1 Pharmacology for Physical Therapists Linda Lawless, Pharm.D. Paul LaStayo, Ph.D.,PT Definitions • Pharmacology – Study of drugs – 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 Terminology • Chemical name • Generic name • Brand (Trade) name • Drug class • Over-the-Counter (OTC) vs Rx 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 – Patients with disease being treated • Dose and safety 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
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Pharmacology for Physical Therapists
Linda Lawless, Pharm.D. Paul LaStayo, Ph.D.,PT
Definitions
• Pharmacology – Study of drugs – 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
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………
Pain Definitions
• Acute pain • Chronic pain
– Nociceptive – Neuropathic – Idiopathic – Mixed
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
• 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
Barriers to Adequate Pain Control
• Misconceptions – Minimizing patients’ reports of pain – Belief that chronic pain is untreatable – Fear of tolerance – Fear of adverse effects
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
• Transdermal Fentanyl (Duragesic®) – Each patch lasts 72 hours – Continued effects up to 17 hours after removal – Requires breakthrough med – 25 mcg/hr patch replaces approx 45mg/day
MS Contin (package insert says 90mg/day) – DO NOT APPLY HEAT TO PATCH
Patient Controlled Analgesia
• sedation and anxiety • patient satisfaction • Patient selection important • Drugs: Morphine, meperidine,
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
Anakinra (Kineret®)
• IL-1 receptor antagonist • Daily SC injection • infection risk if used with TNF inhibitor • Most common ADR – injection site
reactions
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
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
Parkinson’s Disease Pathophysiology
• 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
• 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
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
• Adverse Effects: – Drowsiness, dizziness, malaise, fatigue, and
weakness, seizures, hepatitis • Drug Interactions:
– Watch for additive effects from other CNS depressants
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
Diabetes Mellitus
CAMP LEO!!!! 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
Typical Characteristics
Characteristic Type 1 Type 2
Age at diagnosis Childhood or adolescence Over 40
Onset Rapid Gradual
Etiology Unknown Unknown
Antibodies and immunity Yes No
Body weight Thin Obese
Insulin Secretion diminished initially then absent, insulin
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
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
• 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)
• 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
• CLONIDINE – central α2-agonist • Decreases blood pressure by vasodilation • Third line agent due to many side effects • Advantage is availability as a once-weekly
nocturia, CNS symptoms Signs Tachycardia, pallor, cyanosis of digits,
cardiomegaly
CHF Compensatory Mechanisms 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
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
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
Angiotensin II Receptor Blockers
• Indications similar to ACE inhibitors
• High cost and lack of clinical trials limit these to patients who are ACEI intolerant
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
Spironolactone Adverse Effects • Hyperkalemia
• 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
The Digitalis Investigation Group. N Engl J Med 1997;336:525-533
Mortality in the Digoxin and Placebo Groups
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
• 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:
– MANY MANY MANY – Also food/drug interactions
ASTHMA and COPD
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,
• 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
• 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 - 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
• 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
• 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
Leukotriene Modifiers
• 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
• Zileuton (Zyflo®)
• Montelukast (Singulair®)
• Zafirlukast (Accolate®)
Leukotriene Modifiers - Contraindications
• Hypersensitivity • Pregnancy –
– Zileuton category C – Zafirlukast, montelukast category B
• Zileuton age >18yrs • Zafirlukast age >12 years • Montelukast age >6 years
• Nocturnal Asthma – 1-2 puffs of long-acting β2-agonist prior to
bedtime
Controversies
• MDIs vs nebulizers – Equivalent if proper technique or spacer used
• β2-agonists – When to initiate – Can they increase mortality? – Monitor number of refills
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
• 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 Bronchitis
• 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