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Comprehensive Prescribing Guidelines for Geriatric Pharmacotherapy

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An in-depth overview of geriatric classifications, physiological changes with aging, and their impact on pharmacokinetics and pharmacodynamics to optimize safe and effective medication use in elderly patients.

  • geriatric pharmacotherapy
  • aging
  • pharmacokinetics
  • pharmacodynamics
  • dose adjustment

By Dr. Ayesha Fatima

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  1. Slide 1. GENERAL PRESCRIBING GUIDELINES FOR GERIATRICS Presented by Dr. Ayesha Fatima Assistant Professor Dept of Pharmacy Practice
  2. Slide 2. The World Health Organization (WHO) classifies geriatrics according to age as follows: 1. Young-old: Typically refers to individuals aged 65 to 74 years old. 2. Middle-old: Refers to individuals aged 75 to 84 years old. 3. Old-old: Encompasses individuals aged 85 to 99 years old. 4. Oldest-old or Elite-old: Denotes individuals aged 100 years and older This classification help in understanding the diverse healthcare needs and challenges encountered by older adults across different age groups within the geriatric population. Geriatrics :- It is the branch of medicine that focuses on the health and care of elderly individuals, particularly those aged 65 and older. It encompasses the prevention, diagnosis, treatment, and management of medical conditions and age-related issues specific to older adults. Classification of Geriatrics
  3. Slide 3. Introduction to Geriatric Population 1. There has been a steady rise in the elderly population (people over 65 years) since the early twentieth century. 2. Globally, more than 760 million people are aged 65 years and above, and this number is expected to reach nearly 1.6 billion by 2050. 3. In India, more than 104 million people are aged 60 years and above, accounting for about 8.6% of the population. 4. Elderly individuals often suffer from multiple chronic diseases and therefore are major consumers of medications, accounting for 25–40% of drug expenditure in developed countries. 5. Institutionalized elderly patients usually take more medications than those living in the community.
  4. Slide 4. 6. Pharmacotherapy in older adults helps in curing or controlling diseases and improving health-related quality of life (HRQOL). 7. HRQOL includes improvements in physical functioning, psychological well- being, social functioning, and overall health status. 8. However, age-related physiological and pathological changes can significantly alter drug absorption, distribution, metabolism, and excretion, increasing the risk of adverse drug reactions and polypharmacy. 9. Drug-related problems may compromise the quality of life in older adults. 10. Therefore, healthcare professionals must understand age-specific pharmacotherapeutic considerations to ensure safe, effective, and rational drug therapy in the elderly population.
  5. Slide 5. AGE RELATED PHYSIOLOGICAL CHANGES ● Age-associated physiological changes may result in reduced functional reserve capacity and a decreased ability to maintain homeostasis, making older adults more susceptible to decompensation during stressful situations. ● Homeostatic mechanisms that may become impaired include postural and gait stability, orthostatic blood pressure responses, thermoregulation, cognitive reserve, and bowel and bladder function. ● An event causing functional impairment may involve an insult for which the body cannot adequately compensate, and even relatively small stresses can lead to major morbidity and mortality. ● The clinical response to medications in older adults is the result of complex interactions between pharmacokinetic and pharmacodynamic processes. ● Age-related physiological changes can alter drug absorption, distribution, metabolism, and excretion, thereby affecting drug response. ● Concurrent medications, comorbidities, and frailty also play important roles in determining
  6. Slide 6. Physiologic changes with age Organ System Manifestations of Aging Balance and Gait ↓ Stride length and slower gait; ↓ Arm swing; ↑ Body sway when standing Body Composition ↓ Total body water; ↓ Lean body mass; ↑ Body fat; or ↓ Serum albumin; ↑ α1- acid glycoprotein (may increase further with disease states) Cardiovascular ↓ Cardiovascular response to stress; ↓ Baroreceptor activity leading to ↑ orthostatic hypotension; ↓ Cardiac output; ↑ Systemic vascular resistance due to loss of arterial elasticity and impaired autonomic tone; ↓ Resting and maximal heart rate Central Nervous System ↓ Size of the hippocampus and frontal/temporal lobes; ↓ Number of receptors and ↑ sensitivity of remaining receptors; ↓ Short-term memory, information encoding and retrieval, and executive function; Altered sleep patterns Endocrine ↓ Estrogen, testosterone, TSH, and DHEA-S levels; Altered insulin signaling
  7. Slide 7. Organ System Manifestations of Aging Gastrointestinal ↓ Motility of the large intestine; ↓ Vitamin absorption via active transport mechanisms; ↓ Splanchnic blood flow; ↓ Bowel surface area Genitourinary Vaginal atrophy due to decreased estrogen; Prostatic hypertrophy due to androgenic hormonal changes; Detrusor hyperactivity predisposing to incontinence Hepatic ↓ Hepatic size; ↓ Hepatic blood flow; ↓ Phase I (oxidation, reduction, hydrolysis) metabolism Immune ↓ Antibody production in response to antigens; ↑ Autoimmunity Oral Altered dentition; ↓ Ability to taste salt, bitter, sweet, and sour Pulmonary ↓ Respiratory muscle strength; ↓ Chest wall compliance; ↓ Arterial oxygenation with impaired CO₂ elimination; ↓ Vital capacity; ↓ Maximal breathing capacity; ↑ Residual volume
  8. Slide 8. Organ System Manifestations of Aging Renal ↓ Glomerular filtration rate (GFR); ↓ Renal blood flow; ↓ Filtration fraction; ↓ Tubular secretory function; ↓ Renal mass Sensory Presbyopia (reduced ability to focus on near objects); ↓ Night vision; Presbycusis (high-pitch, high-frequency hearing loss); ↓ Sense of smell and taste Skeletal ↓ Skeletal bone mass (osteopenia); Joint stiffening due to reduced water content in tendons, ligaments, and cartilage Skin/Hair Thinning of stratum corneum; ↓ Langerhans cells, melanocytes, and mast cells; ↓ Depth and extent of subcutaneous fat layer; Hair thinning and graying due to more hairs in resting phase and fewer melanocytes in hair follicles
  9. Slide 9. Human Aging And Changes In Drug PK & PD Parameters Aging results in several physiological changes that can affect the pharmacokinetics and pharmacodynamics of drugs. These changes may influence drug absorption, first-pass metabolism, protein binding, distribution, and elimination. Age-related changes in the gastrointestinal tract, liver, and kidneys include: These physiological alterations can modify drug response and increase the risk of adverse drug reactions in older adults. Gastrointestinal Changes Hepatic Changes Renal Changes 1. Reduced gastric acid secretion 2. Decreased gastrointestinal motility 3. Reduced total surface area for absorption 4. Reduced splanchnic blood flow 1. Reduced liver size 2. Reduced liver blood flow 1. Reduced glomerular filtration rate 2. Reduced renal tubular function
  10. Slide 10. Pharmacokinetic Phase Age-Related Changes in Pharmacokinetics Gastrointestinal Absorption Unchanged passive diffusion and no significant change in bioavailability for most drugs ↓ Active transport and ↓ bioavailability for some drugs ↓ First-pass metabolism leading to ↑ bioavailability for some drugs and ↓ bioavailability for some prodrugs Distribution ↓ Volume of distribution and ↑ plasma concentration of water-soluble drugs ↑ Volume of distribution and ↑ terminal disposition half-life (t½) for lipid-soluble drugs Hepatic Metabolism ↓ Clearance and ↑ t½ for some drugs with poor hepatic extraction (capacity-limited metabolism); Phase I metabolism affected more than Phase II ↓ Clearance and ↑ t½ for drugs with high hepatic extraction ratios (flow-limited metabolism) Renal Excretion ↓ Clearance and ↑ t½ for renally eliminated drugs and active metabolites ALTERED PHARMACOKINETICS
  11. Slide 11. ABSORPTION 1. Aging causes a delay in gastric emptying. 2. Gastric acid secretion is reduced in elderly individuals. 3. Splanchnic blood flow decreases with age. 4. These changes generally do not significantly affect the absorption of most drugs. 5. Some drugs, such as digoxin, may show slower absorption. 6. However, the overall extent of absorption remains similar to that in younger adults.
  12. Slide 12. FIRST PASS METABOLISM 1. After absorption, drugs pass through the portal circulation to the liver. 2. Many lipid-soluble drugs undergo extensive first-pass metabolism in the liver. 3. First-pass metabolism normally reduces systemic bioavailability. 4. In the elderly, even a minor reduction in first-pass metabolism can markedly increase drug bioavailability. 5. Impaired first-pass metabolism has been observed with drugs such as: Clomethiazole, Labetalol, Nifedipine, Nitrates, Propranolol, Verapamil 1. Increased bioavailability may enhance drug effects and toxicity. 2. Example: the hypotensive effect of nifedipine may become more pronounced in elderly patients. 3. Frail hospitalized elderly patients with chronic debilitating diseases may show an even
  13. Slide 13. Elderly patients generally exhibit increased distribution of lipophilic drugs, decreased distribution of hydrophilic drugs, and increased free concentrations of albumin-bound acidic drugs , necessitating careful dose selection and monitoring. Age-Related Change Effect on Drug Distribution Examples ↑ Body fat ↑ Vd of lipid-soluble drugs Diazepam, Thiopental ↓ Total body water ↓ Vd of water-soluble drugs Digoxin, Ethanol ↓ Serum albumin ↑ Free fraction of acidic drugs Warfarin, Furosemide /↑ α1-acid glycoprotein Slight ↓ free fraction of basic drugs Lidocaine ↓ Lean body mass Alters drug distribution and tissue uptake Various drugs DISTRIBUTION
  14. Slide 14. The age-related physiological changes which may affect drug distribution are 1. Changes in body composition a. reduced lean body mass b. reduced total body water c. increased total body fat d. lower serum albumin level e. α1 -acid glycoprotein level unchanged or slightly raised. 2. Effect on Volume of Distribution (Vd) A. Fat-Soluble (Lipid-Soluble) Drugs : Increased body fat increases the volume of distribution (Vd) of lipophilic drugs. These drugs may have: Longer half-life , Prolonged duration of action, Greater drug accumulation Examples: Clomethiazole, Diazepam, Desmethyldiazepam, Thiopental B. Water-Soluble Drugs: Reduction in total body water decreases the volume of distribution (Vd) of hydrophilic drugs. This may lead to: Higher plasma drug concentrations, Increased risk of toxicity Examples: Cimetidine , Digoxin, Ethanol
  15. Slide 15. 3. Effect on Plasma Protein Binding A. Albumin Binding 1. Acidic drugs primarily bind to plasma albumin . 2. Serum albumin levels decrease with age. 3. Reduced albumin leads to: a. Increased free (unbound) drug concentration b. Enhanced pharmacological and toxic effects Examples of acidic drugs affected: Cimetidine, Furosemide, Warfarin B. α1-Acid Glycoprotein Binding 1. Basic drugs primarily bind to α1-acid glycoprotein . 2. Levels remain unchanged or increase slightly with aging. 3. This may cause: a. Slight reduction in free drug concentration b. Usually minimal clinical significance Example: Lidocaine
  16. Slide 16. I. Hepatic Clearance in Older Adults 1. Hepatic clearance depends on: Hepatic blood flow (Q), Hepatic extraction ratio (E) Relationship: Where: ClH = Hepatic clearance, Q = Hepatic blood flow. E = Hepatic extraction ratio 1. Factors Affecting Hepatic Extraction 2. Liver size 2. Hepatic blood flow 3. Uptake into hepatocytes 4. Affinity of hepatic enzymes 5. Activity of hepatic enzymes 1. Age-Related Changes in the Liver 1. Reduction in Liver Size: With aging: Liver mass decreases progressively. Approximately 20–40% reduction occurs between the 3rd and 10th decades of life. 2. Reduction in Hepatic Blood Flow Hepatic blood flow decreases proportionally with liver size. Reduced blood flow decreases hepatic drug clearance. METABOLISM & ELIMINATION Age-Related Changes in Drug Metabolism and Elimination: Renal and Hepatic Clearance
  17. Slide 17. Effect of Aging on Hepatic Drug Elimination Age-related reductions in: ● Liver mass ● Hepatic blood flow result in: ● Reduced clearance of many hepatically metabolized drugs ● Increased plasma drug concentrations ● Prolonged half-life ● Greater risk of adverse effects Causes of Impaired Hepatic Clearance Primary Cause Morphological changes ● Reduced liver size ● Reduced hepatic blood flow These are more important than enzyme changes in healthy older adults. Secondary Cause Reduced enzyme activity Usually not significant in healthy elderly individuals. However, in frail or debilitated elderly patients: ● Plasma esterase activity may decrease. ● Hepatic glucuronyltransferase activity may decrease. This can further impair drug metabolism.
  18. Slide 18. A. Flow-Limited Clearance (High Extraction Drugs) Characteristics: ● High extraction ratio (E) ● Rapid metabolism by the liver ● Clearance depends mainly on hepatic blood flow Rate-limiting step: Hepatic blood flow Examples: Lidocaine, Propranolol, Morphine Effect of Aging: Reduced hepatic blood flow causes reduced drug clearance. B. Capacity-Limited Clearance (Low Extraction Drugs) Characteristics: ● Low extraction ratio (E) ● Clearance depends on: ○ Hepatic uptake ○ Enzyme activity ○ Enzyme affinity Relatively independent of hepatic blood flow Examples: Warfarin, Phenytoin, Theophylline Types of Hepatic Drug Clearance
  19. Slide 19. II. Renal Clearance in Older Adults 1. Age-Related Changes in Renal Function : These changes can reduce the elimination of many drugs and their metabolites. 1. ↓ Glomerular Filtration Rate (GFR) 2. ↓ Effective Renal Plasma Flow 3. ↓ Renal Tubular Function ● Healthy older adults consuming a high-protein diet may maintain GFR values similar to younger adults. ● Declines in renal function may be more related to: Hypertension, Heart disease , Other comorbid illnesse ● Because renal function varies greatly among older adults: 1. Drug doses should be individualized. 2. Renally excreted drugs may accumulate and cause toxicity. 3. Careful monitoring is required, especially for drugs with a narrow therapeutic index.
  20. Slide 20. 1. Drugs Requiring Dose Reduction A. Drugs with a Narrow Therapeutic Index Dose reduction is often necessary because even small increases in concentration can cause toxicity. Examples: Digoxin Aminoglycosides (Gentamicin, Amikacin) B. Drugs with a Wide Therapeutic Index Dose adjustment may not always be required. Example: Penicillins 1. D rugs to Avoid in Severe Renal Impairment: Increased risk of drug accumulation and toxicity. Avoid if Creatinine Clearance < 30 mL/min: Colchicine, Cotrimoxazole, Glyburide, Nitrofurantoin, Probenecid, Spironolactone, Triamterene 1. Drugs Requiring Dose Adjustment in Renal Impairment The following medications require dosage reduction in older adults with reduced renal function: Acyclovir, Amantadine , Ciprofloxacin , Gabapentin, Memantine, Ranitidine, Valacyclovir 1. Active Metabolites that Accumulate with Reduced Renal Function : S ome drugs undergo hepatic metabolism but produce active metabolites that are primarily eliminated by the kidneys. Reduced renal function leads to accumulation of these metabolites. May result in: Prolonged drug action , Increased adverse effects, Drug toxicity Example : Procainamide → N-acetylprocainamide (NAPA)
  21. Slide 21. II. Estimation of Renal Function 1. Creatinine Clearance (CrCl) 1. Creatinine clearance is commonly used to estimate renal function. 2. It serves as a practical guide for drug dosage adjustments. 3. Although not perfectly accurate, it remains the standard method used in clinical practice. 2. Cockcroft–Gault Equation The Cockcroft–Gault equation is the most commonly used method for estimating creatinine clearance in adults with stable renal function. Formula For women: ● Multiply the calculated value by 0.85 Units: mL/min ● Current dosing guidelines for renally eliminated drugs continue to rely on Cockcroft–Gault estimated creatinine clearance. ● It remains the recommended method for renal drug dosing in older adults.
  22. Slide 22. ALTERED PHARMACODYNAMICS Older adults generally exhibit: Altered drug responses, Increased drug sensitivity, Greater susceptibility to adverse drug reactions I. Mechanisms of Altered Pharmacodynamic Response A. Changes in Drug Concentration at the Receptor Site ● Different amounts of drug may reach receptor sites. ● This can alter the intensity of the drug response. B. Changes in Receptor Numbers ● Aging may increase or decrease the number of receptors available for drug binding. ● This alters tissue responsiveness to drugs. C. Changes in Receptor Affinity ● Receptors may bind drugs more or less strongly. ● This can enhance or reduce drug effects. D. Post-Receptor Alterations ● Changes may occur in intracellular signaling pathways after receptor activation. ● Drug responses may be amplified or diminished despite normal receptor binding. E. Impairment of Homeostatic Mechanisms ● Aging reduces the body's ability to maintain physiological balance. ● Older adults are less able to compensate for drug-induced changes.
  23. Slide 23. 3. Reasons for Different Drug Responses in Older Adults Differences in pharmacodynamic responses may result from: A. Altered Sensitivity ● Greater drug effect for a given drug concentration. ● The same dose may produce a larger response than in younger adults. B. Differences in Baseline Performance ● Physiological reserve declines with age. ● Drug effects become more pronounced because baseline function is reduced. C. Differences in Drug Concentration at the Site of Action ● Drug concentrations reaching receptors may differ between young and older individuals.
  24. Slide 24. Increased Sensitivity of the Central Nervous System (CNS) Older adults are particularly sensitive to the CNS effects of medications. I. Age-Related CNS Changes 1. Structural Changes : Decrease in brain size , Decrease in brain weight 2. Neurotransmitter Changes : Alterations in several neurotransmitter systems occur with aging. 3. Increased CNS Drug Penetration : Some drugs may cross the blood-brain barrier more readily in older adults. II. Age-Related Changes in the Dopaminergic System Several changes occur in dopamine pathways with aging: ↓ Dopamine transporter levels ↓ Number of dopaminergic neurons ↓ Density of dopamine receptors These changes contribute to: 1. Increased sensitivity to antipsychotic drugs 2. Greater risk of extrapyramidal symptoms 3. Increased risk of sedation and cognitive impairment
  25. Slide 25. Age-Related Cardiovascular Changes Aging causes multiple structural and functional changes in the cardiovascular system: 1. Reduced baroreceptor sensitivity 2. Reduced cardiac reserve 3. Increased arterial stiffness 4. Reduced autonomic responsiveness These changes predispose older adults to altered responses to cardiovascular drugs. Orthostatic Hypotension : A sudden drop in blood pressure upon standing. Why It Occurs More Frequently Due to: Impaired autonomic responses , Reduced baroreceptor reflexes, Decreased cardiovascular reserve Clinical Consequences: Dizziness, Falls, Syncope, Fractures
  26. Slide 26. Drug/Class Age-Related Pharmacodynamic Change Clinical Consequence Benzodiazepines Increased sensitivity Sedation, falls Opioids Increased sensitivity Respiratory depression, delirium Antipsychotics Increased sensitivity Extrapyramidal effects, sedation Anticholinergics Increased sensitivity Cognitive impairment, delirium Lithium Increased sensitivity Neurotoxicity Calcium channel blockers Increased hypotensive and bradycardic effects Dizziness, syncope β-Blockers Reduced BP response Reduced effectiveness Diuretics Reduced effectiveness Less predictable response Warfarin Increased sensitivity Increased bleeding risk
  27. Slide 28. Drug-Related Problems in Older Adults ● Medications play an important role in improving the Health-Related Quality of Life (HRQOL) of older adults. ● However, drug therapy can also lead to significant negative outcomes. ● Many drug-related problems in older adults are preventable through careful prescribing, monitoring, and medication review. Major Drug-Related Problems in Older Adults Three important and potentially preventable negative outcomes are: 1. A dverse Drug Withdrawal Events (ADWEs) 2. Therapeutic Failure 3. Adverse Drug Reactions (ADRs) Why Older Adults Are Particularly Vulnerable Older adults often have: 1. Multiple chronic diseases 2. Polypharmacy 3. Reduced renal and hepatic function 4. Altered pharmacodynamics 5. Cognitive impairment 6. Increased susceptibility to medication errors These factors increase the likelihood of drug-related problems.
  28. Slide 29. Drug-Related Problem Definition Example Adverse Drug Withdrawal Event (ADWE) Symptoms occurring after stopping a drug Rebound hypertension after stopping β-blockers Therapeutic Failure Failure of drug therapy to achieve desired outcome Uncontrolled hypertension due to inadequate treatment Adverse Drug Reaction (ADR) Harmful and unintended effect at normal doses Bleeding with warfarin
  29. Slide 30. Feature Adverse Drug Withdrawal Events (ADWEs) Therapeutic Failure Adverse Drug Reactions (ADRs) Definition Problems that occur when a drug is suddenly stopped or reduced. Drug therapy fails to achieve the desired effect. Harmful and unintended effects of a drug at normal doses. Main Causes • Sudden drug withdrawal • Rapid dose reduction • No proper tapering • Wrong drug • Low dose • Poor adherence • Drug interactions • Polypharmacy • Multiple diseases • Age-related changes in the body Examples • Benzodiazepine withdrawal • Rebound hypertension • Rebound angina • Opioid withdrawal • Uncontrolled hypertension • Failure to prescribe anticoagulants • Antibiotic treatment failure • Warfarin-induced bleeding • Hypoglycemia • Falls due to sedatives • Delirium Consequenc es • Return of symptoms • Discomfort • Hospitalization • Disease progression • Increased illness • Hospitalization • Functional decline • Hospitalization • Increased mortality Prevention • Taper drugs gradually • Monitor during withdrawal • Review medications regularly • Use correct drug and dose • Start low, go slow • Monitor for side effects • Regular medication review
  30. Slide 31. Risk Factors for Drug-Related Problems in Older Adults Older adults are at increased risk of drug-related problems because of multiple diseases, age-related physiological changes, and the frequent use of medications. The major risk factors include: 1. Polypharmacy The concomitant use of multiple medications. OR The use of more medications than are clinically indicated. ● Polypharmacy is common and increasing among older adults. ● Community-based surveys show that older adults take an average of: 2–10 prescription and nonprescription medications daily. ● Use of dietary supplements further contributes to polypharmacy: Herbal products, Vitamins, Minerals ● Consequences of Polypharmacy : Adverse Drug Reactions (ADRs), Geriatric Syndromes - Falls, Cognitive impairment, Delirium, Frailty, Medication Nonadherence, Functional Decline, Increased Healthcare Costs
  31. Slide 32. 2. Inappropriate Prescribing Prescribing medications outside accepted medical standards. OR Prescribing drugs whose risks outweigh their potential benefits. Common Forms of Inappropriate Prescribing 1. Incorrect Dose 2. Excessive Duration 3. Therapeutic Duplication 4. Drug Interactions 5. High-Risk Medications 3. Underuse of Medications Underuse is: Failure to prescribe medications that are indicated for treatment or prevention of disease. This represents an important but often overlooked drug- related problem. Consequences of Underuse 1. Disease progression 2. Increased morbidity 3. Poor clinical outcomes 4. Increased hospitalization E xamples of Underuse ● Failure to prescribe anticoagulants in atrial fibrillation ● Failure to prescribe ACE inhibitors in heart failure ● Failure to prescribe bisphosphonates in osteoporosis
  32. Slide 33. 4. Medication Nonadherence The extent to which a person's behavior does not correspond with agreed recommendations from a healthcare provider. Factors Contributing to Nonadherence A . Patient-Related Factors B. Condition-Related Factors C. Therapy-Related Factors D. Health-System and Social Factors Consequences of Nonadherence Therapeutic failure Disease progression Increased hospital admissions Increased healthcare costs Reduced quality of life Why Older Adults Become Nonadherent 1. Older patients may fail to follow prescribed regimens because of: 2. Fear of adverse effects 3. Complex medication schedules 4. Difficulty understanding medication instructions 5. Cognitive decline 6. Physical limitations (e.g., poor vision, arthritis) 7. Cost of medications
  33. Slide 34. Assessment Tools STOPP Criteria Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) Used to identify: ● Potentially inappropriate medications ● Drug interactions ● Therapeutic duplication ● Excessive treatment duration ACOVE Criteria Assessing the Care of Vulnerable Elders (ACOVE) Identifies underuse of important therapies such as: ● Bisphosphonates ● Anticoagulants ● Antiplatelet agents ● ACE inhibitors ● β-blockers START Criteria Screening Tool to Alert Doctors to Right Treatment (START) Focuses on identifying omissions of beneficial medications. Particularly useful for diseases involving: Cardiovascular system, Respiratory system, Endocrine system
  34. Slide 35. Provision of Comprehensive Geriatric Assessment (CGA) Comprehensive Geriatric Assessment (CGA) is a systematic approach used to identify, prevent, and manage drug-related problems in older adults and optimize medication use.
  35. Slide 38. References :- ● Pharmacotherapy, A Pathologic Approach by J.Dipiro ● Clinical Pharmacy and Therapeutics by Roger Walker

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