Pharmacology for Physical Therapists 04-08

Definitions •  Pharmacology – Study of drugs

Pharmacology for Physical Therapists Linda Lawless, Pharm.D. Paul LaStayo, Ph.D.,PT

–  Pharmacokinetics •  Absorption, distribution, metabolism, and excretion of drugs

–  Pharmacodynamics •  Biochemical and physical effects of drugs on the body

–  Pharmacotherapeutics •  Use of drugs to treat diseases

–  Pharmacoeconomics –  Pharmacogenomics

Definitions •  Pharmacophysicaltherapy •  Physicalpharmacotherapy •  Physiotherapeuticpharmacology •  Rehabilitativepharmacotherapeutics

How a chemical becomes a drug •  Pre-clinical work –  Lab –  Animal model

•  Food and Drug Administration (FDA) –  Investigational new drug (IND)

•  Phase 1 –  Healthy volunteers with exceptions •  Kinetics and safety

•  Phase II

Terminology •  Chemical name •  Generic name •  Brand (Trade) name •  Drug class •  Over-the-Counter (OTC) vs Rx

How a chemical becomes a drug •  Phase III – Larger patient population •  Efficacy and safety

•  Phase IV – Post marketing analysis, safety

•  Expedited or fast-track – Oncology, HIV

–  Patients with disease being treated •  Dose and safety

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Methods of Administration •  Oral (po) –  Buccal, sublingual, gastric

•  Injection –  Intradermal, subcutaneous (SC, SQ) –  Intravenous (IV) –  Intramuscular (IM) –  Intrathecal (IT) / epidural –  Intraosseaus (IO) –  Intrarticular (IA) –  Intraperitoneal

Methods of Administration •  Topical – Patch, cream, ointment, lotion, gel, ophthalmic, otic, nasal

•  Respiratory – Metered dose inhaler (MDI), SVN, ET tube

•  Rectal / Vaginal

P-Kinetics •  Absorption factors – Drug formulation – Method of administration – Blood supply – First pass effect – Food – Patient specific physical factors

P-Kinetics •  Distribution factors – Blood supply – Solubility – Protein binding

•  Metabolism factors – Liver disease and heart failure – Genetics – Age and stress

P-Kinetics •  Excretion factors – Kidneys / urine, age, heart disease

•  Onset, peak, duration •  Half life (t ½) – 4-5 t ½ s = steady state

P-Dynamics •  Agonist •  Antagonist – Competitive / Noncompetitive

•  Selective / Nonselective •  Potency •  Therapeutic index

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Pharmacotherapeutics •  Acute therapy •  Empiric therapy •  Maintenance therapy •  Supportive therapy •  Palliative therapy

Drug Interactions •  Drug-drug interactions – Enzyme induction in liver – Protein binding competition – P-kinetic changes – Potentiation – Antagonistic effects

•  Food-drug interactions – P-kinetics changes

Adverse Drug Reactions (ADRs) •  May be useful •  Difficult to predict – Individual differences

•  Drug allergy – Hypersensitivity not always anaphylaxis – Symptoms vary: rash, itching, wheezing, swelling, gi, anaphylaxis

Classifications & Compliance •  Antacids 17% •  Estrogens 42% •  Antihypertensives 61% •  Diabetic 78% •  Cardiac 89%

PAIN

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Pain Definition Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” Merskey 1986

Or Whatever the patient feels it is………

Barriers to Adequate Pain Control •  No access to services for pain control – Geographic, cultural, language, financial barriers – Communication barriers – Inadequate education of health care providers – Inadequate numbers of facilities such as pain clinics

Barriers to Adequate Pain Control •  Misconceptions – Minimizing patients’ reports of pain – Belief that chronic pain is untreatable – Fear of tolerance – Fear of adverse effects

Pain Definitions •  Acute pain •  Chronic pain – Nociceptive – Neuropathic – Idiopathic – Mixed

Barriers to Adequate Pain Control •  Lack of knowledge about appropriate use of pain meds – Inadequate dose – PRN rather than RTC – Poor dose titration – Failure to use adjuncts or non-pharmacologic methods

Tolerance, Dependence, Addiction •  Tolerance – Disease progression is a factor – Stable disease = less tolerance

•  Physical dependence – Tapering important

•  Addiction – Rare when treating pain

•  Pseudoaddiction – Solution = adequate pain control

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Pain Assessment •  At regular intervals •  At each new report of pain •  At suitable interval after Rx •  Initial Assessment – History – Physical exam – Psychosocial assessment – Diagnostic evaluation

Pain Assessment •  Patient Self-Report – Pain quality – Location – Intensity or severity – Aggravating or relieving factors – Cognitive response to pain – Goals – Palliation, Quality, Response, Severity, Time

Pain Assessment •  Adults and children > 7 years old – 0 – 10 scale – Categorical scale – Visual analog scale

•  Children < 7 and adults with cognitive impairment – Smiley face scale

Reassessment •  Compliance, adverse effects, use •  Effectiveness at appropriate interval •  Positive and negative effects of nonpharmacologic treatments

Pharmacologic Agents •  General Principles – Drug therapy most effective when combined with non-pharmacologic strategies – Combinations of smaller doses of different drug classes may reduce risk of side effects

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World Health Organization ThreeStep Analgesic Ladder

AHRQ Guidelines Pain Score

Non-opioid analgesics •  Ceiling effect for analgesia •  NO tolerance, physical or psychological dependence •  Antipyretic •  Should be part of an analgesic regimen unless contraindicated

– Maximum 4gm/day – Caution in alcoholics, liver disease, fasting

5–6

“Weaker” opioids

>7

MS, oxycodone, hydromorphone, fentanyl

Aspirin •  Mild pain •  GI upset and bleeding preclude use •  Never use in children < 12 years old with viral illness •  Salicylate salts (choline magnesium trisalicylate, salsalate) –  Possibly less affect on bleeding time and platelet aggregation –  No data in patients with severe clotting abnormalities

Acetaminophen •  Mild pain •  Superior adverse effects profile •  Low cost •  Hepatotoxicity

1–4

Recommended Treatment NSAID or APAP

NSAIDs •  Diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac

•  •  •  • 

Mild to moderate pain Bone pain Variable response to different NSAIDs Reversible inhibition of platelet aggregation –  Relative contraindication in anticoagulation, coagulopathy, thrombocytopenia

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NSAIDs •  GI effects –  Most susceptible: steroids, previous ulcers, extremely ill, advanced age

•  Ibuprofen 85% have disease evidence

Osteoarthritis

OA Treatment Goals •  Maintain ability to function •  Relieve joint inflammation and pain •  Prevent joint destruction •  Preserve quality and style of life

•  Most common cause of chronic disability

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Non-Drug Therapy •  Physical therapy (ROM, water aerobics, strengthening exercises) •  Diet, weight loss •  Education (Self management programs) •  Appliances (OT, ADLs, joint protection) •  Surgery

Pharmacologic Therapy •  Non-opioid analgesics – Acetaminophen 4gm/day

•  NSAIDs – Ibuprofen 3200mg/day

•  Opioid analgesics – Codeine, oxycodone

Actions of NSAIDs

COX -1 vs COX - 2

•  Analgesia - ↓Pg synthesis ↓ the sensitizing effect of Pg’s on pain receptors •  Anti-inflammatory - ↓ Pg synthesis, inhibits other inflammatory mediators (bradykinin, histamine) •  Antipyretic - ↓ Pg synthesis ↓ sensitizing effect of Pg’s in the posterior pituitary which controls temperature

•  COX - 1 – produced continuously for housekeeping functions of the organs/cells (GI cytoprotection, vascular homeostasis, renal function,etc..) •  COX – 2 – produced by macrophages and synoviocytes during an inflammatory process - inducible

NSAID efficacy •  Every NSAID has some anti-inflammatory efficacy greater than placebo •  No NSAID has been shown to be more effective than aspirin •  No NSAID has been shown to be less effective than aspirin

March 23, 2007

Suffering Boomers want to fill Vioxx void Celebrex sales surge despite possible heart risks; firms seek OK on new pain drugs

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RA Treatment Goals Rheumatoid Arthritis

RA •  Aspirin / NSAID – initial therapy for pain – No effect on disease progression

•  Glucocorticoids (prednisone) – pain – No effect on disease progression – Often used short term for “flare”

•  Disease-Modifying Antirheumatic Drugs (DMARDS) – Help prevent disease progression

DMARDS •  Chloroquine, azathioprine, cyclophosphamide, cyclosporine, etanercept, infliximab, adalamab, gold, leflunomide, methotrexate, penicillamine, sulfasalazine

•  Risk vs benefit is of concern •  Most have significant adverse effect profiles •  Earlier use appears more beneficial

•  Pain control to improve function •  Disease management to prevent further degeneration

Chronic Corticosteroid Adverse Effects •  Adrenocortical suppression – Cushing syndrome •  Hypertension •  Hyperglycemia •  Worsening of glaucoma and cataracts •  Catabolic effect on muscle tendon and bone – osteoporosis, muscle wasting and weakness

TNF inhibitors •  Etanercept (Enbrel®), inflixumab (Remicade®), adalamab (Humira®)

•  Binds TNF and thus limits its ability to do joint damage •  Must be given parenterally –  Etanercept - Usually 2 SC injections weekly (2 different sites) –  Inflixumab – Usually loading dose IV then q 8 weeks –  Adalamab – SC q 2 weeks

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TNF Inhibitors Adverse Effects •  Hypersensitivity reaction to infusion of inflixumab •  risk of opportunistic infections •  Not to be used with anakinra

Leflunomide (Arava®) •  Used for those who can’t tolerate MTX •  Similar in efficacy to MTX •  MOA uncertain but may be TKI inhibitor •  Daily oral dose •  Adverse Effects: diarrhea, gi upset, alopecia, teratogenic

Anakinra (Kineret®) •  IL-1 receptor antagonist •  Daily SC injection •  infection risk if used with TNF inhibitor •  Most common ADR – injection site reactions

Abatacept (Orencia®) •  Costimulation modulator –  Inhibits T cell activation

•  IV monthly •  Used if inadequate response to TNF inhibitor •  Cannot be used in combination with anakinra or TNF inhibitor •  Increased risk of infections •  Adverse Effects: HA, infections

Parkinson’s Disease Pathophysiology Parkinson’s Disease

•  Disorder of the extrapyramidal system of the brain involving the basal ganglia •  Loss of melanin containing cells in the substantia nigra (dopaminergic activity) •  Progressive loss of the inhibitory transmitter dopamine in the nigrostriatal tracts and a relative increase in excitatory neurotransmitter acetylcholine •  Decreases in serotonin and norepinephrine are also present

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Parkinson’s Disease Treatment •  Initial treatment for early disease – Exercise – Education – Nutrition – Speech Therapy – Group Support

Anticholinergics •  All agents are equally efficacious •  benztropine (Cogentin®) •  trihexyphenidyl (Artane®) •  diphenhydramine (Benadryl®) •  procyclidine (Kemadrin®) •  biperiden (Akineton®) •  orphenadrine (Disipal®)

Anticholinergics •  Block excitatory neurotransmitter acetylcholine in the substantia nigra •  Most effective in early disease when dopamine depletion is not substantial •  Improve tremor and rigidity, little effect on bradykinesia, postural imbalance or gait disturbances

Anticholinergic Adverse Effects •  •  •  •  • 

dry mouth blurred vision constipation urinary retention increased intraocular pressure

•  confusion •  memory impairment •  hallucinations

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Amantadine (Symmetrel®)

Amantadine Adverse Effects

•  Antiviral with unclear mechanism of action in treating Parkinson’s •  All symptoms are improved within days of initiating drug in 50% of patients. •  Tachyphylaxis develops in 1 to 3 months; use drug holidays •  Especially effective against tremor

•  Sedation, vivid dreams (↓ with time) •  Depression, hallucinations, anxiety, dizziness, psychosis, confusion •  Dry mouth, nausea, vomiting •  Livedo Reticularis in up to 80% of patients •  Eliminated renally so must dose adjust for poor renal function

Livedo Reticularis

Levodopa (Larodopa®) •  Crosses the blood-brain barrier where it is converted to dopamine by enzyme L-amino acid decarboxylase •  Peripheral conversion also occurs so doses need to be large to overcome this •  80% of patients have improvement in symptoms, but may take up to 4 months to see full effect (due to dose titration)

L-dopa Adverse Effects •  Most are caused by the peripherally circulating dopamine •  Nausea, vomiting, anorexia •  Postural hypotension, cardiac arrhythmias •  Confusion, depression, psychosis, vivid dreams –  These occur in long-term therapy or in patients with underlying psychiatric disorders. –  Aggravated by anticholinergics and amantadine

Carbidopa •  Dopa decarboxylase inhibitor that does not cross the blood-brain barrier •  Decreases peripheral conversion to dopamine (↓ levodopa dose by 80%) •  Response time increased (don’t need slow titration to decrease side effects) •  Peripheral side effects decreased; mental side effects the same. Dyskinesias may develop more quickly

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Sinemet® •  Sinemet 10/100 = 10mg carbidopa + 100mg levodopa •  Short-acting and long-acting formulations

Honeymoon Period •  Early phase of levodopa therapy where patients have good response •  May last for 3 to 5 years •  Many practitioners delay initiation of levodopa until patients are clearly bothered by the disease

“On-Off” Effects

“Wearing Off” Effect

•  Random fluctuations from mobility to the parkinsonian state suddenly as if a switch had been turned off •  Fluctuations can last for minutes to hours with increasing severity •  Occurs with long-term levodopa use •  No relationship between timing of doses or levodopa serum levels

•  End of dose deterioration •  More predictable effect •  Occurs at the end of a dosing interval following period of relief •  Can be improved by shortening the dosing interval or adding a dopamine agonist

Drug Holidays

Dopamine Agonists

•  Brief period of drug withdrawal •  Attempted to improve response and lessen side effects for patients on long-term levodopa therapy •  Allows striatal dopamine receptors to be “resensitized” •  Controversial and risky- many complications associated with immobility

•  Directly stimulate postsynaptic dopamine receptors in the corpus striatum •  All agents produce essentially the same clinical effects •  Improve efficacy of levodopa in patients experiencing response fluctuations •  May also be used as monotherapy in early stages of Parkinson’s

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Dopamine Agonists •  Mirapex® - pramipexole •  Requip® - ropinirole •  Permax® - pergolide •  Parlodel® - bromocriptine •  Neupro patch® - rotigotine

Tolcapone (Tasmar®) •  Catechol-O-methyltransferase inhibitor that will increase response to levodopa •  Side effects –  Nausea, vomiting, diarrhea, confusion, dyskinesias, orthostasis, HA –  Fatal liver disease

•  Contraindicated in patients with underlying liver disease (Black Box Warning)

Dopamine Agonists Adverse Effects •  Nausea, vomiting •  Orthostatic hypotension, arrhythmias •  Peripheral vascular effects - Raynaud’s, angina, digital vasospasm •  Dyskinesias •  Confusion, hallucinations

Entacapone (Comtan®) •  Catechol-O-methyltransferase inhibitor •  Adjunct to levodopa/carbidopa in patients with end-of-dose “wearing-off” •  Adverse Effects – hypotension, syncope, diarrhea, hallucinations, dyskinesias, rhabdomyolysis, hyperpyrexia, confusion

•  Use caution in liver disease

Selegiline (Eldepryl®) •  MAO-B inhibitor (blocks dopamine metabolism) •  Blocks breakdown of dopamine so may extend levodopa effects; usually can decrease dose of levodopa •  Adverse Effects – insomnia, hallucinations, dyskinesias

Adjunctive Treatments •  β-adrenergic blockers – Useful to treat parkinsonian tremor in 50% of patients. – Propranolol (Inderal®) and nadolol (Corgard®) have been used most often. Nadolol can be dosed QD and has fewer CNS side effects

•  Not effective as monotherapy

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Skeletal Muscle Relaxants – Centrally-Acting Muscle Relaxants and Treatment of Spasticity

Skeletal Muscle Relaxants – Centrally-Acting •  Adverse Effects – Dizziness, drowsiness, gi distress, heartburn, diarrhea, ataxia, constipation, nausea, vomiting, arrhythmias, bradycardia, withdrawal if stopped abruptly

•  Drug Interactions – Many – Watch for additive drowsy and anticholinergic effects

Skeletal Muscle Relaxants – Direct-Acting •  Adverse Effects: – Drowsiness, dizziness, malaise, fatigue, and weakness, seizures, hepatitis

•  Drug Interactions: – Watch for additive effects from other CNS depressants

•  Baclofen, diazepam, tizanidine, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine •  MOA: Unknown but may be related to CNS depression / sedation •  Use: Painful muscle spasms associated with inflammation or trauma

Skeletal Muscle Relaxants – Direct-Acting •  Dantrolene •  MOA: Interference with calcium ion release from sarcoplasmic reticulum and weakens muscle contraction force •  Use: Management of spasticity – Cerebral palsy, MS, spinal cord injury, stroke

Drugs for Spasticity •  Diazepam and baclofen both work by promoting the inhibitory effects of GABA on muscle contractions •  Diazepam causes more sedation and tolerance than baclofen •  Dantrolene causes more weakness than baclofen •  Baclofen is drug of choice

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Baclofen •  Use: Primarily for paraplegic or quadriplegic patients with spinal cord lesions caused by MS or trauma •  Reduces number and severity of painful flexor spasms •  Does not improve gait stiffness, manual dexterity, or residual muscle function •  May be given intrathecally

CAMP LEO!!!!

Diabetes Mellitus

Diabetes Incidence and Prevalence •  15.7 million people with diabetes in the US – 5.9% of the population

•  10.3 million diagnosed •  5.4 million undiagnosed (34%) •  798,000 new cases diagnosed each year

Diabetes Incidence and Prevalence •  Prevalence for people over 20 years old –  7.8% in non-Hispanic white Americans –  10.8% in non-Hispanic African Americans –  10.6% in Hispanic Americans –  5 – 50% in Native Americans

•  Leading cause of blindness in ages 20-74 •  Leading cause of ESRD •  Account for 67,000 lower extremity amputations annually

Metabolism and Utilization of Carbohydrate, Protein, and Fat •  Insulin functions –  ↑ uptake of glucose by muscle and fat –  ↑ liver glycogen stores –  ↓ glycogen breakdown (glycogenolysis) by liver –  ↑ synthesis of fatty acids –  ↓ breakdown of fatty acids into ketone bodies –  Promote incorporation of amino acids into protein

•  Pancreas secretes 0.5 – 1 unit / hr of insulin

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Metabolism and Utilization of Carbohydrate, Protein, and Fat •  Total daily insulin release from normal pancreas = 25 – 50 units •  Normal plasma glucose concentrations = 60 – 160mg/dl •  Minimum glucose concentration for brain function = 40mg/dl •  Glucose can diffuse into CNS without insulin •  Muscle and fat require presence of insulin to receive glucose

Complications •  Macrovascular – Coronary heart disease, stroke, peripheral vascular disease

•  Microvascular – Nephropathy, retinopathy, neuropathy

Goals of Therapy •  Whole blood –  Fasting 80-120mg/dl –  Bedtime 100-140mg/dl –  2 hour post-prandial < 180mg/dl

•  Plasma –  Fasting = 90-130mg/dl –  Bedtime = 110-150mg/dl –  2 hour post-prandial < 190mg/dl

•  HbA1c = 250mg/dl with ketonuria or > 300mg/dl – Extra carbs prior of BS < 100mg/dl

Insulin Adverse Effects •  HYPOGLYCEMIA – Symptoms – Quick sugar source (10-20gm glucose) followed by complex carb/protein snack if next meal not within 2 hours – Glucagon 1mg SC/IM/IV if unconscious followed by carb when awake – Glucose 25gm IV (D50W 50ml) – Determine cause and correct

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Insulin Adverse Effects •  Lipoatrophy – Due to impure insulin – Uncommon now

•  Lipohypertrophy – Insulin injected repeatedly in same site – Solution = site rotation

Oral Antidiabetic Drugs •  Classes: Sulfonylureas, thiazolidnediones, biguanide, meglitinide, amino acid derivative, combinations •  Uses: Type II diabetes

Oral Antidiabetic Drugs •  Adverse Reactions: – Sulfonylureas: Hypoglycemia, nausea, rash, water retention, photosensitivity – Metformin: Nausea and vomiting, abdominal discomfort, metallic taste – Acarbose: Abdominal pain, diarrhea, flatulence – Thiazolidinediones: Weight gain, swelling

Sick Day Guidelines •  Use usual insulin •  √ BS more frequently •  √ ketones in urine if BS>240mg/dl •  Drink lots of non caloric fluids •  Maintain caloric intake with easily digested food like jello •  Give supplemental insulin doses

Oral Antidiabetic Drugs •  MOA – Increase pancreatic insulin release (sulfonylureas, repaglinide, nateglinide) – Decrease insulin resistance at the tissue level (pioglitzone, rosiglitzone) – Decrease liver glucose production (metformin) – Delay gastric absorption of glucose (acarbose, miglitol)

Oral Antidiabetic Agents •  Drug Interactions: – Watch for other drugs known to alter blood sugar – Metformin must be held when renal function compromised (IV contrast dye)

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Hypertension treatment •  Lifestyle Modifications –  Weight reduction –  Moderation of alcohol intake –  Physical activity –  Moderation of dietary sodium –  Potassium, calcium, magnesium intake –  Dietary fats, caffeine –  Relaxation and biofeedback –  Smoking cessation

Hypertension

Pharmacologic Treatment •  Start with lowest dose of initial drug choice •  Provide 24-hour efficacy with once-daily dose, with at least 50% of the peak effect remaining at 24 hours –  Increase compliance –  Decrease cost –  Better management with persistent smooth control of once-daily dosing (especially if miss one or more doses/week

Classification of Diuretics •  Filtration Diuretics –  Theophylline, Caffeine

•  Proximal Tubular Diuretics –  Mannitol –  Acetazolamide(Diamox®)

•  Loop of Henle Diuretics –  Bumetanide(Bumex®), Ethacrynic Acid(Edecrin®) –  Torsemide(Demadex®), Furosemide(Lasix®)

Diuretics •  •  •  •  •  • 

Sensitive African-American Elderly Obese Diabetic Renal Insufficiency

•  •  •  • 

Non-Sensitive Caucasian Younger Non-obese

Classification of Diuretics •  Distal Tubular Diuretics (K+ losing) –  Thiazides –  Chlorthalidone(Hygroton®) –  Metolazone(Zaroxolyn®)

•  Collecting Duct Diuretics (K+ retaining) –  Amiloride(Midamor®) –  Triamterene(Dyrenium®) –  Spironolactone(Aldactone®) –  Indapamide(Lozol®) K+ Neutral

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DIURETICS •  Effective as monotherapy for primary HTN •  Thiazides are DOC for HTN - can be dosed once daily •  Loop diuretics more potent, but must be dosed 2-3x/day and no arterial vasodilation •  Potassium-sparing diuretics should be reserved for patients with hypokalemia from previous diuretic use

Diuretics Adverse Effects •  Hypokalemia - dose related •  Hyperuricemia - dose related •  Hyperglycemia - dose related (K+ loss) •  Hypomagnesemia - dose related •  Hyponatremia - dose related •  Lipid abnormalities – not dose related •  Sexual dysfunction (thiazides)

β-ADRENERGIC BLOCKERS •  Atenolol, carvedilol, metoprolol, nadolol, propranolol

•  •  •  • 

–  Avoid in asthma & CHF

•  Cardioselectivity –  Can be used in asthma

Beta Blocker Adverse Effects •  Diarrhea or constipation •  Bradycardia •  Hypotension •  Drowsiness, lethargy, depression •  Bronchospasm •  Weakness

First-line therapy Decrease vascular resistance Reduce morbidity and mortality Intrinsic sympathomimetic activity (ISA)

ACE INHIBITORS •  Benazepril, captopril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, quinapril, ramipril, trandolapril

• 

BP by renin-angiotensin-aldosterone mechanism •  Slow the decline in renal function and delay or prevent the onset of ESRN in hypertensive and diabetic patients •  DOC for patients with diabetes and CHF

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ACE Inhibitors Adverse Effects

Angioedema

•  1st dose hypotension if volume depleted; hold diuretic for 1-2 days before starting •  Rash •  Angioedema •  Cough •  Taste disturbance •  Hyperkalemia

ANGIOTENSIN RECEPTOR ANTAGONISTS (ARB’s) •  Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, (aliskiren – renin inhibitor)

•  Mechanism similar to ACEI’s; block angiotensin receptor •  Similar indications as ACEI’s •  Less cough

CALCIUM CHANNEL BLOCKERS •  Amlodipine, diltiazem, nicardipine, nifedipine, verapamil

•  •  •  •  • 

All agents are indicated for hypertension Vasodilatory effects decrease blood pressure Controversy over risk/benefit Nifedipine may increase risk of MI Avoid use if concomitant CHF

Angiotensin II Receptor Blocker Adverse Effects •  •  •  •  •  •  •  • 

Angioedema Hypotension Headache Fatigue Dyspepsia Diarrhea Musculoskeletal pain Hyperkalemia

Calcium Channel Blockers Adverse Effects •  Orthostatic hypotension •  Hypotension •  Edema •  Worsening of heart failure •  Arrhythmias

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CENTRAL α2-AGONISTS •  CLONIDINE – central α2-agonist •  Decreases blood pressure by vasodilation •  Third line agent due to many side effects •  Advantage is availability as a once-weekly patch

PERIPHERAL α1ANTAGONISTS •  Doxazosin (Cardura®), phentolamine, prazosin (Minipress®), terazosin (Hytrin®)

•  Blocks post synaptic alpha receptors resulting in decreased arterial and venous vasoconstriction •  2nd or 3rd line agent for HTN •  BPH •  Alternative in diabetics

α,β-BLOCKER •  Carvedilol (Coreg®) •  No benefit over other cheaper betablockers for hypertension •  May provide more benefit in heart failure •  Intrinsic sympathomimetic activity

Clonidine Side Effects •  Drowsiness, dry mouth , lethargy •  Orthostatic hypotension •  Rebound hypertension (exacerbated with β-blockers •  Do not abruptly DC. Must taper off slowly. DC β-blockers first

Alpha-adrenergic Blockers Adverse Effects •  Significant 1st dose hypotension – take at bedtime •  Dizziness, HA •  Drowsiness •  Tachycardia •  Fluid retention •  Tachyphylaxis

Heart Failure Definition A syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life and reduced life expectancy NYHA Classification of Heart Failure

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CHF Signs and Symptoms RIGHT VENTRICULAR FAILURE Symptoms Abdominal pain, anorexia, bloating, constipation, nausea Signs – Peripheral edema, JVD, hepatojugular reflux, hepatomegaly, ascites

CHF Signs and Symptoms LEFT VENTRICULAR FAILURE Symptoms DOE, orthopnea, paroxysmal nocturnal dyspnea, tachypnea, hemoptysis, cough

Signs Bibasilar rales, S3 gallop, pulmonary edema, pleural effusion, cheyne-stokes respirations

CHF Compensatory Mechanisms

CHF Signs and Symptoms NONSPECIFIC FINDINGS Symptoms Exercise intolerance, fatigue, weakness, nocturia, CNS symptoms Signs Tachycardia, pallor, cyanosis of digits, cardiomegaly

Diuretics •  Should be prescribed for all patients with symptoms of heart failure who have evidence of fluid retention •  Should be combined with an ACE inhibitor and a β-blocker •  Monitor efficacy and toxicity by having patients do daily weights •  Overdosing can lead to renal insufficiency and hypotension if used with ACEI’s, ARB’s and vasodilators

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Diuretic Resistance •  Accompanies the progression of heart failure •  Intravenous diuretics •  Two diuretics in combination (add metolazone or indapamide) •  Short-term use of drugs that increase renal blood flow (dopamine, dobutamine) •  Caused by concomitant use of NSAID’s

ACE Inhibitors •  Drugs of choice for all patients with LV dysfunction •  No absolute “minimum BP” (e.g. 100 mm Hg) •  A rise in serum creatinine is acceptable •  Titrate up to recommended doses •  All agents decrease mortality and risk of hospitalization

Aldosterone Antagonist •  Spironolactone •  Aldosterone antagonist that counteracts the retention of sodium, loss of magnesium and potassium, myocardial and vascular fibrosis, vascular damage, baroreceptor damage. •  Decreased risk of mortality and hospitalization

Clinical Trials •  No long term studies on effect of diuretics on morbidity and mortality •  Many trials have shown efficacy of diuretics in increasing urinary sodium excretion and reducing physical signs of fluid retention

Angiotensin II Receptor Blockers •  Indications similar to ACE inhibitors •  High cost and lack of clinical trials limit these to patients who are ACEI intolerant

Spironolactone Adverse •  Hyperkalemia Effects •  Gynecomastia •  Use caution with concomitant ACEI due to hyperkalemia

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Digoxin •  •  •  •  •  • 

Positive inotrope – ↑force of contraction Negative chronotrope - ↓ heart rate Indicated for systolic heart failure No effect on mortality, but relieves symptoms Use in patients with HF who have rapid AF Monitoring of levels not indicated except for compliance or toxicity

Digoxin Adverse Effects •  Visual disturbances •  Nausea, vomiting •  Ventricular arrhythmias •  Sinus bradycardia •  Fatigue, weakness

Mortality in the Digoxin and Placebo Groups

The Digitalis Investigation Group. N Engl J Med 1997;336:525-533

Incidence of death or admission to hospital due to worsening heart failure in two groups of patients: those receiving digoxin and those receiving placebo Digitalis Investigation Group's study

BMJ. 2000 February 19; 320(7233): 495–498.

β-Adrenergic Blockers •  All patients with stable NYHA class II or III HF due to LV systolic dysfunction should receive a β-blocker unless contraindicated or intolerant (dec mortality in clinical trials) •  Use in combo with ACEIs and diuretics •  SE occur early & ↓with time •  Need 2-3 months for complete response •  May decrease disease progression

Vasodilators •  Nitrates, hydralazine •  Most useful in ischemic cardiomyopathy •  Shown to decrease mortality and improve symptoms •  Need 10-12 hour nitrate free period •  Hydralazine dosed 2-3x/day •  Can improve cardiac output and relieve pulmonary congestion

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Vasodilator Adverse Effects •  Dizziness •  Hypotension •  Headache •  Nitrate tolerance

Antiarrhythmic Agents •  Class I agents (e.g. quinidine, procainamide) should not be used in HF, except in treatment of refractory life-threatening ventricular arrhythmias •  Amiodarone (class III) does not appear to increase risk of death when used to treat atrial arrhythmias in chronic HF •  Monitor & correct K+ and Mg+ to prevent arrhythmias

Calcium Channel Blockers •  No effect on mortality or risk of hospitalization overall •  Amlodipine may be of some benefit in diastolic dysfunction

Amiodarone Adverse Effects •  Electrolyte depletion •  Neurohormonal activation •  Hypotension and azotemia •  Rash, hearing difficulties •  Pulmonary toxicity (pneumonitis) •  Liver toxicity •  Arrhythmias

Coronary Artery Disease Coronary Artery Disease

•  Chronic Stable Exertional Angina •  Variant Angina (Coronary Artery Spasm) •  Silent Myocardial Ischemia •  Unstable Angina •  Microvascular Ischemia

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Pathophysiology •  Atherosclerotic plaques obstruct coronary blood flow, therefore oxygen delivery –  Fixed obstruction - hardening of the arteries –  Dynamic obstruction - degree of stenosis varies with changes in smooth muscle tone (spasms) –  Platelet aggregation (thrombus) - arterial vessel wall damage results in platelet aggregation

Nitrates •  Decrease myocardial oxygen demand by venous and arterial dilation (↓workload) •  Can be used alone in mild angina •  Use in conjunction with beta blocker or calcium channel blocker in moderate or severe angina (nitrate free interval)

Nitrate Tolerance •  Mechanism unclear •  All nitrates can induce tolerance •  Incidence is highest with long-acting and continuous IV infusion •  Need 10-12 hours/day nitrate free

Long-Acting Nitrates •  Indicated to control more frequent anginal episodes •  Nitroglycerin ointment and patches •  Isosorbide dinitrate(Isordil®) •  Isosorbide mononitrate (Imdur®, Ismo®) •  Onset 30-60 minutes •  Duration 2-12 hours

Short-Acting Nitrates •  •  •  •  •  • 

Nitroglycerin SL tablets Nitroglycerin translingual spray Onset 1-3 minutes Duration of action 10-30 minutes Use for acute anginal episodes (infrequent) Counsel pts to sit down, may repeat dose q5 min x 2 doses; if no relief then call 911 •  Pay attention to shelf life

Nitrates Adverse Effects •  Headache •  Syncope •  Dizziness •  Hypotension •  Bradycardia •  Tolerance if dosed more then QD

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β-Adrenergic Blockers

β-Adrenergic Blockers

•  ↓ myocardial oxygen demand by ↓ catecholamine-mediated ↑ in heart rate, blood pressure and myocardial contractility •  Start with low doses and titrate up •  Should not be stopped abruptly! Patients must titrate off slowly to avoid acute MI or sudden cardiac death

•  Decrease mortality by 30-40% post-MI •  Questionable effectiveness in vasospastic angina •  β-1 selectivity

Calcium Channel Blockers

Antiplatelet Therapy

•  ↓ myocardial oxygen demand and ↑ myocardial blood flow by dilating blood vessels and ↓ resistance to blood flow •  Different actions and side effect profiles within the class •  All can be used in angina •  Start with low dose as may make angina worse (10%)

– COPD – Asthma – PVD – DM – will not mask signs of hypoglycemia

•  Aspirin •  Ticlopidine (Ticlid®) •  Clopidogrel (Plavix®)

Aspirin •  Platelet activation produces coronary occlusion •  Aspirin inhibits cyclooxygenase which then blocks the formation of prostaglandin endoperoxides from arachadonic acid •  This results in decreased platelet aggregation

Aspirin •  Antiplatelet drug of choice - cheap •  Contraindications – Allergy – PUD, GI bleed

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Ticlopidine (Ticlid®) and Clopidogrel (Plavix®) •  Second-line antiplatelet agents for aspirin intolerant patients •  Inhibit ADP-induced platelet aggregation •  Ticlopidine rarely used due to neutropenia •  Side effects related to bleeding

Anticoagulants

Heparin •  Unfractionated: Heparin •  Low Molecular Weight: dalteparin (Fragmin®), enoxaparin (Lovenox®), tinzaparin (Innohep®) •  Not well absorbed via GI tract – must be administered parenterally – Heparin=IV – LMW=SC

Heparin •  MOA: Prevents clot formation and extension of existing clots •  Partial thromboplastin time (PTT) must be monitored for unfractionated heparin •  Use: venous thrombus (DVT, PE), DIC, embolus prevention in atrial fibrillation, embolus prevention during MI, clot prevention for surgery

Heparin •  Heparin-induced thrombocytopenia – Must switch to a direct thrombin inhibitor (argatroban, bivalirudin, or lepirudin)

•  Adverse Effects: – Bleeding (reversed with protamine sulfate) – Bruising, hematoma formation

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Heparin • 

risk of bleeding with coumadin (except when used together before INR is therapeutic) •  bleeding risk with NSAID, iron dextran, clopidogrel, dilostazol, or drugs that affect platelets such as aspirin •  Many others

Oral Anticoagulants •  Warfarin (Coumadin ®) •  MOA: Alters the liver’s ability to make Vitamin K dependent clotting factors – Clotting factors already circulating are unaffected •  Use: treatment of thromboembolism (DVT, PE), prevention of DVT, prevention of clots in pts with prosthetic heart valves or diseased mitral valve

Warfarin •  In patients receiving heparin, warfarin must be started before stopping heparin •  Sometimes combined with antiplatelet drugs to prevent arterial clotting. •  Adverse Effects: Bleeding (reversed with Vit K) •  Drug Interactions:

ASTHMA and COPD

–  MANY MANY MANY –  Also food/drug interactions

ASTHMA •  Lung disease with the following characteristics (NIH definition) – airway obstruction that is reversible (but not completely so in some patients) – airway inflammation – increased airway responsiveness to a variety of stimuli – episodic symptoms: wheezing, chest tightness, cough and dyspnea

Pathophysiology •  Hyperreactivity (exaggerated response of the bronchial smooth muscles to trigger stimuli) of the airways to physical, chemical, immunological and pharmacological stimuli. – Inhaled allergens, respiratory viral infections, cold air, dry air, smoke and pollutants, ASA, exercise, emotions, beta-blockers

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Pathophysiology •  The release of chemical mediators (e.g., leukotrienes) of inflammation from mast cells thought to be the central mechanism. •  Mast cell mediator release plays a role in allergen induced asthma in atopic individuals, some occupationally-induced syndromes and exercise induced asthma

Treatment Goals •  •  •  •  •  • 

Achieve and maintain control of symptoms Prevent acute exacerbations Maintain PFTs as close to normal as able Maintain normal activity Avoid adverse effects of medication Prevent fixed, irreversible airway obstruction and damage •  Avoid mortality

Drug Therapy •  Theophylline •  β2-Agonists •  Mast cell stabilizers •  Leukotriene modifiers •  Inhaled corticosteroids •  Inhaled anticholinergic •  Systemic corticosteroids

Theophylline - Limitations •  Caffeine like action can be troublesome •  Requires drug level monitoring - new recommendations are 5-15 mcg/ml •  Many drug interactions –  Erythromycin, cimetidine & quinolone antibiotics inhibit theo metabolism so ↑ theo level –  Phenytoin, phenobarb, carbamazepine, rifampin, cigarette smoking induce theo metabolism so ↓ theo level

Theophylline •  •  •  • 

Relaxes smooth muscle of respiratory tract ↑ production of anti-inflammatory cytokine Structural analog of caffeine Useful as alternative to ICSs in patients with mild persistent asthma and as add-on agent to ICSs in patients with moderate to severe persistent asthma

Theophylline - Side Effects •  GI - nausea, vomiting, diarrhea •  CNS – headache, irritability, insomnia, seizures •  Cardiac - arrhythmias •  Side effects may or may not be related to serum levels

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β2-Agonists •  Short-acting are often referred to as “rescue inhalers” and are indicated to relieve acute symptoms •  Long-acting are recommended only as adjunctive therapy to ICSs in patients diagnosed with moderate or severe asthma

Available Products •  Albuterol (Ventolin®, •  Proventil®) •  •  Metaproterenol (Metaprel®, Alupent®) •  Isoetharine, (Bronkosol®) •  •  Isoproterenol (Isuprel®) •  •  Salmeterol (Serevent®)

Bitolterol (Tornalate®) Epinephrine (Primatene®) Pirbuterol, (Maxair®) Terbutaline (Brethaire®, Brethine®)

β2-Agonists Mechanism of Action •  Sympathomimetic •  Induces bronchodilation by relaxing smooth muscles of bronchioles

β2-agonist - Contraindications •  Angina •  Arrhythmias •  Hyperthyroidism •  Hypertension

β2-agonist – Adverse Effects

Mast Cell Stabilizers

•  Palpitations, tachycardia, arrhythmias, angina, hypertension •  Tremor, shakiness, dizziness, restlessness, headache, insomnia, anxiety •  Nausea, cough, throat dryness •  Sweating, flushing

•  Prophylactic agents only – not “rescue inhalers” •  Must be used regularly to be of benefit •  Do not discontinue therapy abruptly •  Most useful when allergic component is present or in pediatrics due to better safety profile than ICSs

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Mast Cell Stabilizer - MOA •  Inhibits degranulation of sensitized mast cells after exposure to antigens •  No intrinsic antihistaminic, anticholinergic, anti-inflammatory, bronchodilator or vasoconstrictor activity •  Effective only if used prophylactically

Mast Cell Stabilizers – Contraindications/Side Effects •  Hypersensitivity •  Cough, wheezing, dry irritated throat •  Lacrimation, swollen parotid glands •  Dizziness, headache •  Bad taste, substernal burning

ICSs – Mechanism of Action •  Precise mechanism of action in lung unknown •  Decrease number and activity of inflammatory cells

Mast Cell Stabilizers – Available Products •  Cromolyn (Intal®) •  Nedocromil (Tilade®)

Inhaled Corticosteroids •  Most potent anti-inflammatory agents used to treat asthma •  Most effective control of persistent asthma •  Only long-term therapy that has been shown to prevent and reverse airway remodeling

ICSs – Available Products •  Beclomethasone (Beclovent®, Vanceril®) •  Triamcinolone (Azmacort®) •  Flunisolide (AeroBid®) •  Dexamethasone (Decadron®) •  Budesonide (Pulmicort®) •  Fluticasone (Flovent®) •  Ciclesonide (Alvesco®)

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ICSs – Contraindications/ Warnings •  Acute episodes (effective only prophylactically) •  Systemic fungal infections, persistently positive sputum culture for C. albicans •  Caution during transfer from systemic corticosteroids to inhaled corticosteroids – several months required for recovery of HPA axis function

ICSs – Side Effects •  Adrenal Insufficiency: During/after transfer from systemic steroids to inhaled steroids or at high doses (e.g., beclomethasone 40 puffs/day or triamcinolonne 20 puffs/day) •  Dysphonia, hoarseness, throat irritation •  Cough, wheezing •  Dry mouth, bad taste, fungal infections •  Bone loss

ICSs – Patient Education

Leukotriene Modifiers

•  ICSs are not bronchodilators; not effective for rapid relief of acute bronchospasm •  Require 1-2 weeks of regular use for improvement •  May need supplemental systemic steroids during acute stress or severe attacks •  Use bronchodilator first •  Rinse mouth with water or mouthwash to minimize bad taste and prevent fungal infection

•  Inhibit the action cysteinyl leukotrienes. •  Block the pro-inflammatory action of leukotrienes thereby decreasing bronchoconstriction •  May be alternative to low-dose ICSs in mild persistent asthma or an adjunct to ICSs in severe asthma •  May decrease dose of ICSs needed to control more severe asthma

Leukotriene Modifiers – Available Products

Leukotriene Modifiers Contraindications

•  Zileuton (Zyflo®) •  Montelukast (Singulair®) •  Zafirlukast (Accolate®)

•  Hypersensitivity •  Pregnancy – – Zileuton category C – Zafirlukast, montelukast category B

•  Zileuton age >18yrs •  Zafirlukast age >12 years •  Montelukast age >6 years

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Leukotriene Modifiers – Side Effects •  Headache, pain, asthenia, dyspepsia, nausea, myalgia, fever •  Elevation in LFTs (except montelukast)

Leukotriene Modifiers – Drug Interactions •  Zafirlukast /Food – take on empty stomach •  Zafirlukast/Warfarin – increase pT/INR •  Zileuton/Warfarin – incease pT/INR •  Zileuton/Theophyline – increase theophylline levels

•  Monitor LFTs at baseline, qmonth x3, q3months x3, then yearly

Inhaled Anticholinergic •  Competitive inhibitors of muscarinic receptors – produces bronchodilation •  Has no effect on bronchoconstriction caused by vagal pathway (e.g., allergens, histamine, exercise) •  Useful as an adjuct in acute severe asthma not completely responsive to β2agonists

Systemic Corticosteroids •  Potent anti-inflammatory action •  Useful in Acute severe asthma, status asthmaticus and impending episodes of severe asthma unresponsive to bronchodilators •  Oral agents - prednisone, methylprednisolone

Inhaled Anticholinergic •  Ipatropium (Atrovent®) •  Adverse Effects: – Dry mouth, cough, nervousness, gi upset, dizziness, headache

Systemic Corticosteroids •  Limit to short courses of 5-10 days •  Multiple daily dosing provides better asthma control •  Side effects of HPA axis apparent after 8 bursts/year in adults and 4 bursts/year in children

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Corticosteroid Side Effects •  HPA axis suppression •  Osteoporosis •  Immunosuppression •  Growth retardation •  Cataracts, glaucoma •  Hypertension

Controversies •  MDIs vs nebulizers – Equivalent if proper technique or spacer used

•  β2-agonists – When to initiate – Can they increase mortality? – Monitor number of refills

Other Asthma Treatment •  Exercise Induced Asthma – 2-3 puffs of short-acting β2-agonist 15-30 minutes prior to exercise

•  Nocturnal Asthma – 1-2 puffs of long-acting β2-agonist prior to bedtime

COPD - Pathophysiology •  Inflammation, fibrosis, and narrowing of small airways contribute to increased airway resistance and obstruction •  Bronchial changes of enlarged mucous glands with smooth muscle hyperplasia, inflammation and bronchial wall thickening •  Emphysematous changes of acinar enlargement occur after prolonged unchecked protease activity on lung tissue

Emphysema

Chronic Bronchitis

•  Anatomical defects of lung characterized by permanent enlargement of the air spaces and destruction of alveolar walls thus obstruction and airway collapse occur on expiration. •  Patients adapt and use accessory muscles to breathe – prolonged expiratory phase •  “Pink Puffers” – adequate oxygenation through increased work of breathing

•  Chronic excessive mucous production and secretion resulting in airflow obstruction secondary to inflammation and edema •  Inflammation and edema of mucosa and mucous glands in airways of bronchial tree •  Result in copious tenacious sputum that is good medium for recurrent infections •  “Blue bloaters”- obese, hypoxic, cyanotic

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Goals of Therapy •  •  •  • 

Bronchodilation Reduced inflammation Mucous mobilization Pharmacotherapy may offer limited benefit since lung damage is irreversible (asthma is reversible) •  These patients often don’t tolerate medications as well as patients with asthma

TREATMENT •  Smoking Cessation •  Pulmonary Rehab – Physical conditioning, breathing exercises – Adequate nutrition

•  Immunizations •  Proper coughing techniques, postural drainage and chest percussion

The “Winstones”

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