagnesemia Medications e.g. diuretics.  Normal Range Phosphate (PO4-) 2.5-4.5 mg/dL PO4- is found in the bone and the ICF. SI 0.8–1.45 mmol/L PO4- plays a role in neuromuscular function, formation of bones and teeth, body metabolism, and forming and storing of energy as ATP. A relationship exists between PO4- and Ca2+. Therefore, if one value is abnormal, the other might be abnormal (so, should be evaluated as well) Bone destruction (e.g. Cancer), Immobilization Hyperphosphatemia Fracture, Excessive vitamin D, Renal failure Alcoholism, Poor dietary Intake, Limited GI Hypophosphatemia absorption, Pancreatitis, Laxative Use IC / EC Fluids Electrolytes distribution  Lipid Profile Fat is a source of energy Roles of fat in the body: Carrier of some vitamins Helps make hormones Helps make cell membranes Lubricates some body parts Fats are carried wrapped in lipoproteins Triglycerides most common, then cholesterol  Why HDL is good and LDL is bad?. HDL is good because it helps remove cholesterol from the arteries. LDL is bad because it contributes to cholesterol buildup and plaque formation in the arteries, increasing the risk of heart disease.  Total Serum Cholesterol Desirable