Geriatric Pharmacotherapy PDF

**GE** **RIATRICS** **\ ** **Geriatric Pharmacotherapy** **Introductory Case** - 71 YO white female, fasting glucose 280 mg/dL, HbgA1c = 11.2% with symptomatic polyuria and polydipsia Therapy: - 1200 cal/day diet - 98 U NPH before breakfast, 60 U NPH before dinner - Glyburide...

**GE** **RIATRICS** **\ ** **Geriatric Pharmacotherapy** **Introductory Case** - 71 YO white female, fasting glucose 280 mg/dL, HbgA1c = 11.2% with symptomatic polyuria and polydipsia Therapy: - 1200 cal/day diet - 98 U NPH before breakfast, 60 U NPH before dinner - Glyburide 20 mg/day - Metformin 2000 mg/day - What is the HgbA1c treatment goal? 7-8 % - What key assumption is made when setting treatment goals for chronic medical conditions? **Controlled in \~ 1 year; decrease risk of organ damage** - What would be the treatment goal if this 71 YO had a life expectancy of 3 years? **Assuming short life expectancy -- prevent polyuria/polydipsia** - After achieving the treatment goal, glyburide was discontinued, why? **Prolonged activity and risk of hypoglycemia** **Introduction** - Sub-populations: - Age strata: 60-70, 71-80, 81-90, \>90 - Health and functional status: frail vs non-frail older adult - Living or caregiving environment - Community-dwelling, assisted living, comprehensive care - Dependent, independent - Older adults currently make up 13% of the US population but use 33% of prescription medications - Those aged \> 75 years are the fastest growing segment of the US population - Women have longevity, accounting for larger proportions of older adults - 67% of those aged \> 85 years are women - By 2040, it is projected that older adults will be 20% of the population - By 2050, at least ½ of Americans will expect to survive with 85^th^ birthday - Greater risk of death from CHRONIC diseases rather than acute diseases - Role of pharmacists when caring for older adults - Retail pharmacy - Decrease burden of trips to pharmacy - Reimbursement - Vaccines - Ambulatory Care Pharmacy - **Long Term Care (LTC)** - Support providers (MD, NP, PA) to answer questions about medications (legal requirements) - Consult on medication regimens, recommend initiation or adjustments of medications based on clinical data - Review medication administration, patient charts, medication storage at monthly or 3-month intervals - Serve as a provider with prescriptive authority - Supply, distribute, secure medications for short-stay (rehab), assisted living, and long-stay/permanent residents - Identify unnecessary medication, adverse drug reactions, and drug interactions - Review length of therapy, MAR for appropriate administration and use of PRN - Ensure appropriate monitoring of drug therapy - Gradual dosage reduction of psychiatric meds - Provide education to staff as needed - **Sample communication** - Often multiple copies (chart, provider, pharmacist records) - Identify, explain drug therapy problem - Recommend action - Physician/provider response - Pros: - Flexible aging - Work independently and with multiple disciplines at a variety of facilities - LTC regulations clearly describe role of pharmacist - Educational component for facility staff - Cons: - Significant travel time - Rely on facility staff for follow-up - Communication with providers often written, asynchronous - Frustration when recs not accepted - Limited patient interaction **Health Aging** - Defined as "the process of developing and maintain the functional ability that enables wellbeing in older age" - Functional ability is about having the capabilities to engage in activities one values - **Mental Health**: prevent or treat mood disorders & cognitive impairment - **Nutritional Health**: prevent or treat deficiencies, diabetes - **Cognitive Health**: education, cognitively stimulating exercises, social activities - **Stable housing** - **Physical health** - **Access to health care** (preventive) **Common Geriatric 'Syndromes'** +-----------------+-----------------+-----------------+-----------------+ | - Sensory | - Incontinenc | - Constipatio | - Poor | | impairment | e | n | nutrition | | (vision and | | | | | hearing) | | | | +=================+=================+=================+=================+ | - Depression | - Insomnia | - Poverty/inc | - Falls | | | | ome | | | | | generation | | +-----------------+-----------------+-----------------+-----------------+ | - Delirium | - Dementia | - Weakness/fa | - Immobility | | | | tigue | | +-----------------+-----------------+-----------------+-----------------+ **Goals of Care for Older Adults** - Maintain independence (daily activities, finances, transportation) - Avoid need for institutionalization - Maintain Quality of Life (QOL) - Maintain functional ability - Activities of Daily Living (ADLs) - Dressing, bathing, transferring, feeding, toileting, walking/ambulation - Instrumental Activities of Daily (IADLs) - Handling finances, shopping for groceries, meal preparation, using a telephone, housekeeping/laundry, handling medications, using transportation **Risk Factors for Functional Decline** - Age - Immobility/exercise intolerance - *Older adults should continue moving* - *Prevent muscle atrophy* - Poor muscle strength - Poor balance - Malnutrition, weight loss - Hospitalizations (esp. longer) - Morbidity from chronic disease - Cognitive impairment - Depression **Medications and Risks of Falls** - Sedative/hypnotics - Neuroleptics/antipsychotics - Antidepressants - Opioids (esp. long-acting) - Loop diuretics - Alpha-blockers **Medication Problems in the Older Adult** - Age-related increase in chronic conditions = higher medication use - 76% of seniors take at least 3 medications daily - 2/3^rd^ take non-prescription (OTC) in addition to prescription medications - 34% take 8 or more medications daily - May translate to 8-20 doses/tablets daily - 'Successful aging' causes this number to increase with advancing age, disease, and treatments available - Polypharmacy - Medications without indication - Medications treating ADR - 60% understand medications well, leaving 40% that need our attention - Nonadherence - Over 200 barriers to adherence (aging not one) - Altered pharmacokinetics **Physiologic Changes Associated with Aging** - Decreased TBW - Decreased lean body mass - Increased body fat - **Decreased baroreceptor response/activity** - **Reduced heart rate variability** - Decreased hepatic blood flow - Decreased renal blood flow - Decreased neurotransmitter volume (sensitivity to CNS adverse effects) **Pharmacokinetic Changes with Aging** - Generally, no change in bioavailability of most drugs (but slower Tmax) - Decreased V~d~ and increased concentration of water-soluble drugs (atenolol) - Increased V~d~ and increased half-life of lipid-soluble drugs (rifampin) - Decreased clearance and increased half-life of most hepatically cleared drugs (propranolol) - Decreased clearance and increased half-life of most renally cleared drugs (atenolol) **BEERS Criteria** - Criteria for ***potentially*** inappropriate medication use in **older** adults (age 65 years and older) - Generated by an interdisciplinary panel within the American Geriatrics Society - Evaluates risks of medications against benefits with specific considerations for older people - Medications with anticholinergic properties - Focus on risk of cognitive impairment - Sedatives, medications with CNS effects (falls, dizziness) - Diabetic agents: sliding scale insulin, long-acting SU - Medications that may exacerbate chronic conditions (Heart Failure) - Questions to review while reviewing medications: 1. How are decisions about recommendations decided? 2. Who is involved in the decision-making process? 3. What types of evidence/literature are evaluated? 4. How does the committee describe quality of evidence and strength of recommendation? - [Medication Alternatives ] - **Anticholinergics**: Several, indication-specific - **Sedatives**: Non-pharmacologic, other treatments for anxiety - **Sulfonylureas**: Shorter-acting agents, relaxed treatment targets **Recommendations for Rational Prescribing** - **Recognize new symptoms as potential adverse reactions** - Optimize non-pharmacologic treatment options - Support behavior change - Make single changes at a time - Align medication use with patient values - Minimize regimen (deprescribe) and promote adherence) - Avoid medications (whenever possible) with high risk of adverse events and modest benefit - Considerations in choosing medications - Life expectancy - Goals of care - Treatment targets - Time required to benefit - DCCT trials for tight control of FBG - Bisphosphonates in osteoporosis - Review dose and frequency against renal and hepatic function - Define reasonable targets for chronic disease - **Know when to back off** - Use available tools (Beers, others) to identify medications with risk \> benefits - Recognize medications more likely to cause harm than benefits - Become familiar with deprescribing tools - Ask when is it appropriate to stop a medication **Deprescribing** - Definition: The supervised process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes - Align medication use with priorities, multiple stakeholders to support changes, incorporation of safer alternatives, maintain symptom/management **Progressive Disease and End of Life** - Palliative Care: after diagnosis of terminal illness, **disease not responsive to curative treatment or treatment doesn't exist** - Medical, psychological, social, spiritual care for patient and family - Optimize **quality of life** (QOL), focus on symptoms only, not life-prolonging - Stop medications not improving QOL - Hospice Care: provided at home, in LTC, or independent facility - Life expectancy of **6 months or less**, certified by MD - Home or institution-based, interdisciplinary - Diagnostic tests, hospitalizations, labs no longer covered - End of Life Care - Interdisciplinary +-----------------------+-----------------------+-----------------------+ | - Physician (Board | - Nurse/NP | - Social worker | | certification | | | | available) | | | +=======================+=======================+=======================+ | - Pharmacist | - Nutritionist | - Massage therapist | +-----------------------+-----------------------+-----------------------+ | - Home health aid | | | +-----------------------+-----------------------+-----------------------+ - Key role of pharmacists - Align medications with goals (appropriateness) - Ensure effective control of bothersome symptoms - Educate family and providers of medication regimen - Active non-standard dosage form if needed - Support financial concerns - Ensure safe and legal disposal of medications - **Common conditions and symptoms that may be managed** +-----------------------+-----------------------+-----------------------+ | - Pain | - Anxiety | - Insomnia | +=======================+=======================+=======================+ | - Difficulty | - Fatigue | - Constipation/diar | | swallowing | | rhea | +-----------------------+-----------------------+-----------------------+ | - Bowel obstruction | - Delirium | - Dyspnea | +-----------------------+-----------------------+-----------------------+ | - Nausea/vomiting | - Edema | - Dry mouth | +-----------------------+-----------------------+-----------------------+ | - Restlessness | - Respiratory | | | | congestion | | +-----------------------+-----------------------+-----------------------+ - Paths to death: varied and unpredictable - Contradicts what may perceive - Planning ahead can mean better QOL - Evidence shows that palliative care: - Reduces burden of treatment - Reduces transitions, time in acute care settings - Optimizes comfort measures -- better pain management - Greater family satisfaction with care - Advanced Care Directives (ACD) - Verbal and written instructions about future medical care and treatment - Elective, do not take away your right to make current care decisions - May differ from state to state - Include: - **Health Care Representative**: Names someone to make decisions if you are unable (or prevents someone from making decisions for you) - **Psychiatric**: Sets preferences re: mental illness during periods of incapacity - **Power of Attorney**: Financial or Health Care grants power to other you choose - **Physician Orders for Scope of Treatment (POST)** - Legal document declaring: - A: Preferences for resuscitation - B: Medical interventions (intubation, dialysis, hospitalization) - C: Antibiotics - D: Artificial nutrition - Agreement between patient (or legal guardian) and physician - Must be signed and dated to be valid **Communicating with Older Adults** - Recognize higher likelihood of impairment and morbidity, **BUT... avoid stereotyping** - Engage in shared decisions, invite sharing of treatment goals, priorities - Speak to the patient, but mind the caregiver if present - Sensory impairment: May talk louder, slower pace - Slower processing speed: allow time to respond, give options for care - Be supportive in difficult conversations - Align recommendations with goals - Geriatric leaders prefer: "older adult" over "elderly", "the aged", and "seniors" as culturally-appropriate terminology -  **Summary** - The principles of pharmaceutical care of older adults are not particularly different than others - Require personalization to comorbidities, time to benefits and risk, and quality - Sensitive to higher risks, and recognize when benefits may not be realized - Consider comorbidities and life expectancy when managing chronic disease **Urinary Incontinence** - Involuntary leakage of urine - Overactive bladder (OAB) - Affects up to 30% of community-dwelling and hospitalized older adults, and approximately 60% of LTC patients - More common in females than males - Symptoms - Loss of independence: loss of physical, social activity - Lack of self-esteem: Depression & anxiety - Medical complications - **[Normal Bladder Function ]** 1. Stretch receptors notify brain that bladder is full and needs to empty a. **B3 receptors support detrusor relaxation/filling** 2. Neurologic stimulation initiates contraction b. ACh receptors in the dome (top) c. Alpha-adrenergic receptors in the base and proximal urethra 3. Sphincter relaxes allowing release of urine - Age-related changed to the bladder and urethra: - Decreased bladder capacity/elasticity - Increased spontaneous detrusor contractions - Decreased sphincter compliance - May result in: - Incomplete bladder emptying - Decreased ability to postpone urination **Overactive Bladder -- Urge Urinary Incontinence** - Hyperactivity of detrusor muscle causes sudden and poorly predictable voiding - May cause large or small volume 'accidents' - Symptoms include - **Urgency:** Unpredictable or unable to control - **Frequency:** Seemingly excessive feelings of urination - Causes can be neurologic or medications - Acetylcholinesterase inhibitors for Alzheimer's disease - **Treatment:** - **Anticholinergics/antimuscarinic** - Oxybutynin (Ditropan) - If using patch q3-4d rotate - Tolterodine (Detrol) - Clinically similar to Oxybutynin - Solifenacin (Vesicare) - Selective to M3 receptor - Darifenacin (Enablex) - CYP2D6 inhibitor, CYP3A4 sub - Trospium (Sanctura) - Decreased food absorption (\~75%) - Festoterodine (Toviaz) - Prodrug, CYP3A4 substrate - Cheapest treatment option - AE: **Dry mouth, constipation**, fatigue, confusion, tachycardia - **B3 agonist** - Mirabegron (Myrbetriq) - Minor increase in BP, UTI - Vibegron (Gemtesa) - Minor UTI - Most expensive treatment option - **Injections/surgery** - Clinical: - Time to benefit of medications approximately 4 weeks - Active drug: 50% reduction vs placebo: 30% reduction - \~65% experience an AE - Stopping abruptly may result in accidents/episodes that are worse than baseline - Administration: - Do not split or crush oral tablets - Patch applied twice weekly, rotating sites (remove prior patch) - **Example Case**: Mr. Smith is diagnosed with urge UIU and is considering a medication after incorporating non-pharmacologic therapy. At baseline they have 5 accidents/episodes per day. **How would you translate benefits of a medication in a way the medication understands** - Help reduce number of daily episodes to at least 2-3 - Risks: - 2/3^rd^ experience a side effect in the short-term (most often mild) - ? long-term side effects - Costs: \$50-500/month **Stress Urinary Incontinence** - Outlet incompetence (external urethral sphincter) with abdominal pressure - Women \> men - Most often small volume of 'accidents' - Risk factors include multiple childbirths, estrogen deficiency - Can be exacerbated or caused by alpha-antagonists - Symptoms (small volume urine loss) classically associated with: - Cough - Drinking - **Treatment:** - **Non-pharmacologic management:** Kegel - **SNRI --** Duloxetine 40 mg BID - Increased sphincter tone to prevent leaks - **Estrogen (topical) --** vaginal atrophy - Estrogen vaginal cream - Intravaginal cream inserted via applicator - 21 days on, 7 days off - **Alpha-agonists** (rare -- pseudoephedrine) - **Injection/surgery** **Overflow Incontinence** - Results from outlet obstruction or inability to or uncoordinated detrusor construction - Most commonly from BPH or prostatic blockage or urethra - Urine builds up in the bladder - Symptoms: - Abdominal discomfort or pain - Frequency - Feeling the need to urine shortly after urination - **Treatment:** - **Address the obstruction** - **Alpha-adrenergic blockers (if BPH)** - Doxazosin 1-4 mg daily - Tamsulosin 0.4 mg once daily - Slightly more selective for bladder neck subtypes of alpha receptors - Less hypotension - **Catheterization** - **Intermittent straight --** rubber latex, silicone, or PVC - A diagram of a uterus Description automatically generated - **Indwelling (Foley) --** Chronic -  - **Condom catheter** - A diagram of a condom attached to a person\'s thigh Description automatically generated - **Suprapubic** -  **Neurogenic (Atonic) Bladder** - Disruption in neurologic innervation of the bladder - Inability or uncoordinated detrusor constriction - May also be atony of bladder muscle: stroke, spinal cord injury, neuropathy (including severe uncontrolled diabetes) - Symptoms: - Small urine volume during voiding, small volume 'accidents' - Loss of feeling that bladder is full - Dribbling of urine - Frequency, urgency - Increases risk of UTI and kidney stones - **Treatment:** - **Non-pharmacologic management:** Scheduled voiding - **Injections or surgery** - Intermittent catheterization (thin, flexible tubes collecting urine) - Botulinum A toxin (Botox) injections (bladder or urinary sphincter) - Augmentation cystoplasty: bladder walls & intestinal walls connected to improve storage capacity **Functional Incontinence** - Inability to get to the bathroom in a timely fashion - Causes - Physical impairment (mobility) - Change in mental status (dementia) - UTI - Medications (sedating) - Medication Causes: - Frequency: - Diuretics - Alpha antagonists - Urgency: - Acetylcholinesterase inhibitors - Overflow: - Alpha antagonists - Antihistamines **Urinary Incontinence Treatment** - **Should be provided for all types of urinary incontinence** 1. Scheduled/timed voiding 2. Pelvic floor muscle strengthening (Kegel): 30-60x/day 3. Avoiding irritants a. Coffee, alcohol, caffeine (including teas and sods) b. Avoid water before bed 4. Absorbent products (pads, shields, adult diapers) 5. Catheters - Monitoring - Review efficacy after 4 -- 8 weeks - Monitor consistently for adverse events - Most are dose-dependent - Medications largely studied only up to 6 months, unclear risk/benefit profile with long-term use, consider deprescribing/discontinuing **Coagulation Disorders** **\ Hemostasis and Platelet Function** **Normal Homeostasis** - Hemostasis: Arrest of bleeding from a damaged blood vessel - Coagulation: Multi-step process to "plug" the leaking vessel - Phases of Hemostasis 1. Injury to blood vessel 2. Vasospasm bleeding 3. Platelet plug formation 4. Fibrin clot formation a. Prothrombin Thrombin allows fibrinogen to convert to fibrin i. Leads to platelet adherence and aggregation 5. Fibrinolysis b. Plasminogen Plasmin allows fibrin to convert to split products **Deadly Duo -- Atherosclerotic Plaque and Thrombosis** -  **Platelet Formation from Megakaryocytes** 1. The immature megakaryocyte contains a nucleus and some granules 2. The cell undergoes nuclear endomitosis, which means the nucleus divides without the cell dividing. The cell grows in size, organelles and granules are produced, and a structure called the centrosomal microtubule array forms 3. The cell then changes shape and forms pseudopods (finger-like extensions). Microtubules (tiny tubes that help the cell maintain its shape) move to the cell cortex, preparing the cell for platelet production 4. The protrusions, called proplatelets, elongate and branch out due to the sliding of the microtubules. Granules and organelles are transported along these proplatelets towards their ends. 5. The proplatelets continue to elongate and branch out until individ ual platelets are released. The **nucleus, now extruded and no longer needed**, is left behind as the rest of the cell's cytoplasm turns into platelets. **Platelet Adhesion & Shape Change** 1. Adhesion: Upon exposure to [collagen], the **Von Willebrand Factor (vWF)** binds to exposed collagen, and platelets attach through their **Glycoprotein Ib (GPIb)** 1. Platelets also bind directly to collagen via **GP1a** receptors. 2. Secretion: The platelets then release **ADP, TXA~2~, and 5-HT**, promoting the activation of other platelets and causing them to stick together. 2. **TXA~2~ and 5-HT** are potent vasoconstrictors 3. Platelet Aggregation: Activated platelets express **GP IIb/IIIa** receptors, which binds fibrinogen, forming bonds between platelets leading to their [aggregation]. 4. Clotting factor, **Factor Xa**, becomes activated and converts prothrombin to thrombin 3. Thrombin then converts fibrinogen to fibrin stabilizing the platelet plug 5. **Prostacyclin (PGI2),** produced by endothelial cells (EC) inhibits platelet activation to prevent excessive clotting (thrombogenesis) 6.  **Antiplatelet Drugs** **COX-1 Inhibitors** - **Aspirin** - Inhibition of TXA~2~ synthesis in platelets is key to anti-platelet activity - A chemical structure with letters and numbers Description automatically generated - Irreversible inhibition by acetylation of COX-1 - Permanent loss of platelet COX-1 activity -- Decreases **[TXA~2~ ]** - Maximally effective at doses of 50 -- 320 mg per day - **[Prostacyclin (PGI2)]** production in tissue inhibited by higher doses - [Indications] -- **"prophylaxis and treatment of atrial thromboembolic disorders"** - Prevent coronary thrombosis in unstable angina - Adjunct to thrombolytic therapy - Reducing recurrence of thrombotic stroke - [Clinical Actions] - Prolongs bleeding time, but no increase in PT time - Hemostasis returns to normal 36 hours after last dose - [Side Effects ] - Upper GI bleeding - Due to inhibition of **COX**1 mediated prostaglandins are need for gastric mucosa production - Risk increases with age, concurrent use of NSAIDs and/or alcohol - Acute Aspirin overdose - Can be induced by doses above 150 mg/kg - Doses \>500 mg/kg can be fatal - Symptoms: NVD, Fever, Coma - Inhibits platelet COX-1 by acetylation - Interferes with platelet aggregation - Prolongs bleeding time - Prevents arterial thrombi formation - Selective COX inhibitor - **The GOOD: [COX-2 ]**produces prostacyclin in endothelial cells *vasodilation and inhibition of platelet aggregation* - **The BAD: [COX-1 ]**produces thromboxane A~2~ in the platelets *vasoconstriction and platelet aggregation* - **The UGLY:** Selective **[COX-2]** inhibitors blocks synthesis of prostacyclin while not preventing synthesis of **[TXA~2~]** **[INCREAED CV RISK]** 1. Before injury a. Healthy, intact endothelium releases **prostacyclin (PGI~2~)** into plasma b. PGI~2~ binds to platelet membrane receptors causing synthesis of cAMP c. cAMP inhibits release of granules containing aggregating agents 2. After injury d. Thrombin, **thromboxane A~2~** and exposed collagen cause release of arachidonic acid from platelet membrane e. Thromboxane A~2~ is synthesized from arachidonic acid and released from the platelet f. This pathway is inhibited by [aspirin] 3. Thromboxane A~2~ binds to receptors on other platelets thereby initiating release of additional aggregating agents 4. Balance between levels of prostacyclin and thromboxane A2 influences whether platelet aggregates or circulates freely **ADP Receptor Inhibitors** - 2 ADP receptors are involved in activating platelets - **P2Y~1~** -- Coupled to G~q~ -- PLC -- IP3 -- Ca^2+^ - pathway - **P2Y~12~** -- Coupled to G~i~ and inhibition of adenylyl cyclase -  - ⍺1 cAMP Platelet activation (via VSAP and PKA) Stabilization of platelet aggregation - **[Thienopyridine class of ADP receptor inhibitors (Pro-drugs) ]** - **Tioclopidine (Ticlid)** - A chemical formula of a molecule Description automatically generated - **May induce thrombotic thrombocytopenia purpura (TTP)** - **Incudes abs against ADAMTS13 (protease that cleaves circulating vWF) decreasing proteolytic activity** - **Spurious and excessive platelet aggregation** - **Depletion of platelets, hemolytic anemia, renal impairment, neurological symptoms, fever** - **Can be fatal** - **Clopidogrel (Plavix)** - A chemical formula of a molecule Description automatically generated - Lower toxicity profile -  - Taken orally to reduce platelet aggregation - **Irreversibly block ADP receptor on platelet and subsequent activation of GPIIb/IIIa complex** - Action lasts for several days after last dose - Use: Acute coronary syndrome, **recent MI, stroke, established peripheral vascular disease & coronary stent procedures** - **Prasugrel (Effient)** - A chemical structure with letters and numbers Description automatically generated - Approved for treatment of Acute Coronary Syndrome; percutaneous coronary intervention (PCI). Taken orally - **[Prodrug]** requiring esterase's + CYP3A4/2B6 to generate active metabolite -  - Irreversibly binds P2Y~12~ receptor - **High risk of bleeding -- not recommended in elderly, or before CABG** - **Ticagrelor (Brilinta)** - A structure of a chemical formula Description automatically generated - Used in Acute Coronary Syndrome, PCI -- taken orally - Binds to an allosteric site, binding is reversible - Does [not] require bioactivation by metabolic enzymes (**CYP3A4 substrate**) - Fast onset of action compared to clopidogrel, T~1/2~ 7-9 hrs - **Risk of bleeding -- don't use immediately before CABG** - **Cangrelor (Kangreal)** -  - Used as an adjunct to PCI -- given I.V. - Reversibly inhibits P2Y~12~ receptors - Does [not] require bioactivation by metabolic enzymes - Fast onset of action/short T~1/2~ (3-5 min) - **Activation of both is required for platelet activation by ADP** - **Blockers of GPIIb/IIIa receptors** - Mechanism - Inhibits fibrinogen crosslinking of platelets -  - **Abciximab (ReoPro)** - A chimeric mouse-human **monoclonal antibody** directed against the human GPIIb/IIIa - Inhibits platelet aggregation - Administered IV bolus, followed by infusion - Long duration of action -- increased risk of bleeding - Use: Prevent thromboembolism in coronary angioplasty - Combined with t-PA for early treatment of acute MI - **Eptifibatide (Integrilin)** - A chemical structure with red circle around it Description automatically generated - A synthetic peptide which selectively blocks GPIIb/IIIa in a reversible manner - Cyclic heptapeptide derived from rattlesnake venom - Inhibits fibrinogen binding to decrease platelet aggregation - Administration by IV bolus, followed by infusion up to 72 hours - Short duration of action: 6-12 hours - Use: To prevent thromboembolism in unstable angina & angioplastic coronary procedures - **Tirofiban (Aggrastat)** -  - A nonpeptide tyrosine analogue which is specific for the GPIIb/IIIa and inhibits fibrinogen binding - Administered IV in dilute solution (10-25 µg/kg initial) - \> 90% inhibition of platelet aggregation after 30 min infusion - 2 hr plasma half life - **Combined with heparin to treat Acute Coronary Syndrome** **Phosphodiesterase-3 inhibitors** - Platelet aggregation inhibition - Action related to cAMP PDE inhibition (**opposing P2Y~12~ action**) and inhibition of adenosine uptake - **Dipyridamole (Persantine)** - A structure of a chemical formula Description automatically generated - Use: Combined with warfarin to prevent embolization with prosthetic heart valves - With ASA to prevent cerebrovascular ischemia - **Cilostazol (Pletal)** -  - Use: intermittent claudication **Protease-Activated Receptor (PAR) Inhibitors** - **Thrombin activates platelets** at nanomolecular concentrations - COX-suppresses thrombin in platelets - ADP receptor inhibit platelet aggregation - Mechanism -- **proteolytic cleavage** of PAR-1 receptors on platelet surface - PARs are **GPCRs** coupled to release Ca2+ from stores - **Vorapaxar** (Zontivity) inhibit interaction of thrombin - **Reversible PAR-1 receptor antagonist** on platelets competitive inhibitor - Oral, once daily - **Prophylactic to prevent thrombosis in patients with a previous MI or peripheral arterial disease (PAD)** - **Used with aspirin or clopidogrel** - **Contraindication -- history of stroke, TIAs, or intracranial hemorrhage** - **Half-life of 3-4 days** **antiplatelet effect persists for days after** discontinuation - **Metabolized by CYP3A4 -- avoid concomitant use with strong 3A4 inhibitors or inducers** **Anticoagulant Drugs** **Clot Formation in Hemostasis** - A strong clot forms by a cascade mechanism that culminates in activation of thrombin, an enzyme that converts fibrinogen to fibrin (key clotting factor) - **Clotting (Coagulation) Factors** - Serine Proteases - Cleave down-stream factors to activate them (thrombin activation) - **Factors XII, XI, X, IX, VII, II (Pro-coagulants)** - When cleaved results in coagulation - Cleave factors Va and VIIIa - **Protein C (Anti-coagulant)** destruction of factors - Glycoproteins - Co-factors for activation of proteases (helps w localization) - **Factors VIII, V, III (Tissue factor), Protein S**, bind to and inhibit **anti-thrombin III** (target for heparin) - Ca^2+^ (Factor IV) -- Links certain factors to phospholipid membranes - Transglutaminase (enzyme)-- cross-links fibrin fibers (Factor XIII) - Fibrinogen/Fibrin: Ultimately, the **substrate protein for factor IIa** (thrombin) that polymerizes to form clot - **[Genetic Clotting Factor Diseases]** - Hemophilia A -- deficiency in factor VIII -- 1 in 5,000 males (X-linked) - Hemophilia B -- deficiency in factor IX -- 1 in 25,000 males (X-linked) - Bleeding or increased risk for coagulation - Queen Victoria is a carrier - Factor V Leiden -- resistance to cleavage by protein C (\~5% of Caucasians) - Can increase risk for coagulation - **[Where are clotting factors produced? ]** - All except for von Willebrand factor are made in the liver (secreted into blood stream) [ ] - vWF is produced in the endothelium, subendothelium, and megakaryocytes - Factor VIII is also produced in the endothelium - **Liver disease can have unpredictable effects of coagulation** - *b/c liver is the source of coagulation factors* - **[Where does coagulation occur? ]** - **Extrinsic pathway** -- Requires a factor (tissue factor) extrinsic to the blood - Important when vessel is damaged and blood leaks out - Important for stopping bleeding - *Blood leaks out upon interaction of blood and tissue factor; initial coagulation reaction* - Relied on factors outside bloodstream for activation - Release of tissue [thromboplastin] initiates pathway - Rapid \~15 sec to start clot formation - Factor 7 to factor 10 (cleaves prothrombin to thrombin) - **Intrinsic Pathway** -- Triggered when collagen is exposed on the wall of the blood vessel - All components in blood - Initiated by contact with [negatively charged] collagen of diseased or injured vessel - Blood in test tube clots by this mechanism - Factor 9 to factor 10 - **[Activation of the Extrinsic or Tissue Factor Pathway to Coagulation]** - Tissue factor is expressed on the surface of cells outside of but near blood vessels - Factor VII normally resides in blood - TF binding to Factor VII activates it - Factor VIIa binds and cleaves factor X - **[Common Pathway ]** - Thrombin activation plays a central role in final steps of clot formation - Converts fibrinogen into long strands of insoluble fibrin - Activates factor XII which then cross-links fibrin to form a stable clot incorporated into platelet plug -  - **[Feedback Regulation of Coagulation ]** - **Feedback mechanisms which INCREASE coagulation:** - **Thrombin**: - Activates factor V and VIII - Enhances platelet activation (PAR1 receptor) - **Platelet activation** increases activation of factor VII, factor X, and cleavage of prothrombin (occurs on membrane) - **Feedback mechanisms which DECREASE coagulation:** - **Antithrombin:** - Neutralizes *(inactivates)* procoagulant serine proteases (thrombin, Xa, IXa); **[reaction is accelerated by heparin ]** - **Protein C system:** - Activated by thrombin binding to **thrombomodulin** - Activated protein C complex (APC) forms a complex with protein S to inactivate factors Va and VIIIa (surface of endothelial cell) - **Factor Xa:** - **[Activates tissue factor pathway inhibitor (TFPI)]** to block initial activation of factor VII **Common Tests for Hemostatic Function** - Used for diagnostic purposes or to monitor anticoagulant therapy - **Commonly ordered as a coagulation profile called DIC panel** - **Platelet Count** - Too low (thrombocytopenia) = bone marrow malfunction, nutritional deficiencies - Too high (thrombocytosis) - **Prothrombin time (PT/INR)** - Plasma + thromboplastin + Ca -- clots in 12-14 sec - *Adding tissue factor to determine how quick coagulation occurs* - INR (international normalized ratio) is a normalized value for each lot of thromboplastin - **Normal INR 0.8 -- 1.2, therapeutic INR \~2-3** - **\>3 risk of hemorrhage** - [\$\\mathbf{INR = \\ }{\\mathbf{(}\\frac{\\mathbf{\\text{PTtest}}}{\\mathbf{\\text{PTnorm}}}\\mathbf{)}}\^{\\mathbf{\\text{ISI}}}\$]{.math.inline} - **aPPT** - Plasma + phospholipid (no TF) + activating agent -- clots in 26-33 sec - Used to monitor heparin therapy - **Fibrinogen** -- less common, range from 200-400 mg/dL - **D-dimer** -- product of fibrin breakdown - **[In vitro measurement of coagulation ]** - \+ EDTA/citrate (calcium chelator) - Calcium only - Recalcification time (2-4 min) - Calcium and partial thromboplastin (just phospholipids) and kaolin - Activated partial thromboplastin time - aPPT; 26 -- 33 seconds - Intrinsic pathway - Calcium and thromboplastin (T.P. is tissue factor and phospholipids) - Prothrombin time - PT; 12 -- 14 seconds - Extrinsic pathway **Therapeutic Indications for Anticoagulants** - Prevent excessive clotting that can lead to occlusion of blood vessels - Stroke - Post MI - Unstable angina (HA) - Deep venous thrombosis - Pulmonary embolism - Artificial surfaces **Anticoagulant Drugs** - **[Vitamin K Antagonists ]** - **Warfarin (Coumadin)** -  - Racemic mixture -- S isomer most potent - [Coumarin Anticoagulants ] - Originally found in spoiled clover hay as substances that caused hemorrhage in cattle - All derivatives are water soluble lactones - Warfarin is the most commonly used - **[Mechanism of Action]** - **Vitamin K** Action - Vitamin K is essential for post-translation modification (*extra carboxyl group*) of clotting factors VII, IX, X, and prothrombin (II) and anticoagulation protein C & S - Vitamin K carboxylase catalyzes the **[γ-carboxylation]** of Glu in prothrombin - Role of γ-carboxylation of clotting factors - Carboxyl group added, so it can bind to phospholipid membrane - Ca2+ bridges molecule to membrane - Calcium chelation happens because of two neg charges -  - Vitamin K is oxidized in the process - Coumadin inhibits Vit K-epoxide reductase (VKORC1), thus blocking reduction of vit K. epoxide back to its active form - Warfarin acts by inhibiting the synthesis of clotting factors II, VII, IX, and X - **[Therapeutic Actions ]** - **Delayed onset of action** - Must deplete the pool of circulating clotting factors - Maximal anticoagulant effect is not observed until 3-5 days after initiation of therapy - Loading dose: 5 mg/day - Maintenance dose: 2.5 or 5 mg/day - **After discontinuing therapy** - Factors must be re-synthesized to return to normal PT (several days) - **[Metabolism ]** - Metabolized in liver by **CYP2C9 (S-warfarin)** - *Most variability among patients* - *S-warfarin is the active metabolism* - t1/2 = 36 -- 48 hours - **Termination of action** is not correlated with plasma warfarin levels, but reestablishment of normal clotting factors - **Overdose** -- latrogenic hemorrhage *(increased bleeding)* - Discontinue warfarin therapy - Administer Vitamin K~1~ - High levels of Vitamin K1 can activate warfarin-inhibited reductase - *Bypasses Warfarin's inhibitory effect* - In serious hemorrhage -- plasma replaces clotting factors faster than Vit K therapy - **[Warfarin Necrosis ]** - Some patients have a **deficiency of protein C** (*anticoagulatory factor, vit K carboxylation)* - Protein C is an innate anticoagulant that requires vitamin K-dependent carboxylation for its activity - *Gets depleted (carboxylated) before other coagulation factors* - Since **Warfarin initially decreases protein C levels faster than the coagulation factors,** it can paradoxically increase the blood's tendency to coagulate when treatment is first begun - Many patients when starting on warfarin are given heparin in parallel to combat this - A deficiency in protein S would lead to the same necrosis - **[Adverse effects]**: - Hemorrhage: requires close monitoring when starting treatment and during heparin coadministration - Drug-drug interactions: - 99% of warfarin is bound to plasma albumin (interaction with other albumin bound molecules) - Long elimination half-life (\~36 hours) - Hydroxylated by CYP2C9 - Co-administration with albumin-bound drugs or drugs that affect P450 metabolism can influence the plasma concentration of both drug s - **[Contraindications: ]** - Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy such as uncontrolled alcohol or drug abuse or unsupervised dementia/psychosis *(patients that are more likely to fall and start bleeding)* - **Never use in pregnancy (can cross the placenta and cause hemorrhage disorders in fetus, teratogen, causes facial deformities)** - **Drug interactions** **Drugs that Diminish Warfarin's Anticoagulant Effect** --------------------------------------------------------- ------------------------------------------------------------------ Cholestyramine Inhibits warfarin absorption in the GI tract Barbiturates, carbamazepine, rifampin Accelerated warfarin metabolism by inducing P450 enzyme Nephrotic syndrome/hypoproteinemia Decreased albumin, increased free warfarin, decreased t1/2 **Vitamin K (reduced)** **Bypasses warfarin -- induced epoxidise reduction inhibition** Pregnancy Increased levels of clotting factors **Drugs that Enhance Warfarin's Anticoagulant Effect** Chloral Hydrate Displaces warfarin from plasma albumin Chloramphenicol, SSRI's, amiodarone Decreases warfarin metabolism by inhibiting hepatic P450 **Broad-spectrum antibiotics** **Reduce availability of vitamin K in the GI tract** Anabolic steroids (e.g. testosterone) Inhibits synthesis and increases degradation of clotting factors - **[Vitamin K ]** - Fat-soluble vitamin - A structure of a molecule Description automatically generated - Involved in post-translation modification of prothrombin, factor VII, IX, and X (vit. K dependent) - Uses: - Individuals with abnormalities in fat absorption (vitamin K deficiency) - Reverse anticoagulant effect of excess warfarin - **[Reversal of Warfarin Effects: ]** - For emergent situations (acute major bleeding) where the effects of warfarin need to be reversed immediately, **exogenous vitamin K** along with prothrombin complex concentrates (factors II, VII, IX, and X with proteins C and S: **Kcentra**) are administered IV - *Rapidly replacing clotting factors inhibited by Warfarin* - The effects of warfarin can be reversed (albeit slowly) by the oral administration of **vitamin K** - **Overdose in the absence of acute major bleeding** - **[Indirect Factor IIa/Xa inhibitors ]** - **Heparin (Unfractionated heparin -- UFH)** -  - **[Mechanism of Heparin ]** - Free antithrombin (AT) can inactivate factors Xa, IXa, Xia, XIIa, IIa, and VIIA, but the rate is very slow - **Heparin** binding to AT changes the conformation of the protein and allows the formation of a ternary complex (heparin-AT-target factor) - *Greatly accelerates binding to thrombin* - **Heparin** binding to AT the subsequent conformation change increases the interaction of AT with the target factors - The ratio of AT activity is typically 3:1 (thrombin:factor Xa) - **Low molecular weight heparins** (LMWH) are too small to bind antithrombin and thrombin, thus have greater specificity for inhibition of factor Xa - *1/3 of heparin* - *Doesn't really interact with thrombin* - **Heparin acts by accelerating AT reactions to inactivate thrombin and factor Xa** - **[Clinical Use ]** - **Administration -- effective immediately** (*immediately anticoagulant effect)* - Intermittent IV injection - Continuous IV infusion -- easiest to control - SC injection - **Adjust dosing according to coagulation tests** - aPPT therapeutic range = 1.5-2x normal - Cleared rapidly from blood (t1/2 = 30-180 min) - *Administered frequently* - **Anticoagulant effect disappears within hours of discontinuation of therapy** - **[Adverse Effects]** - Latrogenic Hemorrhage - Hemorrhage can occur at any site - Risk factors - Patients over 50 (patients already bleeding) - Ulcer patients - Severe hypertension - Antiplatelet drugs - Treatment - Stop heparin (short t1/2) - Life threatening bleeding: adm specific antagonist - **Protamine sulfate** -- binds tightly to heparin to neutralize the anticoagulant action - **Thrombocytopenia (HIT)** - **Type 1:** Mild, transient (\~25% of patients) due to direct action on platelets - *Decrease in platelet levels; typically rebounds* - **Type 2**: Severe (up to 5% of patients) - Develops 7-12 days after starting therapy antibodies develop to platelet (PF4) -- heparin complex -  - **Osteoporosis** - Associated with extended therapy (3-6 months) - **Heparin Reversal (b/c of overdose)** - Heparin Inhibitor: **Protamin Sulfate** - A low MW **polycationic protein** which forms a stable complex with the negatively charged heparin through multiple electrostatic interactions - Administered IV to reverse rapidly the effects of heparins in situations of life-threatening hemorrhage or great heparin excess - Not as effective with LMWH - Does not reverse effects of fondaparinux - **Heparin Chemistry** - A diagram of a chemical formula Description automatically generated - *Active binder of anti-thrombin* - Straight chain sulfated mucopolysaccharides **produced by mast cells and basophils** - Mixture of 5-30 kDa (mean \~15 kDa) compounds - **Extracted from porcine small intestine or bovine lungs** - Anticoagulant activity standardized by bioassay -- expressed as units \~120 USP units/mg is std activity - **Sulfate groups (negative charge) required for binding to antithrombin are indicated in blue** - **Low Molecular Weight Heparins (Enoxaparin, Daltaparin)** - Characteristics - Obtained from depolymerization of unfractionated porcine heparin - Comparison to standard heparin - Equal efficacy - Increased bioavailability from SQ site of administration (only route) - Less frequent dosing (1-2x daily) -- longer t1/2 than heparin - No monitoring of clotting needed - **Non-heparinoids (Fondaparinux)**