CONGESTIVE HEART FAILURE

Semisolid dosage forms

Ointments

OINTMENTS

Pharmaceutical ointments (termed unguents) are semisolidsystems that are applied externally, primarily to the skin and also to mucous membranes, e.g. the rectum, the vagina/vulva, the eye.
Typically, medicated ointments are used for the treatment of infection, inflammation and pruritus. However, non-medicated ointments are commonly used due to their emollient/lubricating
properties. 

“Ointments are semisolid preparation intended for application to the skin with or without inunction. they may be oleaginous e.g., white ointment; they may be entirely free of oleaginous substances e.g., polyethylene glycol ointment, or they may be emulsions of fatty or wax like material containing relatively high proportion of water e.g., hydrophilic ointment.”

  ADVANTAGES
Handling of ointments is easier than bulky liquid dosage forms.
They are chemically more stable than liquid dosage forms.
They facilitate application of the directly to the effected body part and avoid exposure of other parts to the drug.
They are suitable for patients who find it difficult to take the drugs by parenteral and oral routes.
They prolong the contact time between the drug and effected area.
The bioavailability of drugs administered as ointments is more since it prevents passage through liver.
DISADVANTAGES
They are bulkier than solid dosage forms.
When applications of an exact quantity of ointment to the affected area is required, it is difficult to ascertain the same.
They are less stable than solid dosage forms.

• The various types of ointments are

Medicated ointments
Unmedicated ointments

MEDICATED OINTMENTS
These ointments contain drugs which show local or systemic effects. These are of several sub-types
Dermatologic ointments
Opthalmic ointments
Rectal ointments
Vaginal ointments
Nasal ointments
DERMATOLOGIC OINTMENTS
These ointments are applied topically on the external skin. The ointment is applied to the affected area as a thin layer and spread evenly using gentle pressure with the fingertips.These are of three types
(1) Epidermic ointments: The drugs present in these type of ointments exert their action on the epidermis of the skin.
Example: Ketoconazole ointment.
(2) Endodermic ointments: The drugs present in these types of ointments exert their action on the deeper layers of cutaneous tissue.
Example: Demodex ointment.
(3) Diadermic ointments: The drugs present in these types of ointments enter into the deeper layers of skin and finally in the systemic circulation and exert systemic effects.
Example: Nitroglycerine ointment.
OPTHALMIC OINTMENTS
These are sterile preparations which are applied inside the lower eye lid. Only anhydrous bases are used in their preparation. The ointment is applied as a narrow band of approximately 0.25 - 0.5 inch.
Example: Sulfacetamide sodium ointment.
RECTAL OINTMENTS
These are the ointments to be applied to the perianal or within the anal canal. The bases used are combinations of PEG 300 and PEG 3350, cetyl alcohol and cetyl esters, wax, liquid paraffin and white paraffin.
Example: Benzocaine ointment.
VAGINAL OINTMENTS
These ointments are applied to the vulvovaginal area or inside the vagina. As vagina is more susceptible to infections, the ointment should be free from micro-organisms, moulds and yeasts.
Example: Candicidin ointment.
NASAL OINTMENTS
These are used in the topical treatment of nasal mucosa. Drugs get absorbed into the general circulation through the rich blood supply of the nasal lining.
Example: Ipratropium bromide ointment.
UNMEDICATED OINTMENTS
These ointments donot contain any drugs. They are useful as emollients, protectants or lubricants.
Example: Petroleum jelly.

CLASSIFICATION OF OINTMENT BASES

Four different classes of bases are available
Hydrocarbon or oleaginous bases
Absorbent bases
Emulsion bases
Water-soluble bases
HYDROCARBON BASES: 
These are semisolid hydrocarbons obtained from petroleum.
Examples: Hard paraffin, yellow soft paraffin, white soft petroleum and gelled oleaginous vehicle.
ABSORBENT BASES: 
These are hydrophilic mixtures of hydrocarbons and substances with polar groups. Substances like cholesterol, lanolin, lanosterol etc., may be used in the formation of absorption bases.
Examples: Hydrophilic petrolatum, hydrous wool fat and oily cream.
EMULSION BASES:
 These are miscible with water and contain oil-in-water emulgents. They can be easily removed from the skin. They contain surfactants which serve the purpose of emulgents.
Based on the nature of surfactant present, emulsion bases are of three types.
(a) Anionic emulsion bases: contains anionic surfactants like sodium lauryl sulphate.
Examples: Hydrophilic ointment and emulsifying ointment.
(b) Cationic emulsion bases: contains cationic surfactants like cetrimide.
Example: Cetrimide emulsifying ointment.
(c) Non-ionic emulsion bases: contains nonionic surfactants like cetomacrogols.
Examples: Cetomacrogol emulsifying wax.
WATER - SOLUBLE BASES:
 They donot contain oily ingredients and are called greaseless bases. They are completely soluble in water.
Examples: Polyethylene glycols (PEGs), polyoxyl 40 stearate, and polysorbates.

•   Preparation of Ointments

In either large or small-scale production, the manufacture of ointments generally involves either of two processes—incorporation or fusion.  The objective of both the methods is to disperse the finely divided or dissolved drug substance uniformly through out the vehicle.  The method for a particular preparation depends upon the nature of the ingredients.
The incorporation method involves the blending of an ingredient into the vehicle.  This is done using a glass slab and a pair of spatulas for small volumes or using a mortar and pestle for larger volumes.  Generally, stainless-steel spatulas should be used but if the possibility of any interaction exists between the substance and the spatula blade, hard rubber spatulas must be used.
When solid ingredients are incorporated into a base it is important that the particle size be as small as possible. Solid chemicals are size reduced by levigation.  This is a process of reducing a substance to an extremely fine state of subdivision by rubbing it in a glass mortar using a pestle or on a glass slab with a metal spatula.  The ingredient can be levigated with a small volume of the base until a smooth, grit-free paste is prepared.  This is then geometrically diluted with the remainder of the base.  This procedure is useful with petrolatum or oleaginous bases.
If the compound is water soluble, it is dissolved in water and is incorporated in the base.  If the base is an anhydrous oleaginous base the liquid is first incorporated into lanolin and then blended into the oleaginous base to make the final preparation.  This blending is easily accomplished using an ointment slab and spatula to levigate the mixture until a homogenous preparation is obtained.  Compounds such as volatile oils and camphor are first dissolved in a small quantity of alcohol and then incorporated into oleaginous or emulsion bases.  However, the alcohol will evaporate and result in depositions of gritty solute on standing.  Therefore, it is usually best to evaporate the alcohol from the preparation prior to incorporation into the base.
Large volumes of ointments should be blended in mechanical mixers.  Paint-type and roller-type mills replace the hand-driven spatula or pestle to ensure a uniform consistency and homogeneity of ingredients.
The fusion method is used to incorporate ingredients with solid, hard properties such as waxes or spermaceti with soft oleaginous bases.  Frequently, all of the components are combined, melted together, and cooled with constant stirring until congealing occurs and a homogenous mixture is formed.  When heat-labile substances are incorporated, those with the highest melting point are usually heated first and then as the liquid cools the other ingredients are added at temperature a few degrees above their respective melting points.  This method prevents decomposition or volatilization of heat-labile substances.  On a small scale, the fusion process can be conducted in porcelain dishes or glass beakers; on a large scale it is commonly carried out in large steam-jacketted kettles.  Once congealed, the ointment may be further levigated on an ointment slab or if a large volume is being prepared, a commercial mill can be used.

 

INTERESTING QUESTION AND ANSWER FOR PHARMACY

Can we give erthyromycine and cefexime in same prescription?

ANS;,,

NO, because erythromycine is a bacteriostatic and cefexime is bacteriocidal. Bacteriocidal  is only active and kill those bacterial cells which are growing while statics inhibits the growth. so effect of cefexime will be vanish

RAPID PHARMACY REVIEW PAGE 3

Foot, skin and mucous membranes

Due vascular changes and peripheral neuropathy à alter nerves that control blood flow and skin hydration

Infection by staph, beta-hemolytic strept, fungus à cutaneous infection (furunculosis, carbuncles), Candida (genital, upper thighs, under breast), cellulites, lower-extremity vascular ulcers

Atrophic round painless lesions, diabetic dermopathy (red-brown popular spots) esp. in lower extremities. 

Necrobiosis lipoidica diabeticorum (ulcerative necrotic lesion)

Peripheral neuropathy à loss of protective sensation, inability to detect minor trauma à ulcers

Infection, injury, neuropathy, vascular disease à gangrene

Sensory exam of feet (protective sensation) à 10 g monofilament

Protective footwear (deep sole shoes, molded shoes, orthotics)

Significant interactions affecting glycemic control

Hyperglycemia (direct glucogenic effect): corticosteroids, furosemide, thiazides, sunburns, nicotinic acid, phenytoin, pentamidine, protease inhibitors, sympathomimetics, isoniazid, sulfinpyrazone, theophylline toxicity. 

Hypoglycemia: MAO-I, fluoxetine, salicylates (↑ dose), alcohol, fenfluramine, pentamidine

Prolonged hypoglycemia / masking hypoglycemic symptoms: B1 beta blockers (e.g. propranolol)

Therapy

Medical nutrition therapy (MNT)

Carbohydrate counting: 50% of total calories.  DM therapy may include pre-meal short acting bolus insulin (lispro, regular, semilente).  Otherwise, maintain consistent CHO intake.

Fat: limitations on type and amount.  Critical for weight loss and treating hyperlipidemia.  Target: < 30% of calorie intake and < 300 mg/day cholesterol. 

Protein: important in end stage renal disease and may delay dialysis.

Fiber:  bran, beans, fruits, vegetables may help BG and lipids.

Alter diet based on stress, illness, exercise, etc. 

Spaced meal intervals help match hypoglycemic therapy effect.

Physical activity

Careful exercise ↑ cell glucose uptake à ↓ BG

Careful if patient has severe retinopathy. 

Patients with cardiovascular disease or over 45 à cardiovascular evaluation and stress test.

Aerobic activity: e.g. swimming, walking, running, preferred due to positive effect on BG (↓), cardiovascular, BP, lipids, circulation, weight loss.

Anaerobic activity: e.g. weight lifting, should be avoided.  Potential negative cardiovascular, BP, retinopathy effects.

Insulin and insulin analogues

For type 1 DM and only uncontrolled type 2.

Mechanism / structure: see above

Factors ↑ insulin requirement: infections, weight gain, puberty, inactivity, hyperthyroidism, Cushing’s disease

Factors ↓ insulin requirement: renal failure, weight loss, ↑ exercise, nutrient malabsorption, hypopituitarism, adrenal insufficiency. 

Concentration: U-100 or U-500 for insulin resistance. 

Source: human, bovine, porcine, synthetic (Lispro insulin, Humalog), or a mixture. Human insulins are made by enzymatic conversion of terminal amino acid of porcine insulin (Novolin, semisynthetic), or by recombinant DNA (Humulin). Human insulin à ↓ antigenicity. 

Short-acting: Lispro à synthetic, shortest onset and duration. Regular à soluble insulin with neutral pH, only clear insulin (IV), only insulin that can be mixed freely.  Semilente (prompt insulin zinc suspension) à finely divided amorphous prep, use acetate buffer, mix only with other lente, similar duration to Regular, Aspart insulin analogues.

Intermediate-acting: NPH (isophane insulin suspension) à similar to protamine zinc but with no excess protamine. Lente (insulin zinc suspension) à mixture of 70% ultralente crystals and 30% semilente powder. 

Long-acting: Protamine zinc à use phosphate buffer.  Ultralente (extended release zinc suspension) à large crystalline. Glargine insulin analogue (very long acting). 

Pre-mixed insulin: 50/50 Regular/NPH, 70/30 Regular/NPH, 75/25 Lispro/Protamine Lispro à regular as pre-meal bolus and NPH intermediate for later control of hyperglycemia.  Other mixtures can be prepared extemporaneously for tailored ratios. 

DM Type 1 example: pre-breakfast is 2/3 of total daily dose (TDD) 1:2 short : intermediate.  Bedtime is 1/3 of TDD 1:2 like pre-breakfast.  Or give pre-supper rapid/short and then bedtime intermediate.

DM type 2 example: bedtime only or 2-3 daily injections. 

Subcutaneous: for routine administration.  Absorption of regular insulin is fastest from abdomen > arm > buttock > thigh.  Monitor variations in absorption.  Randomly rotate injection site to avoid lipohypertropy.  If ↑ variations à avoid random rotation of injection site. Exercise, hot showers, baths, massages à ↑ blood flow to injection site.  Abdomen is least likely to have ↑ absorption à preferred site for pre-exercise insulin. 

Continuous Intravenous (insulin drip): provide Regular insulin for acute hyperglycemia, ketoacidosis, HHNK, or during surgery.

Continuous SC infusion (insulin pump): short acting insulin is infused continuously during the day to deliver ↓ doses (basal insulin).  Bolus dose (determined by algorithms) is delivered by the patient before each meal. Offers tighter glycemic control. Used for diabetics with ↑ BG fluctuations, irregular work schedules, lifestyles, or meals.  Require frequent SMBG (BG self-monitoring) and training.

SE: hypoglycemia (tachycardia, sweating, hunger, convulsions and insulin shock), hypersensitivity, injection site local irritation.

Insulin secretagogues

Drugs (all acidic): Sulfonyrlureas: First gen: chlorpropamide, tolbutamide, acetohexamide, tolazamide, more lipid-soluble, more potent.  Second gen: glyburide, glipizide, glimperide.  Also repaglinide.

Mechanism: block ATP-sensitive potassium channels à ↑ insulin pancreatic release (primary), and also as sensitizers with time (secondary). 

Use: Type 2 (useless in type 1, require functioning beta cells).

Chlorpropamide: longest duration of action.  CI in liver and kidney disease.  ↑ SE severity and frequency, disulfiram-reaction (also with tolbutamide). 

Use insulin instead during stressful conditions (↑ risk of hyperglycemia due to ↑ counter-regulatory hormones release).

SE: severe / prolonged hypoglycemia (esp. in the elderly, w/ glipizide / glyburide), GI upset, sulfa sensitivity, sun sensitivity, headache, rash, tachycardia, hematologic problems, cholestatic jaundice. 

CI: allergy to sulfa drugs, pregnancy, lactation. 

Altered protein binding of sulfonylureas: alcohol, salicylates, NSAID’s, methyldopa, chloramphenicol, MAO-I, clofibrate, probenecid.

Therapy failure: due to ↓number of functioning beta cells.  Primary: failure to control BG within 4 weeks.  Secondary: initial control of BG, but fails to maintain control, due to progression of DM.

Repaglinide: less hypoglycemia.

Insulin sensitizers

Drugs: biguanides (metformin, basic drug), thiazolidinediones (rosiglitazone, pioglitazone).

Mechanism: anti-hyperglycermic not hypoglycemic.  ↑ sensitivity to insulin, à (metformin à work on liver, ↓ hepatic glucose production, gluconeogenesis), (glitazones à ↑ sensitivity / ↓ insulin resistance in muscle and adipose tissue).  Thiazolidinediones bind to PPARs.

Use: significant insulin resistance. 

Biguanides SE: fatal lactic acidosis, metallic taste, GI upset, ↓ vitamin B12, no hypoglycemia.  May be fatal if at ↑ risk of lactic acidosis (liver / kidney disease, hypoperfusion, hypoxia, radiography). Phenformin was d/c.

Glitazones SE: liver toxicity / failure (monitor), weight gain, edema, GI upset, no hypoglycemia. Troglitazone was d/c due to liver toxicity.  CI: liver disease.  May resume ovulation in premenopausal women. Highly protein bound (99%).

Alpha-glucosidase inhibitors

Drugs: acarbose (polysaccharide), miglitol (basic monosaccharide)

Mechanism: inhibit intestinal enzyme alpha-glucosidase à ↓ absorption of complex carbohydrates (starch, dextrins, disaccharides). Use only glucose or lactose for correcting hypoglycermia if it occurs.

Use: significant post-prandial hyperglycemia. Minimal effect on pre-prandial or fasting BG. Good combination with insulin secretagogues. Take with first bite of meal.

SE: GI (diarrhea, abdominal pain, flatulence) due to undigested carbohydrates in the lower GI, no hypoglycemia.  CI: GI conditions (inflammatory bowel, colonic ulcer, obstructive bowel, intestinal gas), liver cirrhosis (monitor liver function), pregnancy.

52. Thyroid Disease

Physiology

Thyroid hormone regulation / function

Thyrotropicn-releasing hormone (TRH): secreted by the hypothalamus, triggers the release of TSH through negative feedback mechanism.

Thyroid stimulating hormone (TSH): released by the anterior pituitary gland, controls thyroid hormone secretion and transport.

Thyroid gland produces thyroxine (T4), triiodothyronine (T3) (both for growth, development, metabolic rate), and calcitonin (↓ blood calcium).

Thyroid hormone is transported in the circulation by thyroxine-binding globulin (TBG), and albumin.  Protein binding protects hormone from premature metabolism, excretion, and prolongs its t1/2. 

Metabolism: T4àT3 conversion in pituitary gland, liver, kidneys.

Degradation: by deiodination à feces / urine excretion.

Function: Activate mRNA and ↑ protein synthesis or catabolism (↑ dose).  ↑ growth, development, ↑ basic metabolic rate, ↑ blood flow, ↑ cardiac output, ↑ heart rate, fine muscle tremor, fatigue wakefulness, ↑ lipid mobilization and degradation, ↑ bone remodeling (rate of resorption > rate of formation).

Biosynthesis

Dietary iodine: critical for thyroid hormone synthesis, reduced to inorganic iodide then exracted from plasma by the thyroid by iodide trapping (iodide pump). 

Organification: oxidation of iodide by peroxidase.  Synthesis starts with iodide-tyrosine binding à modoiodo then dioiodo-tyrosine. 

Thyroid function studies

Serum total thyroxine (TT4):

Most direct reflection of thyroid function by indicating hormone availability in tissues. Total (free and bound) T4 is determined by radio-immunoassay (sensitive, rapid).

TBG ↑ during pregnancy à misleading results (bound T4).

↑ TT4 à hyperthyroidism, and vice versa

Serum total triiodothyronine (TT3):

Measures total (free and bound) T3.  TT3 rise before TT4, useful for early detection.  ↑↑ in hyperthyroidism (more than T4), responsible for symptoms.  Pregnancy à ↑ TT3.

Resin triiodothyronine (RT3U):

Evaluates the binding capacity of TBG.  Clarifies whether abnormal T4 is due to thyroid disorder or abnormal protein binding. If abnormal thyroid in the blood à RT3U changes in same direction (↑ in hyperthyroid).  If abnormal protein binding à RT3U changes in opposite direction (↓ in hyperthyroid). 

Serum thyrotropin (TSH) assay:

Serum TSH assay: most sensitive test for hypothyroid, but nor reliable in hyperthyroid (TSH is suppressed).

Sensitive TSH assay: uses monoclonal antibodies known as immuno-radiometric or immunometric (IMA) method (vs. the older radio-immunoassay).  ↑ sensitivity, ↑ cost, more commonly used to control over treatment of replacement therapy. 

Free thyroxine (T4) index (FTI):

Not a separate test but rather an estimation of free T4 level by a calculation involving serum T4 and RT3U.  ↑ FTI à hyperthyroid or ↓ TBG.

Strategies for testing

Most common and ↓ expensive: TT4, RT3U, FTI.

Thyroid disease screening for healthy population is not cost effective. Screen only target population (elderly, chronic disease hospitalization,

Use FTI and Sensitive TSH for disease diagnosis.

Hypothyroidism

Classification

Primary hypothyroidism: due to gland destruction or dysfunction caused by disease or therapy (radiation, surgery).

Secondary hypothyroidism: due to ↓ TSH secretion (pituitary disorder). Thyroid gland is normal but not enough TSH stimulation.

Tertiary hypothyroidism: ↓ TRH (hypothalamus) to stimulate pituitary

Causes

Hashimoto’s thyroiditis: chronic autoimmune thyroiditis.

Treatment of hyperthyroidism: e.g. radioactive iodine, subtotal thyroidectoym, antithyroid drugs.

Goiter: enlargement of the thyroid gland.  Endemic goiter: due to inadequate dietary iodine (malnutrition).  Sporadic goiter: due to foods or drugs containing progoitrin (inactive à hydrolysis à active goitrin) à ↓ oxidation of iodine to iodide.  Goitrogenic drugs: propylthiouracil (PTU), iodides, cobalt, lithium, phenylbutazone.  Other causes: thyroiditis, thyroid cancer.

Surgical excision

Signs and symptoms

Vague early symptoms: lethargy, fatigue, sensitivity to cold, weight gain, constipation.  Later: features of Myxedema such as dry flaky inelastic sin, coarse hair, puffy face / hands / feet, eyelid droop, slow speech / thought, ↓ libido, coma (if not controlled). 

Myxedema coma

Life threatening condition in old patient with undiagnosed hypothyroidism

Precipitating factors: alcohol, sedative / narcotic use, antithyroid overdose, d/c thyroid replacement, infection, cold exposure, radiation, surgery. 

Symptoms: coma, hypothermia, ↓ respiratory rate à failure, hypometabolism à fluid / electrolyte retention à fluid retention, hyponatremia, ↓ heart rate / contractility, ↓ heart output. 

Treatment: rapid restoration of T3 and T4 to normal levels.  IV bolus levothyroxine, oral liothyronine, then oral levothyroxine.

Drugs

Desiccated thyroid preparations: not commonly used anymore.  Different preparations are not bioequivalent (varying amounts of actives depending on source (bovine, ovine, porcine). 

Fixed ratio (liotrix) preparations: standard ratio of T4/T3.  T3 is, however, unnecessary (T4 converts to T3) à cause SE tremor, headache, palpitations, diarrhea.

Levothyroxine: agent of choice, predictable results, no T3.  Individual variable response to different preparations à care if to switch.  Use ↓ dose for elderly or chronically ill patients.  Results start after 2 wk, full response after 4-5 months (TSH levels ↓ to normal levels). 

  Precautions

Careful in the elderly and in case of cardiac disease.  Start with ↓ doses.

Watch for cardiac complications (palpitations, arrhythmia, angina).

Monitor thyroid levels (T4, RT3U, FTI, sensitive TSH). 

Long term levothyroxine therapy can cause thyrotoxicosis. 

Accelerated bone loss due to over treatment à nontraumatic fracture.

CI: cholestyramine (bile acid sequestrant) à ↓ thyroxine bioavailability.  Separate drug by 6 hours. 

Hyperthyroidism / thyrotoxicosis

Grave’s disease (diffuse toxic goiter)

Most common form.  Occurs usually in young women. 

Autoimmune disease, antibodies (long-acting thyroid stimulators, LATS) bind to and activate TSH receptors (does not actually increase TSH itself).

Symptoms: enlarged goiter, exophthalmos, stare, nervousness, irritability, anxiety, insomnia, heat intolerance, ↑ sweating, ↑ appetite, ↓ weight, muscle tremor / weakness, tachycardia, palpitations, diarrhea.

Signs:

Plummer’s disease (toxic nodular goiter)

Less common.  Common in the elderly.  Caused by adenoma nodules autonomously secreting excessive thyroid. 

Symptoms: same as Grave’s with nodular masses rather than diffusion enlargement.

Other forms

Jodbasedow phenomenon: hyperthyroid due to ↑↑ iodine ingestion or amiodarone.

Factitious hyperthyroidism: due to abusive ingestion of thyroid replacement drugs to lose weight.

Drugs

Beta blockers – propranolol

Propranolol ↓ peripheral symptoms (tachycardia, sweating, tremor, nervousness).  It also ↓ peripheral T4àT3 conversion (deiodonation). 

Antithyroid drugs

Examples: propylthiouracil (PTU), methimazole.

Mechanism: interferes with thyroid hormone synthesis by ↓ iodide oxidation.  PTU ↓ peripheral T4àT3. 

Dosing: initial dose (2 mo), maintenance dose (12 mo), gradual withdrawal (2 mo).  Restart therapy if signs of hyperthyroidism appear.

Monitor serum thyroid, FTI and goiter size.

SE: skin rash, urticaria, pruritus, hair loss, skin piementation, drowsiness, myalgia, arthralgia. Severe SE: blood (agranulocytosis, granulocytopenia, thrombocytopenia), monitor blood count.

Radioactive iodine (RAI)

Mechanism: thyroid gland picks up the radioactive element iodine-131 as it would regular iodine.  Radioactivity destroys cells. 

Advantages: ↑ cure rate (100%), avoid surgical risks, ↓ cost

Disadvantages: risk of delayed hypothyroidism, delayed effect.

SE: only for women past childbearing years.  Response is hard to gauge (too much, too little). 

Subtotal thyroidectomy

Partial removal of the thyroid gland. Last resort. 

Advantages: ↑ success rate, rapid cure.

SE: thyroid storm, permanent hypothyroidism.

Complications

Hypothyroidism: may follow Grave’s disease.

Thyroid storm (thyrotoxic crisis): is a sudden exacerbation of hyperthyroidism caused by rapid release (leakage) of thyroid hormone (↑↑ T4) à fever, tachycardia, restlessness, tremor, hyper-meabolism à dehydration, shock, death if not treated rapidly.  Precipitating factors: thyroid trauma, surgery, radiation, infection, sudden d/c of antithyroid therapy.  Treatment: PTU, methimazole, proproanolol, potassium iodide (↓ intrathyroidal iodine intake), supportive therapy (rehydration, cooling, AB, rest, sedation).

54. Cancer Chemotherapy

Principles of oncology

Cancel cells

Tumors arise form a single abnormal cell, which continues to divide indefinitely. Characteristics: no growth control, can invade local tissues, can spread (metastasize).

Incidence

Second leading cause of death in the US.

Affects 30% of all people at some point in life.

Some forms of cancer are curable if detected / treated early.

Etiology

Viruses: Epstein-Barr virus, hepatitis B, human papilloma viruses.

Environmental / occupational exposures: ionizing / UV radiation, chemicals (benzene, asbestos, vinyl chloride).

Life-style: ↑ fat, ↓ fiber diet, ethanol, tobacco.

Medications: alkylating agents, immunosuppressants.

Genetics: inherited mutations, cancer-causing genes (oncogenes).

Detection / diagnosis

Warning signs: CAUTION.  Change in bowel / bladder habits, A sore that does not heal, Unusual bleeding / discharge, Tissue thickening or lumps (e.g. breast), Indigestion of difficulty swallowing, Obvious change in a wart or mole, Nagging cough or hoarseness.

Guidelines for screening: for asymptomatic people à mammography (breast cancer), fecal occult blood test (colon cancer), Pap smears (cervical cancer).

Tumor markers: biochemical indicators of the presence of neoplastic proliferation in serum, plasma, other body fluids. Not definitive. Include: prostate specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP).

Tumor biopsy: definitive test for cancer cells is pathology of a biopsy.

Imaging studies: x-ray, computerized tomography scans, MRI, positive emission tomography.

Lab tests: complete blood count, blood chemistries.

Staging

It is the categorizing of patients according to extent of the disease.  Used to determine prognosis. Two system are used for neoplasm staging.

TNM: T = tumor size (0-4), N = regional lymph node spread (0-3), M = presence of absence of distant metastases (0-1).  Example: T2N1M0.

AJC: by the American Joint Committee on staging.  Scale: 0-IV.

Survival

Depends on tumor size, disease extent, treatment received.

60% survive more than 5 years, but not all survivors are cured. “Complete response or remission” when no evidence of disease after treatment. Slow growing tumors à 10-15 disease free years.

Cell life cycle

Phases of the cell cycle

M phase (mitosis): cell divides into two daughter cells

G1 phase (postmitotic gap): synthesis of RNA and proteins

S phase (synthesis): synthesis of DNA

G2 phase (premitotic / postsynthetic gap): production of RNA and topoisomerisae I/II enzymes (important for DNA replication and RNA transcription).

G0 phase (resting): cell is not dividing. Cells now are not sensitive to chemotherapy. Recruitment: resting cells re-enter actively divided cell cycle caused by some chemotherapy agents.

Cell growth kinetics

Cell growth fraction: proportion of the cells in the tumor dividing or preparing to divide. Large tumor à ↓ nutrients and blood supply to some cells à ↓ cell growth fraction.

Cell cycle time: average time for a cell that has just completed mitosis to grow and again pass through mitosis (divide). Cycle time is specific  for each individual tumor.

Tumor doubling time: time for the tumor to double in size. Large tumor à ↓ cell growth fraction à ↑ doubling time

Gompertzian growth curve: illustrates cell growth kinetics concepts.

Tumor cell burden

Number of tumor cells in the body. Number required for clinical symptoms: 10⁹ (large number) à tumor may be in plateau phase of growth curve when detected_.  Body immunologic defenses may be able to keep tumor cells less than 1000 under control.

Each cycle of cancer chemotherapy kills a certain percentage of tumor cells (depending on the dose). When tumor cells are killed à Cells in G0 phase may be recruited to G1 phase à tumor regrowth. Therefore, repeated cycles of treatment are required for complete response or remission.

Drug reliance on cell cycle kinetics for cytotoxic effect

Phase specific agents: M à vinca alkaloids / taxanes, G1 à asparaginase / prednisone, S à antimetabolites, G2 > bleomycin / etoposide.

Phase nonspecific agents: effective when cell are at any phase of the active cycle.  Examples: alkylating agents, cisplastin, antitumor antibiotics.

Cell cycle nonspecific agents: effective in all phases including G0.  Example: nitrosoureas, radiation.

Combination of drugs that are active in different cell cycle phases will result in greater cell kill.

Chemotherapy

Therapy objectives

Cure: sought with aggressive therapy for long time to eradicate all disease. Example for leukemia: remission induction, attempt maximal cell kill and therapy consolidation to eradicate all clinically detectable disease and get tumor cell count ↓ 1000.

Palliation: goal is to control symptoms when complete eradication of tumor is unlikely or if patient refuses aggressive therapy.

Adjuvant: given after more definitive therapy (e.g. surgery) to eliminate any remaining disease.

Neoadjuvant: goal is to ↓ tumor burden before surgery or radiation.

Dosing

May be bases on body weight, BSA or AUC. BSA is preferred (correlates with cardiac output which determines renal / hepatic blood flow / elimination). Adjust dose for liver or kidney dysfunction.

Dosing is usually given as short courses in cycles.

Combination chemotherapy

To overcome or prevent resistance, achieve cytotoxicity to resting and dividing cells, enhance biochemical effect, rescue normal cells.

Acronyms are often used to indicate certain combinations.

Administration

IV is the most common

Inrathecal: for methotrexate, hydrocortisone, cytarabine, thiotepa.

Response to chemotherapy

Does not always correlate with survival.

Complete response: disappearance of all disease (clinical, gross, microscopic).

Partial response: > 50 reduction in tumor size for a period of time.

Response rate: defined as complete response + partial response.

Progression or no response: > 25 increase in tumor size or appearance of new lesions.

Classification of chemotherapeutic agents

Alkylating agents

Prototype: mechlorethamine (nitrogen mustard)

Mechanism: cross-linking and abnormal base-pairing of DNA strands à ↓ DNA replication.

Nitrogen mustards: chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan.

Ethylenimines / methylmelamines: thiotepa, altretamine.

Alkyl sulfonates: bisulfan

Nitrosoureas: carmustine, lomustine, semustine, streptozocin.

Triazenes: dacarbazine

Platinum coordination complexes: cisplatin, carboplatin

Substituted ureas: hydroxyurea

Others: procarbazine, temozolomide.

Antitumor antibiotics

Most come from Streptomyces

Mechanism: alkylation (mitomycin) or intercalation. Intercalation: drug slides between DNA base pairs and ↓ DNA synthesis.

Anthracyclines: daunorubicin (daunomycin), doxorubicin (adriamycin, hydroxydaunorubicin), epirubicin, idarubicin.

Anthracendiones: mitoxantrone

Others: bleomycin, dactinomycin, mitomycin, plicamycin (mithramycin).

Antimetablites

Structural analogs of naturally occurring substrates for biochemical reactions. 

Mechanism: false substitution in production of nucleic acid à ↓ DNA synthesis.

Adenosine analogs: cladribine, fluudarabine, pentostatin (deoxycoformycin).

Folic acid analogs (folate antagonists): methotrexate, trimetrexate, raltitrexed.

Purine analogs (purine antagonists): mercaptopurine, thioguanine

Pyrimidine analogs (pyrimidine antagonists): fluorouracil, capecitabine, cytarabine, gemcitabine.

Plant alkaloids

Vinca à prevent formation of the mitotic spindle à arrest cell division.  Examples: vinblastine, vincristine, vindesine, vinorelbine.

Camptothecins à inhibit topoisomerase I.  Examples: irinotecan, topotecan.

Podophyllotoxins à inhibit topoisomerase II.  Examples: etoposide, teniposide.

Taxanes à ↑ microtubule assembly / stabilization à ↓ cell division. Examples: taxol (paclitaxel), taxotere (docetaxel).

Hormones

Androgens: testosterone, fluoxymesterone

Antiandrogens: bicalutamide, flutamide, nilutammide.

Antiestrogens: tamoxifen, toremifene.

Aromatase inhibitors: letrozole, anastrozole, exemestane, aminoglutethimide.

Corticosteroids: prednisone, dexamthasone

Estrogens: ethinyl estradiol, diethylstilbestrol.

Estrogen/nitrogen mustard: estramustine

Progestins: medroxyprogesterone, megestrol

Luteinizing hormone releasing hormone analogs: leuprolide, goserelin

Asparaginase

Mechanism: enzyme that causes the degradation of essential AA asparagine to aspartic acid and ammonia. Normal cells can synthesize asparagine but tumor cells can not.

Biologic response modifiers

Mechanism: alter the patient’s immune system to fight cancer or to ↓ SE of cancer treatment. Examples: Bacillus Calmette-Guerin (BCG), Colony-stimulating factors (erythropoietin, filgrastim, sargramostim), interferons (alpha, beta, gamma), interleukins (IL-2, IL-11), levamisole, monoclonal antibodies (rituximab, trastuzumab).

Toxicity of chemotherapeutic agents

Most toxic to the most rapidly proliferating cells (mucous membranes, cells, hair, GI tract, bone marrow).

Bone marrow depression

Most life threatening SE.  Effect is dose related.

↓ WBC (especially neutrophils; neutropenia) à serious infections.

Colony stimulating factors: used to ↓ extent of neutropenia.

↓ platelets (thrombocytopenia) à bleeding à give platelet transfusion.

Anemia is not as common because RBC lifespan is 120 days.

Time course: onset à 1 week, lowest count point (nadir) à 2 weeks, count recovery à 3 weeks.

Dermatological

Alopecia: partial or complete, can not be prevented.

Local necrosis: results from extravasation during administration of vesicant drugs à immediate pain / burning + possible delayed reaction à tissue damage, necrosis, ulceration à require plastic surgery. Treatment: cold for all drugs except vinca and taxanes (use heat).

Skin changes: dryness, sun sensitivity (methotrexate, fluorouracil).

GI toxicity

Nausea and vomiting

Most distressing SE from the patient’s viewpoint.

Acute, delayed or anticipatory.

Antiemetics are used for prophylaxis.

Vomiting à dehydration, electrolyte imbalance, esophageal tears à d/c therapy.

Stomatitis

Common with methotrexate, fluorouracil (same as skin changes)

General inflammation of the oral mucosa or other areas of the GI with rapid turnover of cells.

Symptoms: erythema, pain, mouth dryness, lip tingling / burning, ulceration, bleeding à infection, inability to eat. 

Time course: starts in 1 week, resolve in 2 weeks.

Other SE: fluorouracil à diarrhea, vincristine à constipation.

Pulmonary

Irreversible and may be fatal. Especially with bleomycin, mitomycin.

Symptoms: breath shortness, unproductive cough.

Cardiac

Acute: transient ECG abnormalities. Not important.

Chronic: irreversible CHF due to drugs or radiation.

Dexrazoxane: cardioprotective (use with doxorubicin).

Neurotoxicity

Due to intrathecal or systemic therapy.

Autonomic / peripheral neuropathy: due to vincristine. Vincristine is fatal if given intrathecally.

Peripheral neuropathy / ototoxicity: due to cisplatin.

Arachnoiditis: due to intrathecal methotrexate, cytarabine.

Hemorrhagic cystitis

Bladder toxicity due to cyclophosphamide and ifosfamide. Acrolein: metabolite of these drugs à chemical irritation of bladder mucosa à bleeding. Prevention: aggressive hydration with frequent urination, mesna (binds to acroltein à prevents it from contacting bladder mucosa).

Other

Hypersensitivity: may be life threatening (anaphylaxis).

Chills / fever: especially with bleomycin.

Hepatoxocity: ↑ liver function tests, jaundice, hepatitis.

Nephrotoxicity: ↑ serum creatinine, ↑ BUN, electrolyte imbalance. Use amifostine to protect the kidney if using cisplatin.

Secondary malignancies: such as leukemia, solid tumors, lymphoma.

Female infertility: may be temporary or permanent .

Other chemotherapeutic modalities

Surgery: can be diagnostic or therapeutic

Radiation: ↑ doses of ionizing radiation directed at the cancerous tissue. SE: stomatitis, myelosuppression, GI (nausea, vomiting, diarrhea).

It’s common to combine drugs, surgery and radiation.

55. Pain Management

Definitions

Pain: unpleasant sensory and emotional experience that usually is associated with structural or tissue damage.  No objective measurement.

Acute pain: lasts < 30 days.  Occurs after muscle strains and tissue injury.  Self limiting, ↓ w/ time as injury heals, linear process with beginning and end, ↑ autonomic NS: ↑ heart rate, ↑ breath rate, ↑ BP, mydriasis, anxiety.

Chronic pain: persistent or episodic, > 6 months. 

Chronic non-malignant pain: complication of acute injury, disease (osteoarthritis, rheumatoid arthritis, fibromyalgia, degenerative disorders).  Cyclic, constant, does not improve w/ time.  No ANS stimulation.  Depression, insomnia, weight loss, sexual dysfunction

Chronic cancer pain: similar to non-malignant pain, depression, fear, anger, agony.  Due to cancer therapy or tumor (bone metastasis, compression of nerves, occlusion of blood vessels, obstruction of bowel, infiltration of soft tissue). 

Breakthrough pain: intermittent, transitory ↑ in pain. 

Principles of pain management

Comprehensive pain management:  chronology, history, symptomatology, onset, location, intensity, duration, quality, distribution, provoking factors, underlying disease / trauma, allergies, analgesic response, side effects. 

Pain management targets: ↑ patient comfort (may aid healing in acute pain), break pain cycle (chronic pain), ↓ breakthrough pain, improve sleep, well-being, self-esteem, mobility, psychology, etc.

Individual management regimens: dose, intervals, mode of administration, adjunct therapy.  Avoid narcotics for chronic non-malignant pain.  Long acting analgesics (round the clock) for cancer pain.  Intermittent prn short-acting analgesics for breakthrough and acute pain.  Reassess and change regiment as needed. 

Analgesics

Non narcotic analgesics

General uses: antipyretic, anti-inflammatory (except acetaminophen), analgesic ceiling effect, no tolerance, no dependence.  OTC: aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen (low doses). 

General SE

1.  Gastro-intestinal:

Due to PG inhibition.  With all except acetaminophen, COX-II inhibitors, choline magnesium trisalicylate, etanercept. 

Symptoms: dyspepsia, ulceration, bleeding, perforation. 

Especially in the elderly, ulcers, smokers, alcoholics. 

Avoid by combo therapy with GI protectants (PPI, misoprostol, H₂-antagonists, antacids, sucralfate) or enteric coating (aspirin). 

2.  Hematologic:

Exceptions: acetaminophen, choline mg trisalicylate, etanercept. 

Inhibit platelet aggregation by reversibly inhibiting PG synthase.  Aspirin is an irreversible inhibitor. 

Contraindicated with anticoagulants (warfarin, heparin, etc)

3.  Renal:

PG inhibition, interstitial nephritis, impaired renin secretion, ↑ tubular water/Na reabsorption à reversible abrupt oliguria

Salicylates

Chemistry: derivatives of salicylic acid (from Willow bark).  Weak acids with excretion ↑ by ↑ pH.  Aspirin is acetyl salicylic acid, hydrolyses easily, unstable in water, moisture.  Other salicylates: diflunisal, methyl salicylate (topical, wintergreen oil), salsalate, mesalamine, olsalazine, sulphasalazine, sodium thiosalicylate (injection), choline salicylate (oral liquid).

Pharmacology: ↓ cyclooxygenase (COXI/II) à ↓ local PG à analgesic, antipyretic, anti-inflammatory.  Aspirin is the only salicylate that ↓ COX irreversibly by covalent acetylation.  Also, ↓ platelet COX à ↓ thromboxane A2 formation à ↓ platelet aggregation / thrombus formation.

Indications: analgesics (skeletal muscle pain, headache, neuralgia, myalgia, spasmodic dysmenorrhea), anti-inflammatory (arthritis, rheumatic fever), antipyretic (avoid in children with viral infection à Rye’s syndrome), prophylaxis of MI.  Mesalamine, sulphasalazine, olsalazine à ↓ inflammation in inflammatory bowel disease, Crohn’s disease.  Methyl salicylate à topical counter irritant.  

SE: GI upset (nausea, vomiting, discomfort, irritation, ulceration, hemorrhage), ↑ bleeding, delayed labor, ↑ depth of respiration, hyperglycemia, glycosuria.  Low dose (2 g) à ↓ urate excretion (↑ blood level).  High dose (5 g) à opposite.  Toxicity: salicylism (tinnitus).  Oral methyl salicylate can be fatal. Sulphasalazine à male infertility.  Acute hypersensitivity (asthma, rhinitis, urticaria, shock, etc).  May have cross-sensitivity to other NSAID

DI: Oral anticoagulants (due to platelet inhibition and gastric mucosal damage à↑ bleeding). Methotrexate: ↑ toxicity with salicylates by blocking methotrexate renal tubular secretion. 

NSAIDs

Examples: (x-profen) ibuprofen, ketoprofen, fenoprofen, flurbiprofen, naproxen (sodium), indomethacin, piroxicam, diclofenac, ketorolac (oral, IM), etodolac, oxyprazocin, tolmetin, sulindac, meclofenamate, mefanemic acid, nabumetone.  COXII inhibitors: celecoxib, rofecoxib, valdecoxib.

Chemistry: Many are acid derivatives.  Most are from propionic (x-en) or acetic acid.  Others: fentamates, oxicams or anthanilic acid derivatives.  COX-II inhibitors à pyrazole derivatives. 

Pharmacology: COX-I produces PG cytoprotective of stomach lining. COX-II produces PG for pain / inflammation.  NSAIDs: ↓ COXI/II à ↓ local PG synthesis. COX-II inhibitors: ↓ COXII only.

Indications:  NSAIDs: mild to moderate pain, rheumatoid arthritis, osteoarthritis, gout, additive analgesia with narcotics.  COX-II inhibitors: rheumatoid arthritis and osteoarthritis. 

Ketorolac IM: for moderate to severe pain (strongest NSAID for analgesia) when narcotic are undesirable (addicts, respiratory depression, sedation). 

Indomethacin: strongest NSAIDS for inflammation, ↑ CNS SE.  Use for ductus arterisous in premature infants.

SE: NSAIDs: GI upset (dyspepsia, mucosal erosion), CNS depression / drowsiness, ↓ platelet function, skin rash, kidney damage.  COX-II inhibitors: kidney damage, ↓ GI upset. 

DI: NSAIDs ↓ effect of diuretics (due to ↓ renal perfusion). COXII inhibitors are CI in allergy to sulfonamides, aspirin, NSAID’s

p-Aminophenols

Acetaminophen is the prototype (APAP, acetyl para-amino phenol).  Also, phenacetin. 

Mechanism: ↓ central PG à analgesic, antipyretic.  No peripheral PG blocking à no effect on inflammation, platelets. 

Use: alternative antipyretic, analgesic to salicylate.  Unlike aspirin, safe as antipyretic for children with viral infections.

SE: ↓ at normal doses (skin rash).  Acute overdose à liver failure.  Antidote: N-acetyl cysteine. CI: alcoholism.

Pyrazolones

Chemistry: prototype is phenylbutazone, its metabolite is oxyphenbutazone.  Also sulfinpyrazone. 

Mechanism: ↓ PG synthesis, stabilize lysosomal membrane à analgesic, antipyretic, anti-inflammatory, uricosuric.  Sulfinpyrazone à only uricosuric à↓ hyperuricemia in gout. 

Use: (oxy)phenylbutazone à short term treatment of rheumatoid arthritis and gout (not first choice).  

SE: ↑ SE.  blood dyscrasias (agranulocytosis, thrombocytopenia, anemias), GI uspet, ulceration, kidney damage, hyperglycemia, skin rash, CNS (drowsiness, headache). 

Narcotic analgesics (opioids)

Chemistry

Include natural opiate alkaloids and synthetic analogs

Derived from opium (oldest drug) from poppy seed capsule. 

Morphine: phenolic hydroxyl group is critical for activity.  Most important alkaloid (pharmacologically and quantitatively).  Amphoteric structure à erratic oral absorption.

Agonists: morphine, codeine, heroin, oxycodone, oxymorphone, hydromorphone, hydrocodone, dihydrocodone, meperidine, fentanyl (transdermal), propoxyphene, loperamide, methadone / levorphanol (both long t_1/2), diphenoxylate, sufentanil, dezocine.

Antagonists: methyl group on nitrogen atom is replaced by bulkier group. Examples: naltrexone, naloxone, levallorphan (?).

Mixed agonists-antagonists: nalbuphine, buprenorphine, butorphanol, pentazocine, can ppt withdrawal symptoms if used after agonists.

Mechanism

Endogenous peptides (enkephalins, endorphins, dynorphins) provide self-pain relief.  Opioid receptors: in the brain / spinal cord (Types: μ, κ, σ, δ, ε)

Effects of mu receptor stimulation (morphine-like): analgesia, sedation, miosis, euphoria, physical dependence, respiratory depression, bradycardia

Other actions: cough suppression, CTZ stimulation (nausea, vomiting).

Opioids mimic the action of endogenous opioid peptides at CNS opioid receptors à ↑ pain threshold and tolerance. 

Clinical use

Moderate to severe pain, acute or chronic, of visceral or somatic origin, e.g. MI, cancer, labor, etc. Pre-anesthesia and adjuncts during anesthesia. Anti-tussives (codeine, dextromethorphan). Antidiarrheal (loperamide, diphenoxylate).

Pure antagonists are used as antidotes to reverse SE of agonists or agonists-antagonists (respiratory depression, CV depression, drowsiness).  Naltrexone is used for opioid addition.

Dose is increased gradually until the appearance of limiting SE

Mixed agonist-antagonist preferred for acute pain respiratory depression risk is ↑.  Avoid with chronic opioids à withdrawal. 

Oral: preferred esp. for chronic stable pain.  CR morphine and oxycodone available for continuous pain (e.g. cancer)

IM, SC: used post-operatively.  Absorption is not predictable.

IV bolus: most rapid, predictable onset for breakthrough pain

IV infusion: to titrate pain relief rapidly for unstable chronic pain, esp. morphine. 

IV PCA: for acute post-operative pain.  Small doses delivered at frequent intervals (10 min). 

Epidural / intrathecal: for acute post-operative pain and chronic cancer pain.  Intrathecal dose = 0.1 epidural dose.  Must be preservative free due to neurotoxicity of parabens and benzyl alcohol.  Intrathecal local SE: itching, urinary retention. Epidural: ↓ brain level à ↓ SE à give if respiratory depression risk is ↑. Labor à meperidine (less neonatal respiratory depression).

Rectal: alternative to oral.  Patient un-preferred, poor absorption. 

Transdermal: CR fentanyl (3 days).  Alternative to oral for chronic pain.  Slow onset, require oral supplement.

Adverse effects

Constipation: due to ↓ intestinal tone and peristalsis.  After several days (↑ with codeine).  Prophylaxis: laxative / stool softener combo (bisacodyl / docusate) if to be used chronically. 

Respiratory depression: most serious.  Monitor respiratory rate if at risk.  Use IV naloxone (antagonist) to reverse life-threatening depression, but may ppt withdrawal if on chronic opiates. 

Nausea / vomiting: due to central stimulation of chemoreceptor trigger zone, esp. in parenteral dosing for acute pain.  May need anti-emetic (hydroxyzine, prochlorperazine), but may ↑ sedation. 

Sedation: dose-related and ↑ with other sedatives (BZD, anti-emetics).  Tolerance develops if chronically used.  May need CNS stimulant (methylphenidate, dextroamphetamine).  Different from physiological sleep (pain is controlled à patient rests).

Anticholinergic: dry mouth, urinary retention. 

Hypersensitivity: not true allergy.  Itching or wheel at injection site due to histamine release, esp. with intrathecal or epidural. 

Meperidine à CNS excitation: seizure-like, esp. in renal failure patients.  Due to accumulation of normeperidine metabolite. 

Tolerance: to analgesic, sedative and euphoric effects.  Combo with NSAID may help overcome this problem.

Other SE: miosis, euphoria, confusion / hallucinations, coma, orthostatic hypotension, arrhythmias, histamine release (itching, vasodilation à ↓ BP, bronchoconstriction).

Dependence: Withdrawal symptoms: anxiety, irritability, insomnia, chills, salivation, rhinorrhea, diaphoresis, nausea, vomiting, GI cramping, diarrhea, piloerection.  Long t_1/2 à less intense / delayed withdrawal.  Reduce acute withdrawal by using antagonist (naloxone) or agonist-antagonist (pentazocine). 

Drug interactions: additive CNS depression (alcohol, anesthetics, antidepressants, antihistamines, barbiturates, benzodiazepines, phenothiazines).  Meperidine with MAO inhibitors à hypertension, excitation, rigidity. 

Tramadol

Oral, centrally acting, non-controlled, analgesic with weak opiate (mu) activity for moderate to severe pain.  Chemically unrelated to opioids.

Mechanism: bind to opiate receptors à ↓ norepinephrine, serotonin reuptake.  Naloxone is a partial antagonist. 

SE: GI (nausea, constipation, dry mouth), CNS (dizziness, drowsiness, headache), ↓↓ respiratory depression, histamine release.

DI: ↑ sedation with alcohol and hypnotics.  Inhibits MAO à avoid with MAO inhibitors (à seizures)

Miscellaneous agents

Glucosamine sulfate and chondroitin sulfate

For degenerative joint disease (arthritis)

Glucosamine: substrate and stimulant for biosynthesis of hyalouronic acid and glucosaminoglycans forming proteoglycans in structural matrix of joints. SE: GI, drowsiness, headache, rash.

Chondroitin: substrate for formation of healthy joint matrix

Analgesic adjuncts

Other drugs affect non-opiate pain pathways à may help with certain types of pain (e.g. neurogenic / neurologic), or to ↓ SE

Examples: tricyclic antidepressants, anticonvulsants, BZD, neuroleptics, corticosteroids, antihistamines, amphetamines. 

Non-pharmacological pain management

Include Cognitive Behavioral Interventions (education, instruction, relaxation, biofeedback, hypnosis), and Physical methods (acupuncture, physical therapy, compression gloves, orthotic devices, heat / cold, massage, immobilization, exercise, rest, transcutaneous electrical nerve stimulation (TENS)

56. Nutrition and the Hospitalized Patient

I.  Nutritional problems in hospitalized patients

a. Malnutrition:

Pathologic state resulting from the relative or absolute deficiency or excess of one or more essential nutrients.

b. Marasmus:

Chornic state (over months or years) that result from deficiency in the total calorie intake à depletion of fat stores and skeletal proteins to meet metabolic needs. 

Visceral protein is preserved (normal serum albumin, prealbumin, transferrin).

Immune competence, wound healing and ability to handle short term stress are preserved

Aggressive nutritional repletion can result in metabolic distrubances (e.g. hypokalemia, hypophosphatemia)

c.  Kwashiorkor

Acute pricess (within weeks) due to inadequate protein intake

Visceral protein depletion, impaired immune function

Hypermetaboism (e.g. trauma, infection, surgery) + protein deprivation à kwashiorkor malnutrion, hypoalbuminemia, edema

Aggressive nutritional protein repletion is warranted

d.  Mixed marasmus kwashiorkor

Severe protein-calorie malnutrition when marasmic patients are hypermetabolic

II.  Nutritional assessment of metabolic requirements

A. Nutritional assessment

1.  Subjective global assessment (SGA): relies on patient history

2. Prognostic nutritional index (PNI)

Derived from a formula that quantifies patient’s risk of developing complications based on markers of nutritional status such as: serum albumin (visceral protein), triceps skn fold thickness and delayed hypersensitivity skin-test reactivity (immune competence). 

PNI<40 à low risk,  PNI>50% à high risk. 

3. Body composition analysis: measure and compares the ratios of body compartments. 

a.  Bioelectrical impedence: calculates lean body mass based on resistance to electrical current.  Inaccurate in critically ill patients, and those with fluid or electrolyte abnormalities.

b. Dual energy x-ray absorptiometry: measures fat and lean body mass.  Depend on hydration status

c. Total body potassium: uses whole body counter to measure potassum isotope concentrated in lean tissue à measures lean body mass

d.  Total body water:  measures lean body mass from deuterium total body water (impractical).

e.  In-vivo neutron activation analysis: divides the body into compartments.  Requires large dose of radiation.

4.  Test of physiologic function:

Quantify malnutrition based on decrease in muscle strength due to amino acid mobilization.

a. Maximum voluntary grip strength: measured with isokinetic dynamometry and correlates to total body protein.

b.  Electrical stimulation of the ulnar nerve: measures muscle contraction. 

B. Metabolic requirments:

1. Energy requirments

Determined as nonprotein calories (NPC).  Can be measued by:

a. Indirect calorimetry or Measured Energy Expendure (MEE)

Most accurate.  Directly measures O2 consumption and CO2 production.

Energy requirment is directly related to oxygen consumption.

Respiratory quotient (RQ) = CO2 produced / O2 consumed

Oxidation of nutrients: carobohyrates RQ = 1.0, fat RQ = 0.7,

Lipogenesis: conversion of excess carbohyrate calories to fat, produces more CO2 than oxidation. 

b. Estimated energy expendure (EEE)

Requires calculation of basal energy expendure (BEE) from Harris-Benedict equation.  BEE is then multiplies by stress and substrate utilization factors.

c. Simple nomogram

Based on patient weight, least accurate.  Range from 2535 Kcal/kg/day depending on degree of stress.

2. Protein (nitrogen) requirments

a. Nitrogen balance techniques

16% of protein is comprised of nitrogen

Nitrogen balance = 24hr nitrogen intake – 24hr nitrogen output

Nitrogen output = urine urea nitrogen + nonurea urine nitrogen (ammonia, creatinine) + nonurine nitrogen loss (skin/feces)

Positive nitrogen balance of 3-6 g is the goal (not for the renally impaired)

b. Nomogram method: estimates protein needs based on lean body weight (1.5-2.0 g protein/kg/day)

c. Nonprotein calorie to nitrogen (NPC:N) ratio: normally 125-150:1

3. Essential fatty acids (EFAs):

EFAs are polyunsaturated fatty acids not synthesized by humans. 

Linoleic acid: principal EFA.  It’s omega-6 polyunsaturated fatty acid.

Linoleic acid deficiency à diarrhea, dermatitis, hair loss

Prevent EFAs deficiency by giving ~5% of patient’s calorie intake as linoleic acid from lipid emulstion. 

4. Vitamins:

Fat soluble: A, D, E, K; Water soluble: B, C

Vitamin A: essential for vision, growth, reproduction.  IV form binds to plastic and glass.

Vitamin D: regulate calcium / phosphorous homeostasis together with calcitonin and parathormone. 

Vitamin E: antioxidant, ↓ oxidation of free unsaturated fatty acids.  Need to ↑ Vitamin E in diets ↑ in unsaturated fatty acids.

Vitamin K: critical for synthesis of clotting factors. 

Vitamin B1 (thiamine): coenzyme in phosphogluconate, structural component of nervous system membranes.  Deficiency à acute pernicious beriberi.  Prolonged deficiency à Wernicke’s encephalopathy.

Vitamin B2 (riboflavin): coenzyme in oxidative phosphorylation.  No intracellular stores maintained.

Vitamin B3 (niacin): conenzyme in oxidative phosphorylation.  Deficiency à pellagra. 

Vitamin B5 (pantothenic acid): functional form is coenzyme A, essential for all acylation reactions.

Vitamin B6 (pyridoxine): coenzyme in enzymatic reactions.  Deficiency when taking isonizid, penicillamine, cycloserine.

Vitamin B7 (biotin): synthesized by intestinal floar.  Involved in carboxylation reactions. 

Vitamin B9 (folic acid): folate cofactors are needed for purien and pyrimidine (DNA) synthesis.  Deficiency in B12 à deficiency in (B9) folate à megaloblastic anemia.  Deficiency during pregnancy à neural tube fetal defects. 

Vitamin B12 (cyanocobalamin): large stores à deficiency develops in years.  Deficiency: megaloblastic (pernicious) anemia, peripheral neuropathy (needed for myelin synthesis). 

5. Trace minerals

Iron: necessary for hemoglobin and myoglobin production, enzymatic reactions (cofactor).  Deficiency: hypochromic, microcytic anemia, immune deficiency. 

Zinc: necessary for RNA, DNA synthesis and enzymatic reactions (cofactor).  Deficiency: imparied wound healing, growth retardation, hair loss, anorexia.  ­ risk of deficiency in long-term steroid therapy, mal-absorption, surgery.

Copper: necessary for heme synthesis, electron transport, wound healing.  Deficiency: anemia, leukopenia, neutropenia.

Manganese: involved in protein synthesis

Selenium: for antioxidant reactions.  Deficiency: muscle pain, cardiomyopathy.

Iodine: component of thyroid hormones.  Deficiency: goiter

Chromium: critical for glucose use, ­ insluin effect.  Deficiency: hyperglycemia, glucose intolerance.

Molybdenum: essential to xanthine oxidase

100. The Patient Behavioral Deterimants

102. Drug Education

103. Patient compliance

Definition: extent to which an individual’s behavior coincides with medical or health advice. Noncompliance can be intentional or unintentional.

About 50% of the population is noncompliant with drug therapy in some way.

Causes in the elderly: complicated drug regimen, inability to read labels, difficulty opening lids, etc.

Noncompliance can affect and bias the results of clinical studies.

Types of noncompliance

Not filling Rx: because they do not feel they need or want the Rx.  Example: an infection with Tylenol is feeling better and improving.  May be because of cost.

Omission of doses: common for drug that are taken frequently for long time.

Wrong dose: amount of does or frequency of administration is incorrect. 

Incorrect administration: for example, not using the right technique with aerosols, or wrong route of administration. 

Wrong time: for example, drug taken at the wrong time in relationship to meals. Drugs such as tetracycline, fluoroquinolones, erythromycin should be taken on empty stomach. Diuretic should be taken in the morning.

Premature d/c: common with antibiotics (symptoms subside) or chronic drugs such as for ↑ BP (asymptomatic).

Storage: improper storage and improper disposal of unused drugs.

Consequences of noncompliance

Over and under utilization have major economic impact.

Always, the benefits from ↑ compliance outweigh the costs of compliance enhancing programs.

Overutilization: may cause toxicity.  Examples: double dose to make up for missed dose, if one pill is good then more must be even better.

Noncompliance is one of the most commonly missed diagnoses (e.g. poorly controlled BP). 

Consequences of noncompliance are not always negative.  Some patients are “intelligent noncompliant” where they alter the dose based on SE emergence while treatment goals is still achieved.

Detection of noncompliance

Diagnosis of the problem is a key.  Behavior may change with time.

Ideal detection takes place at the time and place of taking the medication.

Indirect measures:

Self-reports and interview: simplest, but overestimates compliance. “Most people have trouble remembering to take their medicine.  Do you have trouble remembering to take yours?”

Pill count: commonly used in clinical studies.  Pill dumping is a common problem (study participants try to deceive physicians).  Overestimate compliance. Change of weight of MDI can be used.

Achievement of treatment goal: examples: normal BP, BG, intraocular pressure.  However, patients may load-up on medication or use other regimens (diet) before doctor visit. This is called toothbrush effect (people toothbrush before dentist visit). 

Computerized compliance monitors: most reliable indirect method.  Started with electronic eye-drop dispensers.  A microprocessor is located in the cap of the container.  Time and date are recorded every time the patient removes the cap.  Very useful in clinical studies. 

Refill rate: commonly used in community pharmacy settings.

Direct measured:

Direct methods are more reliable.  Use of at least 2 methods is recommended.

Biological markers and tracer compounds: indicate patient compliance over extended period.  Example: glycosylated hemoglobin assesses BG control over the preceding 3-months.

Tracer compounds: small amounts of agents such as Phenobarbital or digoxin (long half life, indicate compliance for past weeks) are added to drugs and measured in biological fluids.

Drug concentration in biological fluids: limited usefulness due to variability between individuals, does not indicate the timing of the dose, can be fooled by loading-up prior to biological fluid sampling.

The noncompliant patient

No consistent pattern has been observed regarding noncompliance with certain age, education, occupation, socioeconomic status, personality, race, severity or type of illness, etc. 

Intentional noncompliance is more common in patients who used two or more drugs or two or more physicians.

Health Belief Model: developed initially to explain preventative health behaviors such as immunizations and prophylactic dental care.  It also applies to compliance with prescribed medical regimen. 

Third Generation Model: focuses on health decisions.

Health Decision Model: combines decision analysis, behavioral decision theory, and health beliefs to give a model for health decisions and resultant behavior. 

Compliance and health beliefs: patient has to believe that: he has the illness diagnosed, illness can cause severe consequences to daily functioning, treatment will ↓ present and future severity of condition, benefits or regimen outweigh perceived disadvantages and costs.

Stimulus to trigger positive health behavior can be internal (patient’s concern) or external (interaction with physician or pharmacist). 

Myths: “need to take medication only when experiencing symptoms”, “need to d/c medication occasionally to prevent dependence and maintain efficacy”.

Other factors: patient who live alone are more noncompliant.  Patient may have fear of dependence for any drug that is used chronically.  They may d/c or ↓ dose occasionally to prevent this or to prove to themselves that is not the case.

Factors associated with noncompliance

Disease

Psychiatric patient are more noncompliance due to an attitude or inability to cooperate.

Patients with chronic asymptomatic disease are more noncompliant (hypertension, hypercholesterolemia, tuberculosis). 

Occurrence of significant symptoms upon d/c may ↑ compliance.

↑ disability caused by the disease à ↑ compliance.

No general correlation between disease severity and compliance.

Therapeutic regimen

Multiple drug therapy: ↑ number of drugs à ↑ noncompliance (e.g. in geriatrics).  The similarity in appearance of drugs may lead to confusion.  Combination drugs may help but therapy should start with individual drugs and then switched to the combo when optimum dose is reached.

Frequency of administration: may cause interruption of normal routine or work schedule à inconvenience, embarrassment, forget.  Very critical factor in compliance.  However, patient may be skeptical about the effective of a QD drug.

Duration of therapy: rate of noncompliance ↑ as duration ↑.

Adverse effects: change dosage or use alternative drugs if possible.  Big problem when the medication makes the patient feel worse than before (e.g., BP drugs).  Sexual dysfunction is common cause (e.g. with antipsychotics, antihypertensives).  Just communicating potential SE may cause the patient not to take the drug.

Asymptomatic conditions: includes lack of symptoms before the drug, lack of appearance of symptoms if drug is d/c, disappearance of symptoms (antibiotics). 

Cost: ↑ cost à Rx not filled, ↓dose is taken, ↓frequency, prematurely d/c. 

Administration: for example, incorrect measure of liquid medications, MDI use, oral antibiotic drops for ear infection instilled in the ear, using suppository by the oral route. 

Taste: common for oral liquid in children (e.g. liquid KCl). 

Patient/pharmacist interaction

Psychological support should be provided in a compassionate manner.

Patients are ↑ compliance with a physician they know and respect.

Not appreciating importance of therapy: if therapy does not meet their own or taught expectations à noncompliance.

Poor understanding of instructions: “as directed” should be avoided on label.  “every 8 hours” is more specific than “three times a day”.  Auxiliary instructions are also key.  Example: apply one nitroglycerin patch a day, patient got confused and added a new patch without removing the old ones. 

Improving compliance

Identification of risk factors

All patients should be viewed as potential noncomlpiers. Evaluate the probability of being noncompliant based on the risk factors.

Development of treatment plan

Recommend longer acting drugs or dosage forms.

The more actively participating patient in the plan is more compliant.

Plan should be individualized.

Tailor regimen to ↓ inconvenience and forgetfulness by fitting it to regular activities in the patient’s schedule.  Indicate specific times of the day to take medications if possible.

Patient education

Effective communication is the key for ↑ compliance.

Patients should be asked to repeat the instructions to show understanding.

Key points: name of medication, action, how much to take, when, for how long, food interactions, possible SE, what to do about SE, information sheet.

Oral communication / counseling: more important than written, as it gives patient a chance to interact and ask questions.  Ensure privacy and ↓ distractions.  Separate consultation area is ideal.  Call the patient if possible if face to face is not possible. 

Written communication: important is a future reference for the patient as he is not expected to remember all details.  Written info ↑ compliance only for short term therapy (e.g. antibiotics). 

Audiovisual materials: very useful in certain situations (e.g. insulin, sumatriptan, MDI). 

Controlled therapy: it is recommended that patients start self-medication before hospital discharge to transition them from complete dependence in the hospital to complete independence at home. 

Special compliance programs: example: behavioral program for schizophrenics.  Training include learning on obtaining information about drug benefits, correct self-administration and evaluation of effects, identify SE, talking about issue with professionals.  Programs may be useful also for sight or hearing impaired patients. 

Patient motivation

Good knowledge about the illness and medication does not necessarily translate to ↑ compliance.  Patients need to be motivated not only educated. 

Information must be presented in a manner that is not coercive, threatening, or demeaning.  Use special packaging or reminder systems if possible.  A contract approach may be useful with some patients where agreement is reached on specific actions. 

Compliance aids

Labeling / auxiliary: must be clear, accurate and specific

Calendars / Reminder charts: helps the patient understand which medication to take and when to take it. 

Special containers / caps: for example, system with four compartments for different time periods (morning, noon, evening, bedtime) for each day of the week.  Special caps can display the time of the day when the last dose was taken.  It flashes / beeps when it is time for the next dose. 

Compliance packaging: defined as pre-packaged unit that provides one treatment cycle of the medication.  Usually based on blister packages.  A good example is special packaging for birth control pills.  Another example: prednisone decreasing dose regimen.  Child-proof caps may be a problem for the elderly or patients with arthritis.

Dosage forms: for example ER, XR and transdermal patches.

Monitoring therapy

Self monitoring: by the patient of the treatment regimen, response parameters.

Pharmacist monitoring: based on inadequate frequency of refills, follow up by phone or mail reminders.  Automatic phone call reminder systems have been used.  Brown bag program: elderly pull all medications in a bag and take them to a professional for review. 

Directly observed treatment: watch patient swallow drug (e.g. in TB).

112. Pharmacoeconomics

Innovative roles for pharmacists: home IV therapy, drug level monitoring, parenteral nutrition management, self-care counseling.

Pharmacy services may provide positive outcomes by ↓ morbidity, ↑ therapeutic control, ↓ cost of treatment by using efficient therapy, ↓ # of physician visits, ↓ rate of drug related hospitalization, ↓ incidence and intensity of SE.

Extra years of life for a patient population can be converted to dollars for society.

Economic methods

Technique	Inputs	Outputs
Classical operations analysis	Units (e.g. pharmacy hrs)	Units (e.g. patients monitored)
Cost effectiveness analysis	Dollars	Natural units
Cost benefit analysis	Dollars	Dollars
Cost utility analysis	Dollars	Utiles/preferences
Cost minimization analysis	Dollars	Assumed equal

Cost benefit analysis

Medical care is an investment good (in human capital) and a consumption good. 

Measure of investment benefit: present value of a person’s lifetime productivity.

Both inputs (costs) and outputs (benefits) have to be quantified in dollars.

Both $ amounts are discounted to their present value at a certain interest rate.

Economic value = present value of benefits – present value of costs.

Benefits may be difficult to measure or to convert to $, or both.

Benefits

Benefits: defined as the ↓ in costs realized due to program implementation.  Can be direct, indirect, or intangible.

Direct benefits: savings on direct costs in medical care.  Easy to measure. 

Indirect benefits: savings on indirect costs in the medical care.  Difficult to measure.  It’s avoidance of earnings and productivity losses which would have been incurred without the health program. 

Intangible benefits: difficult, if not impossible, to measure.  Intangible costs are psychological (pain, suffering and grief). 

Discount rates

Discount rate is the conversion of dollar amount to present values through the use of interest rate.

↑ discount rate: favors projects with benefits occurring in distant future.

↓ discount rate: favors projects with costs occurring in distant future.

Commonly used discount rate is the yield rate on long term gov bonds.

Mathematical models are used to calculate benefit/cost ratio.

Net Present Value (NPV):  a new model for calculating benefits-costs.  Very popular and currently recommended by many economists.

Rate of Return on Investment: calculates the interest rate from an initial program investment over a potential stream of benefits over time.

Cost effectiveness analysis

Alternative ways are compared for achieving results (↓BP, life expectancy). 

Similar output measurements must be achieved to compare programs.

Cost Benefit Analysis	Cost Effectiveness Analysis
Output: dollar values	Output: units not dollars
Determines maximum benefit or investment	Determines least cost combination
Assumes limited resources	Assumes adequate resources
Fast comparison of programs	Different ways to reach same objectives
Less flexible	More flexible

Economic perspectives

A pharmacy service with positive benefit/cost ratio may be good for the society as a whole but not to every segment of the society.  Example: drug regiment that ↓ # of patient days in acute care is good for the society but may not be good for the hospital that depends on patient stays for revenue.

Always consider who pays the costs and who receives the benefits.

Quality of life outcomes and patient decisions

Quality of life and satisfaction with service are critical.  Elements may include: probability of success, associated pain, likely outcomes, etc.

Example: the quality of years within life extension (healthy years?).  

Example: untreated hypertension may not critical affect daily life, but a MI would ↓ quality of life.

Health-related quality of life (HRQL) is a humanistic outcome.

Using decision-analysis techniques, a decision tree can be made of what happens to the patient from diagnosis to cure.

The FDA has been leery of drugs that ↑ quality but ↓ life expectancy.

Diseases are associated with physical, mental and social impairments (which can be difficult to measure). 

Pharmacy Management (PDF files)

Basic accounting

Accounting: process of collecting, recording, summarizing, using financial data

Auditing: accounting that deals with verifying that records are kept and computations are made.

Bookkeeping: process that documents flow of resources ($$, goods) into / out of the business, and claims of creditors / owners to those resources

Dual effects of accounting: most transactions are recorded twice with the result of a balanced sheet.

T Account: with debt on the left and credit on the right. Debits = Credits.

Transactions: fiscal / financial events that are recorded.

Accounting period: period of time over which transactions are recorded, at the end of which income is measured.  Usually 1 year.  Not always a calendar year.

Methods of recording transactions: Accrual: transactions are recorded at the time they occur. Cash: transactions are recorded when cash transfers hands.

Revenue: measurement of goods sold or services rendered for which the business receives cash or the promise of cash.

Expenses: resources used up during a period of time to earn revenue.

Types of accounts: owner equity = assets - liabilities. 

Assets: resources owned by the business, e.g. cash, account receivable, buildings, inventory, equipment, furniture, prepaid insurance.

Liabilities: debt owned by the business to creditors. It arises when business borrows cash (e.g. bank loan) or purchases goods or services on credit. Examples: accounts payable, notes payable.

Owner equity (Net Worth): claim of the owners to the assets of the business after all creditors have been paid. It ↑ when owners make investments in business or when revenue is earned. It ↓ when expenses are paid. Examples: contributed capital, sales revenue, service revenue, expense accounts.

Expenses: not a liability because they are used up resources that require the immediate payment of cash for the amount in full, otherwise à liability.  Prepaid expenses are assets because they’re resources that have not yet been used up.

Income = revenues – expenses.

Cost of Goods on Hand: on last day of accounting period à physical inventory to determine cost of inventory not sold. No physical inventory is needed if perpetual inventory is kept by computer systems.

Fixed assets: tangible, long-lived resources used in business operation, e.g. building, machinery, fixtures, equipment, etc.

Current assets: resources owned by the business which are expected to be realized in cash, sold or consumed in one year, e.g. account receivable, inventory, etc.

Depreciation: wear and tear that occurs on fixed assets calculated as an expense.  Most fixed assets, except land, are depreciated.

Contra (offset) accounts: reside directly below the fixed asset account to which they pertain.

Income statement

Summary of operations, income earned during accounting period.

Constructed using revenue and expense account balances.

Revenue: sales of good and services

Cost of goods sold: such as inventory and transportation expenses.

Gross margin = revenue – cost of goods sold.

Net profit (income) = revenue – all expenses.

Net income = net profit – income tax

Balance sheet

Presents the financial position of the business at a certain point in time

Constructed using all asset account, liability accounts, OE accounts

Retained earnings: link income statement and balance sheet.

Purchasing and inventory

Inventory management

Involves planning, organizing, controlling inventory for profitability

Inventory control objectives: ↓ investment, ↓ purchasing / carrying costs, balance supply and demand.

Inventory is the largest pharmacy investment à critical to manage.

Total inventory costs = acquisition costs + stock out costs + carrying costs + procurement costs.

Acquisition costs: amount the pharmacy pay for the product.

Stock out costs: cost of not having the product available when needed

Carrying costs: storage, handling, insurance, loss/theft, damage, capital

Procurement costs: cost of placing orders, receiving items, stocking shelves, processing documentation

Objective of holding inventory: to guard against fluctuations in demand and later delivery, take advantage of bulk discount.

Goals of inventory management: minimize investment in carrying and procuring inventory by balancing supply and demand.

Inventory costs à significant impact on financials.  ↓ procurement and carrying costs, ↑ sales by avoiding stock-outs

Cash flow: prompt payment, ↓ COGS, ↑ gross margin

Inventory turn-over rate (ITOR) = COGS/average inventory. Target: ↑ ITOR to ↑ return on investment in inventory, ↓ investment in inventory to free up capital for other ventures.

Inventory return on investment = net profit/average inventory. 

What to buy? product, manufacturer, competitor consideration.

Where to buy? consider order cycle time, minimum order required.

How much and when to buy? difficult to determine.

Cycle stock: inventory kept on hand to fulfill orders

Buffer/safety stock: inventory for case of supply/demand fluctuations.

Anticipatory/speculative stock: inventory for expected ↑ in demand

Steps of purchasing

Cost of goods sold (COGS): have dramatic effect on profits

Purchasing objectives: right product / variety, quality, quantity, price, time

1. Market research: to determine needs/wants of patients / prescribers, identify pharmacy image and business goals, space limitations, potential sales.  Determining needs: usage reports, other pharmacies, pharmacy employees, questionnaires, sales reps, published top X drugs, formularies.  Example: area with young families à children items, older families à elderly items. Consider special disease management areas, e.g. asthma, diabetes.

2. Effective purchasing policies: Use “open-to-buy purchase budget”.  Control total $ investment in inventory.  Use prior year data to forecast purchase budget for each month in the upcoming year, based on sales and COSG.  Adjust (↑ / ↓) each month purchases based on previous month sales and purchases.  Gross margin = sales – COGS. 

3. Selecting supply sources: must be dependable, prompt, frequent delivery, good return policy, ↓ frequency of out-of-stock, customer service, price, financing arrangement.  Options: wholesales, manufactures, buying groups, rack jobbers, etc.  Wholesales: advantages include storage of good until needed, rapid delivery, financing options, help with advertising promotions, store layout and design. Rack jobbers: stock and maintain a specified assortment of goods (e.g. eyeglasses) in a fixture in the pharmacy.  Manufacturers: not common, large minimum purchases.  Central purchasing groups: pool buying power of independent pharmacies for better terms.

4. Negotiating terms: price, discounts, dating, return policy.  Pharmacy margin = suggested retail price – pharmacy cost.  Quantity discounts: cumulative (generic rebate) or non-cumulative ($ or % per quantity).  Cash discount: for prompt payment (typical: 2% if paid in 10 days, net amount due in 30 days), or discount for Electronic Fund Transfer.  Final price is calculated after subtracting trade, quantity and cash discounts. Dating: time for discount and payment (prepayment, collect-on-delivery (COD), delayed).  Returned goods policy: full credit within x days, partial credit after y days, non-returnable after z days. Check shelves regularly for items not sold.  Consider using a returned goods service company (charge a fee).

5. Transferring merchandise title (?)

6. Receiving, marking, stocking: count shipment, check for damage, check invoices, mark prices (merchandise, computer), stock.

Stock depth considerations: average demand, review time, lead time, safety stock.  Inventory control includes the following:

1. Visual: look at # of units in inventory and compare with how many should be carried, order more if needed.

2. Periodic: count stock on hand at certain intervals, compare to minimum target levels, order more if needed.

3. Perpetual: monitor inventory all the time (usually using a computer).

Computer systems: sales, analysis, trends, perpetual, automatic ordering, interface inventory and dispensing systems at point of sale.

Financial analysis / planning

Comparative analysis: express each financial statement component as percent of sales, and compare with Digest data.

Ratio analysis: compare financial ratios with ratios for the same company during recent years, and similar group of pharmacies in NCPA Pharmacia Digest.

Solvency: overall ability to pay legal debts. Calculate Current and Acid Test ratio

Current Ratio = current assets / current liabilities. Target > 2

Acid Test Ratio = (Cash + account receivable) / current liabilities. Target > 1

Other solvency ratios: current liabilities / inventory, total liabilities / net worth, long-term liabilities / net working capital, fixed assets / net worth,

Efficiency: how well available capital is used.  Inventory turnover ratio.

Inventory turn over ratio = COGS / average inventory.  Target: 5-6.

Other efficiency ratios: net sales / inventory, account receivable and account payable collection period, net working capital turnover. 

Profitability: the bottom line, important but not the only measure of success.

Return on net worth = net profit / net worth.  Target 25%. 

Net worth = total assets – total liabilities.

Net profit / net sales: target 5%. 

Net profit / total assets.  Target 15%.

Net profit / inventory.  Target 20%.

Expenses: salaries, wages, rent, utilities, accounting / legal fees, taxes, licenses, insurance, interest, equipment, depreciation. 

Balance sheet: includes assets and liabilities. Current assets: cash, account receivables, inventory.  Current liabilities: account payable, accrued expenses.

Pricing

Components of price = ingredient cost + service cost (dispensing) + income.

Actual Acquisition Cost (AAC): price the pharmacy pays for the product.  Varies depending on source, volume, incentives and deals, type of pharmacy

Average Wholesale Price (AWP): NOT (?) the average price the wholesalers sell the product at.  Cost assigned to product by manufacturer, overstates AAC

Estimated Acquisition Cost (EAC): established by third party payers to estimate AAC. Usually a percentage of AWP (e.g. 90%).

Service cost: average or per unit cost of providing a service. Covers expenses such as salaries, rent, utilities, depreciation.  Includes cost to dispense.

Direct costs: results directly from providing the service.  No direct cost if service is not provided.  Dispensing direct costs: labels, containers, computer, delivery costs, patient education materials, pharmacy licenses.

Indirect costs: costs shared by all services, e.g. rent, utilities, salaries, benefits, advertising, etc.

Cost of providing a service = all direct costs + “fair share” of indirect costs.

Cost allocation: determining the fair share of indirect costs. Difficult. Estimate % of employees time and facility space devoted to dispensing.

Cost to dispense (COD): total dispensing costs / expected Rx volume. It is an estimation of the average cost to dispense Rx.  Sensitive to volume. 

Differential costs; differ among alternative courses of action, i.e. additional costs the pharmacy incurs for providing a new service.

Non-cost factors: demand, competition, image, quality signaling, goals, non-monetary costs.

Demand: quantity consumers will be at a certain price.  Function of price. 

Elasticity of demand: measures sensitivity of demand to price ∆.

Elastic demand: small ↓ in price results in big ↑ in demand.  Sellers make money by lowering the price.  Inelastic demand is opposite (↑ price à ↑ profit)

Consumers are more sensitive to price when: cost of product is large part of total cost, ↓ differences among products, comparisons are easy, consumers can judge quality, switching costs are small, commodity.

Image: consumers can select based on perceptions of pharmacy image. Image is affected by: prices, size, location, services offered, personnel, promotions, etc

Price as a signal of quality: more likely when consumers cannot judge quality, more for services than products.

Penetration pricing: ↓ price to ↑ sales volume. Loss leader pricing: ↓ Rx prices to ↑ OTC sales.  Price skimming: ↑ price for superior service.

Basic Management

Management components: self, controllable surroundings, uncontrollable surroundings, external environment.

Management activities: satisfy various entities, deal with emergencies, purchasing, recruiting, accounting, training, planning, negotiating, sales, dealing with regulatory officials. 

Management actions: identify tasks, organize resources, monitor performance / task completion, plan for future requirements, deal with problems.

Functions of management actions: target setting, problem solving, leadership, team building, dealing with emergencies.

Management functions: controlling, directing, organizing, planning, staffing

Controlling: establish standards based on objectives, measure / report performance, take corrective / preventative actions.

Directing: motivation, communication, performance appraisal, discipline, conflict resolution.

Organizing: division of labor, delegation of authority, departmentalization, span of control, coordination.

Planning: vision, mission, objectives, coals

Staffing: recruiting, selecting, hiring, training, retaining

Know self, who we are, what we aspire to become, new info, what we need to know, who else need to work with us, etc.

Manager’s skills: intellectual, technical, ethical, interactive, emotional.

Intellectual skills: logical thinking, problem solving

Ethical skills: define right from wrong

Interactive skills: communicate intelligently and create an atmosphere that facilitates communication.

Most problematic issues: poor communication, developing people, empowerment, lack of alignment, entitlement, balancing work / personal life, confronting poor performance, coaching senior management, cross-functional strife, fascination with programs.

Decision making: identify objectives, analyze relevant factors, consider all alternatives, selection best option, implement the decision, evaluate the results

Management style: depends on organization, situation, personal values, personality, chance.

Self-development methods: observation, reflection, guided readings, attachments / visits, seeking feedback, seeking challenges.

Strategic planning: must complement strategic thinking / acting. Includes where we are going (mission) and how we get there (strategy).

SWOT analysis: strengths, weaknesses, opportunities, threats.

Vision of success: mission, basic philosophy, core values, goals, strategies, performance criteria, decision rules, ethical standards.

Environment: stability, complexity, market diversity, hostility, competition

Cascade of information: should flow not only downward, but also upward

Project management failures: lack of focus / attention, inability to cope with different project characteristics, feeling being used / exploited, lack of experience

Project management process: develop ideas and proposals, approve the project, project kick-off / start, monitoring / reporting / managing, termination.

Project management 10 commandments: concentrate on interfacing, organize project team, plan strategically / technically, remember Murphy’s law, identify stakeholders, manage conflict, expect the unexpected, listen to intuition, apply behavioral skills, take corrective actions.

Project management functions: scope / quality / time / cost management

PDCA Cycle: Plan, DO, Check, Act

Problem solving: define the problem à identify the criteria à weight importance of criteria à generate alternatives à rate alternatives on each criterion à compute the optimal decision

Continuous Quality Improvement (CQI): philosophical / structural / healthcare-specific elements. Use PDCA cycle.

Philosophical elements: strategic focus (mission, values, objectives), customer focus (patient, provider, payer), systems focus.

Structural elements: process improvement teams, top management commitment, statistical analysis, customer satisfaction measures, benchmarking, seven tools (flow charts cause/effect diagrams, check sheets, histograms, etc).

Healthcare specific elements: epidemiological studies, governance processes (QA, committees, peer review), risk-adjusted outcome measures, cost-effectiveness analysis.

Barrier to quality transformation: lack of constancy of purpose, emphasis on short-term profits, personal view system, management mobility, using only visible figures, ↑↑ cost of employee healthcare, ↑↑ cost of warranty / insurance. 

5. Extemporaneous Prescription Compounding

18. Nuclear Pharmacy

19. Pharmaceutical Care and Disease Management

21. Adverse Reactions and Post Market Surveillance

34. Clinical PK and Therapeutic Drug Monitroing

53. Renal Failure

57. Immunosuppressants in organ transplantation

58. Outcomes Research and Pharmacoeconomics

Health care system

Preferred Provider Organization (PPO): Broad network of providers available, generally management is less strict.  52%

Point of Service (POS): HMO plan with the option of going outside the narrow provider network if willing to pay higher cost-sharing. 18%

HMO: Narrow choice of providers, tighter management.  26%

Types of outcomes:

Humanistic outcomes:  Health Related Quality of Life, Patient Satisfaction, Caregiver Impact, Patient Preferences, Functional Status

Economic: Cost Analysis, Cost-of-Illness, Cost-Minimization, Cost-Benefit, Cost-Effectiveness, Cost-Utility

Clinical: Efficacy, Safety, Impact of therapy on “natural history” of the disease

Methods for setting health insurance rates

Experience rating: everyone in a specific area is charged the same premium based on the average cost of providing health services to all people in the area

Community rating: premium adjusted individually according to a person’s or group’s average health history, risk, and past claim experienc