Pharmacotherapy

[Clinical Skills] Therapeutics Planning

April 12, 2016 Clinical Skills, Pharmacotherapy, Practice, Therapeutics No comments , , , , , , , , , , , , , , ,

Also see Pharmacy Profession Forum for the thread "[Diagnosis] Diagnostic Series" at http://forum.tomhsiung.com/pharmacy-students-and-residents/clinical-skills/817-diagnosis-diagnostic-series.html

Identify the Problems

Step 1 Obtain Patient Data

Consider all available patient data. Review all previously charted data (history, physical examination findings, results of laboratory and diagnostic tests) and interview the patient for the patient's medication history. Reviewall relevant data resources, including data from the current patient chart, data from past charts, data obtained from patient interviews or interviews with relatives or significant others if the patient is not capable of providing information, and uncharted data available from team members. Seeking out and then identifying relevant data requires patience and methodical scrutiny. Note that the patient's story may vary depending on who interviewed the patient and when the patient was interviewed. Some data may be contradictory. But it is important to gather and then consider all available data.

Patient factors that by themselves appear unimportant may be important when considered in the context of other patient data. Pertinent positive data (abnormal findings) include abnormal laboratory results such as a serum potassium level that exceeds the upper limit of the reference range, abnormal signs and symptoms described by the patient, and abnormalities noted on physical examination, and are easy to identify. Pertinent negative data (findings that are normal but, given the patient's disease or condition, would have been expected to be abnormal) are more difficult to recognize, and identifying them requires a good understanding of human disease and pharmacotherapeutics.

Create a working list of the data. Subdivide the data into lists of subjective data and objective data. Subjective data, such as coughing, pain, and itching, are describable but cannot be precisely measured or quantified. Some clinicians view all data obtained directly from the patient to be subjective data, because the data are not verifiable by an independent observer and must be considered just a story. Objective data, such as blood pressure, heart rate, and temperature, are data that can be precisely measured or quantified. By convention, data that are obtained by the health care professional by direct observation of the patient or are obtained during the physical examination but that cannot be precisely quantified are considered objective data because the data were obtained by an objective, trained clinician. Data documented by other health care professionals are considered objective data.

Step 2 Group Related Data

Evaluate the list of objective and subjective data for possible relationships among the data. This step requires comprehensive knowledge of the signs and symptoms of disease and pharmacotherapy and becomes easier with experience. For example, subjective complaints of fever, one episode of chills, and productive cough combined with objective data of leukocytosis with an increased percentage of bands, a chest radiograph showing right middle lobe consolidation, and sputum positive for gram-positive encapsulated cocci in pairs are related. A less experienced clinician should be able to recognize that the patient has some kind of lower respiratory tract bacterial infection.

Work through the list of patient data making sure that every piece of patient data is considered. Note that it only takes one piece of data to identify a patient problem. For example, a patient may smoke tobacco but have normal physical examination findings and normal laboratory results. The patient's self-identification of the smoking history is enough to categorize the patient as a smoker (the problem). Some data may belong with more than one group of data. For example, a blood pressure of 160/110 mm Hg belongs with data related to the patient's diagnosis of hypertension, but if the patient had been prescribed antihypertensive drug therapy but missed many doses, the blood pressure of 160/110 mm Hg also belongs with data related to patient nonadherence.

Step 3 Determine Each Problem

Evaluate each group of related subjective and objective data items to determine the specific patient problem or issue. The problem is not always a specific diagnosis but may be a preliminary identification of the issue pending acquistition of additional data (e.g., acute diarrhea, not shigellosis). The problem list is refined as more data become available. Patient problems include current medical problems such as hypertension, pneumonia, asthma, diabetes, and gastrointestinal bleeding; past medical problems such as history of migraine headache, hip fracture, deep vein thrombosis, and myocardial infarction; past surgeries such as appendectomy, tonsillectomy, coronary artery bypass grafts, and transurethral resection of the prostate; and issue such as nonadherence, obesity, illicit drug abuse, alcohol use, tobacco use, and allergies.

Step 4 Assess Each Problem

  • Each problem is then assessed in terms of each of the following characteristics:
  • Acuity (acute or chronic)
  • Severity (mild, moderate, or severe)
  • Symptom level (symptomatic or asymptomatic)
  • Treatment status (treated or untreated)
  • Degree of control (controlled or uncontrolled)
  • Classification (staging of disease)

Knowing these characteristics is useful when prioritizing patient problems and when planning patient-specific drug and nondrug interventions. Management of a patient's acute, severe, uncontrolled, untreated asthma exacerbation will take precedence over treatment of any of the patient's other chronic and controlled problems. Because historical problems cannot be assessed for these characteristics, by convention these problems are simply documented as "S/P" (meaning "status post" or "a history of").


Prioritize The Problems

Prioritization means ranking the patient problems with the most urgent problems at the top of the list and the least urgent problems at the bottom of the list. Prioritization is a way of ordering the relative need for intervention and is not meant to imply a rank ordering of importance or significance to the patient's overall health care needs. Problems of equal urgency are still listed in a rank order although the plans document the need to address each problem simultaneously. Historical (inactive) problems are not ranked but are simply listed at the bottom of the problem list. Problem lists are dynamic lists that evolve and are modified as new data become available.

Step 1 Identify the Active Problems

Active problems are problems that require some kind of drug or nondrug intervention to resolve and/or manage the problem.

Step 2 Identify the Inactive Problems

Inactive problems are problems that do not require any kind of drug or nondrug intervention and are of historical interest only. Examples of inactive problems include a history of an appendectomy at age 12, a history of pneumonia 2 years ago, a history of smoking two packs of cigarettes per day until quitting 10 years ago, etc. Although inactive problems do not require planning for current drug or nondrug therapy interventions, inactive problems are still identified and listed on the patient problem list so that they can be considered when planning drug and nondrug interventions for active problems. For example, a patient with a history of splenectomy is at increased risk of infection with some pathogens. Knowledge of this risk will help in planning patient-specific antibiotic therapy in the event that the patient has signs and symptoms consistent with infection.

Step 3 Rank the Problems

Rank-order the active patient problems. One approach to ranking patient problems is to identify the problem that needs the most immediate attention and then rank the remaining active problems in order of need for intervention. The number one problem is the problem that if left untreated will cause the most harm to the patient in the shortest amount of time. Another approach is to work from the bottom of the list up by determining the problem requiring the lest attention. This problem is ranked as the least important problem. The pharmacist repeats the ranking process with the remaining problems until all are ranked. Regardless of the approach, the active problems are placed at the top of the list, inactive problems are at the botton of the list, and active but less acute problems are in the middle. As noted previously, the rank ordering is rather arbitrary if the the problems all have relatively equal need for intervention.

Clinicians given the same list of patient data may develop different prioritized lists. This is not unexpected; no one list is correct. Lists are developed based on the clinical judgment and experience of the practitioner. In addition, because the focus of the pharmacist is on therapeutic issues rather than on differential diagnosis, the pharmacist-generated patient problem list may be similar although not necessarily identical to the problem list generated by physicians, nurses, or other health care professionals.


Select Patient-Specific Drug and Nondrug Interventions

Once the prioritized patient problem list is developed, the next step is to select patient-specific drug and nondrug interventions for each and nondrug interventions.

Determine appropriate nondrug interventions, including patient eduation. For example, an important part of the management of allergic rhinitis is avoidance of allergens; patients may benefit from education regarding allergen avoidance.

Determine an appropriate medication regimen for each patient problem that can be treated and/or managed with medications. For each medication selected, include the dosage, the dosage formulation, the route of administration, dosing interval, duration of therapy, and rationale (the evidence-based reason for selecting the patient-specific therapeutic intervention). The general approach is to develop the therapeutic plan for each problem and then integrate the individual plans, with care taken to ensure that each component of the plan is appropriate given the other plans and that the overall integrated plan is achievable for the pateint. For example, when considered individually plans for therapeutic interventions for a patient with multiple chronic medical conditions may seem reasonable and appropriate, but when considered together they may not be doable if the multiple medication regimens require the patient to adhere to multiple sets of complicated instructions (e.g., take with food, take 2 hours before eating, take every 4 hours around the clock, take every 8 hours around the clock, do not take within 2 hours of taking another medication, etc.).

Selection of a specific regimen requires assessment of each patient problem in the context of everything that is known about the patient such as other patient problems and medications, social habits, cultural beliefs, and willingness to commit to a course of therapy, as well as external factors such as insurance coverage and access to refrigeration for storage of refrigerated medications. See below,

Patient-specific factors

  • What regimens have effectively managed the problem in the past?
  • What regimens have not effectively managed the problem in the past?
  • How might other patient problems influence the proposed regimen?
  • How might the proposed regimen influence other patient problem?
  • Does the patient have any culturally based needs?

External factors

  • State-of-the-art therapeutics (e.g., current guidelines)
  • Cost of the proposed therapy
  • Formulary limitations

For example, a patient who has responded well to a specific decongestant in the past will most likely respond well to the same decongestant in the future. A patient with renal insufficiency is at risk of developing seizures from the accumulation of normeperidine, a renally eliminated metabolite of meperidine. A drug with negative inotropic effects may worsen a patient's congestive heart failure.

Step 1 Determine Short-Term and Long-Term Goals of Therapy

All drug and nondrug interventions should be in the context of the specific short-term and long-term goals of therapy, which may or may not be the same depending on the specific patient problem. For example, the short-term goal for patient being treated for a hypertensive emergency is to reduce the diastolic blood pressure to 100 to 105 mm Hg within 2 to 6 hours of presentation with a maximum reduction of 25% or less of the initial diastolic blood pressure. The long-term goal is to reduce the diastolic blood pressure to 85 to 90 mm Hg over the next 2 to 3 months to reduce the long-term morbidity and mortality associated with the elevated diastolic blood pressure.

Determine specific goals and outcomes of therapy before doing any other planning. Set specific goals for each patient problem and for the overall therapeutic outcome in general. When setting therapeutic goals, consider long-term factors such as the impact of the therapeutic regimen on the patient's quality of life and survival. For example, a long-term weight reduction plan is not appropriate for a patient with a short life expectancy. Select target therapeutic ranges for all objective parameters (e.g., systolic blood pressure between 110 and 130 mm Hg; serum potassium level between 3.5 and 4.5 mEq/L, etc.)

Consider the severity of disease and the short-term or long-term nature of therapy when setting therapeutic goals. For example, consider the differences in the goals of insulin therapy for a young patient with newly diagnosed type 1 diabetes mellitus and significant cardiovascular and peripheral vascular disease. Evidence suggests that tight control of blood glucose levels may delay the onset and decrease the severity of the complications of diabetes. Therefore the target blood glucose level for the young patient with newly diagnosed daibetes is lower and has a narrower acceptable range than that for the elderly patient with diabetes and longstanding disease who has already developed complications from the disease and is at risk of hypoglycemia-related falls.

Step 2 Create A List of Options

Identify all classes of drugs and possible therapeutic approaches for each problem; do not eliminate any option at this stage of planning. The options list is usually a mental list, although students and inexperienced clinicians may find it helpful to create and then work from a written list. Depending on how familiar the pharmacist is with the management of the medical condition, this step may require review of current pharmacotherapeutics and human disease textbooks, literature searches of the current pharmacy and medical literature, review of current treatment guidelines, or consultation with colleagues. This step becomes easier and more time efficient with practice and experience. As the member of the heath care team with the most knowledge of pharmacotherapy, it is the pharmacist's responsibility to identify all possible drug therapy options.

Step 3 Eliminate Options Based on Patient-Specific and External Factors

Once all therapeutic options are identified, eliminate options based on the comparative effectiveness of the drugs; the suitability of the drug for the patient given the other patient medical conditions and drug therapies; the ability of the patient to adhere to the proposed regimen; and other factors such as the effectiveness of previous treatment regiments, cost, and formulary restrictions. Consider the impact of the therapeutic option on other patient problems and the influence of other patient problems on the therapeutic option.

Drug-specific factors

  • Effectiveness of the clinical outcome (e.g., evidence-based benefit)
  • Pharmacologic mechanisms
  • Effectiveness of the drugs (e.g., physiologic effect, potency, maximum effect, slope of effect-concentration curve)
  • Evidence-based toxicity of the drug
  • Toxicity of the drugs (e.g., therapeutic index/window)
  • Drug delivery systems (e.g., inhalant, sublingual, oral)
  • How drug get active in the body (e.g., prodrug)
  • In-body drug process/pharmacokinetics (e.g., absorption, distribution, metabolism, excretion)
  • Drug interactions

Patient-specific factors

  • What regimens have effectively managed the problem in the past?
  • What regimens have not effectively managed the problem in the past?
  • How might other patient problems influence the proposed regimen? (e.g., renal failure, hepatic failure, genetic variability/mutation, etc.)
  • How might the proposed regimen influence other patient problem?
  • Does the patient have any culturally based needs?
  • The severity of the problem
  • How the patient's life style affect the proposed regimen?
  • The past patient experiences
  • The patient's ability to adhere to the proposed regimen

External factors

  • State-of-the-art therapeutics (e.g., current guidelines)
  • Cost of the proposed therapy
  • Formulary limitations
  • Risk of medication errors

Step 4 Select Appropriate Drug and Nondrug Interventions

Decisions about appropriate drug and nondrug interventions are based on past patient experiences, assessment of the severity of the problem, drug-specific factors such as the therapeutic index of the drug, and specific patient factors such as the presence of chronic renal or hepatic disease that may influence the elimination or metabolism of the drug. Determine the best drug and nondrug regimen, including each specific drug to be used, dosage, route, duration of therapy, and rationle for the selection of each drug and nondrug component of the regimen. For example, if a patient failed to stop smoking because the patient developed varenicline-associated side effects and stopped taking the medication, then the patient should not be prescribed varenicline the next time the patient attempts to quite smoking. If a patient's prescription medication insurance no longer covers a specific branded product, then every effort should be made to find an equivalent medication, generic or otherwise, that is paid for by the prescription medication insurance plan.

The rationale, the reason why the specific intervention was selected, should be patient specific and based on current published evidence. The rationale should be documented in the SOAP note in the patient chart even if verbally discussed with the prescriber. For example, the recommendation to initiate antihypertensive drug therapy with hydrochlorothiazide 12.5 mg daily for a patient with newly diagnosed uncomplicated hypertension is based on the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The recommendation to vaccinate or note vaccinate a person with the influenza vaccine is based on current Centers for Disease Control and Prevention recommendations.

Step 5 Identify Alternative Interventions

An important part of the planning process is anticipation of potential patient problems with the prescribed and/or recommended drug and nondrug interventions ("what if"). A well-though-out plan includes alternative medication regimens for common potential problems, such as the development of an allergy or adverse reaction to the initial therapeutic regimen, lack of desired therapeutic response to the initial therapeutic regimen, and identification of additional patient problems that may influence the effectiveness or pharmacokinetic profile of the initial therapeutic regimen. Anticipation of these potential issues allows the creation of well-thought-out alternative therapeutic plans instead of therapeutic plans hastily chosen when unanticipated patient problems suddenly appear. For example, therapeutic planning for a patient with newly diagnosed hypertension should include plans for what to do if the initial treatment fails to lower the blood pressure or has to be discontinued because of the development of intolerable side effects (both very common issues).

(The End)

Polymorphisms in Pharmacotherapy

November 10, 2015 Pharmacodynamics, Pharmacogenetics, Pharmacokinetics, Pharmacotherapy, Therapeutics No comments

dna_istock_rustycloudPolymorphisms related to pharmacotherapy include polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in drug transporter genes, and polymorphisms in drug target genes.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. eTable 6-1 lists examples of polymorphic metabolizing enzymes and corresponding drug substrates whose plasma concentrations and pharmacologic effects may be altered as a consequence of genetic variation.


Screen Shot 2015-11-10 at 2.38.46 PMPolymorphisms in the CYP2D6 gene are the best characterized among all polymorphisms in genes for drug-metabolizing enzymes. For example, the presence of two defective alleles coding for CYP2D6 in PM (poor metabolizer) results in significant impaired ability to metabolize CYP2D6-dependent substrates. Depending on the importance of the affected CYP2D6 pathway to overall drug metabolism and the drug's therapeutic index, clinically significant side effects may occur in PMs as a result of elevated drug concentrations.Screen Shot 2015-11-10 at 2.39.27 PM
Conversely, if the polymorphisms in CYP2D6 genes significantly enhance the activity of the drug-metabolizing enzyme, large amount of drugs will be metabolized and as a result the serum concentraton and pharmacologic effect of the drug would probablely be significantly lower.Screen Shot 2015-11-10 at 2.39.54 PM

The therapeutic implication of CYP2D6 polymorphism is different if the substrate in question is a prodrug. In this case, PMs would not be able to convert the drug into the therapeutically active metabolite (if low CPY2D6 activity).

Polymorphisms in Drug Transporter Genes

Certain membrane-sparnning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells.

Absorption

Polymorphisms in drug transporters on gastrointestinal tract would affect the absorption of drugs. The role of drug transproters on gastrointestinal tract is to put the drug molecule back into GI lumen. So the activity of these drug transporters would significantly alter the bioavailability/absorption of the drug.

Distribution

Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.

Excretion

Some drug are transported into bile or urine by drug transporters. So the polymorphisms in these transporters which result in significant change of the activity of the drug transporters would enhance or weaken the ability of these drug transporters's ability to excret the drug.

Drug Uptake by Target Cells

Even the drug could reach the therapeutic sites of action, efflux pumps (drug transporters) available on the surface of target cells could put the drug molecules back into extracellular environment, which prevent the pharmacologic effect of the drug if the drug's target receptors are inside the target cells.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for durg target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drugs could bind to enzymes, ion channels, and intracellular signaling proteins directly to produce pharmacologic effects, or they just only bind to the receptor and the after-binding (drug-receptor) process is altered by polymorphisms in enzymes, ion channels, and intracellular signaling proteins.

Receptor Genotypes and Drug Response

The beta1-adrenergic receptor gene (ADRB1) has been the primary focus of research into genetic determinants of responses to beta-adrenergic receptor antagonists in hypertension and cardiovascular disease. The polymorphisms in beta1-adregergic receptors causes pharmacologic (or even clinical) responses in different extent to its agonists and antagonists.

Enzyme Genes and Drug Response

Some drugs exert their clinical efficacy by affect enzymes which play some roles in the life of a cell. Polymorphisms in these enzymes therefore determine what degree of responsiveness they respond to these drugs. One example is the warfarin resistance, where there is a SNP in the VKORC1. Warfarin exerts its anticoagulant effects by inhibiting VKOR and thus preventing carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X. VKORC1 encodes for the warfarin-sensitive component of VKOR. Mutations in VKORC1 coding region cause rare case of warfarin resistance, with carriers of these mutations requiring either exceptionally high doses (>100 mg/wk) to achieve effective anticoagulation or failing to respond to warfarin at any dose (the mutated VKOR lose sensitivity to warfarin).

Genes For Intracellular Signaling Proteins, Ion Channels, and Drug Response

Cellular responses to many drugs are mediated through receptor-coupled guanosine diphosphate (GDP)-bound proteins also called G-proteins. Following receptor activation, the receptor couples to the G-protein, resulting in dissociation of GDP from the alpha subunit in exchange for guanosine triphosphate (GTP) and activation of the alpha, beta, and gamma subunits. The alpha subunit and beta-gamma subunit complex are released intracellularly and interact with various effectors to produce a cellular responses. Changes in the activity of G-proteins might influence response to agonists/antagonists which bind the receptors coupled with G-proteins.

The Management of Hypertension (Clinical Evaluation)

September 12, 2015 Cardiology, Diabetes, Infectious Diseases, Pharmacotherapy, Therapeutics No comments , , , , , , , ,

Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation including a comprehensive medical history, physical examination, and laboratory and/or diagnostic test is recommended after diagnosis to identify secondary causes, identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and assess for the presence of absence of hypertension-associated target-organ damage.

For the patients who have been diagnosed with hypertension, we should ask a few questions that are necessary to make a clinical evaluation for these patients. Here is an example of a patient with hypertension.

D.C. is a 44-year-old black man who presents to his primary care provider concerned about high BP. At an employee health screening last month he was told he has stage 1 hypertension. His medical history is significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and hypertension and died of a stroke at age 68. D.C. smokes on pack per day of cigarettes and thinks his BP is high because of job-related stress. He does not engage in any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination show he is 175 cm tall, weighs 108 kg (BMI, 35.2 kg/m2), BP is 148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, heart rate is 80 beats/minute. Six months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary-care provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking, with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen, 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL (Fasting?)

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol, 141 mg/dL

High-density lipoprotein cholesterol, 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram is normal except for left ventricular hypertrophy.

PS: Normal values are marked in green and abnormal values are marked in orange.


Clinical Presentation

Question 1 What is the clinical presentation D.C.?

All the information above could be the part of D.C.’s clinical presentation. Besides, we could classify the stage of D.C.’s hypertension as shown below.

D.C. has uncontrolled stage 1 hypertension. He has had elevated BP values, measured in clinical environments, and meets the diagnostic criteria for hypertension because two or more of his BP measurements are elevated on separate days. SBP values are consistently stage 1, whereas DBP values are all in the prehypertension range. The higher of the two classifications is used to classify hypertension.

Question 2 Why does D.C. have hypertension?

D.C. has essential hypertension; therefore, the exact cause is not known. He has several characteristics (e.g., family history of hypertension, obesity) that may have increased his chance of developing hypertension. Race and sex also influence the prevalence of hypertension Across all age groups, black have a higher prevalence of hypertension than do whites and Hispanics. Similar to other form of CV disease, hypertension is more server, more like to include hypertension-associated complications, and occurs at an earlier age in black patients.


Patient Evaluation and Risk Assessment

The presence of absence of hypertension-associated complications as well as other major CV risk factors (Table 14-5) must be assessed in D.C. Also, secondary cause of hypertension (Table 14-3), if suggested by history and clinical examination findings, should be identified and managed accordingly. The presence of concomitant medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be evaluated so that they can be used to guide therapy.

  • Hypertension-associated complications
  • Secondary causes of hypertension
  • Concomitant medical conditions

Question 3 Dose D.C. has secondary cause of hypertension?

The most common secondary causes of hypertension are list in Table 3-1. Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorders.

Table 3-1 Secondary Causes of Hypertension.

  • Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension.
  • In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness.
  • Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscle weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism).
  • Patient with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses.
  • Patient with renal artery stenosis may have an abdominal systolic-diastolic bruit.

Also, routine laboratory tests may also help identify secondary hypertension. For example, Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma rennin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renoascular disease.

Certain drugs and other products can result in drug-induced hypertension. For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identify a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.

Question 4 Which hypertension-associated complications are present in D.C.?

Screen Shot 2015-09-11 at 10.18.35 AM

A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Question 5 What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate of decline is greatly accelerated by hypertension. Hypertension is associated with nephrosclerosis, which is caused by increased intraglomerular pressure. It is unknown whether a primary kidney lesion with ischemia causes systemic hypertension or whether systemic hypertension directly causes glomerular capillary damage by increasing intraglomerular pressure. Regardless, CKD, whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need for dialysis. Studies have demonstrated that controlling hypertension is the most important strategy to slow the rate of kidney function decline, but it may not be entirely effective in slowing the progression of renal impairment in all patients.

In hypertension, stage 3 CKD or worse is considered a hypertension-associated complication (GFR values of <60 mL/min/1.73 m2). An estimated GFR of less than 60 mL/min/1.73 m2 corresponds approximately to a serum concentration of greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average woman. This level of kidney compromise lowers an individual’s BP goal to less than 130/80 mm Hg according to multiple guidelines. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine collection or 200 mg albumin/g creatinine on a spot urine measurement) also indicates significant CKD, for which achieving the more aggressive BP goal is a strategy to minimize the rate of progression to kidney failure.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

Question 6 Which major CV risk factors are present in D.C.?

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

PS: Estimated GFR calculated from online calculator for D.C. is 105 mL/min/1.73 m(online calculator: http://www.davita.com/gfr-calculator/).

So according to D.C.’s clinical presentation, he has major CV risk factors that are marked in orange, that is, 5 factors in total, including the essential hypertension.

Question 7 What is D.C.’s BP goal and how can Framingham risk scoring influence BP goal determination?

D.C. is a primary prevention patient because he does not yet have any hypertension-associated compilations (or compelling indications). He has multiple CV risk factors, so controlling his BP is of paramount importance to reduce the risk of developing hypertension-associated complications. The JNC-8 guidelines recommend the initial BP goal for hypertension patients with age of <60 years should be 140/90 mm Hg, which has grade A evidence (strong recommendation) for patients from 30 through 59 years of age, and grade E (expert opinion) for those from 18 through 29 years of age. So D.C.’s initial BP goal should be below 140/90 mm Hg.

The framingham risk scoring system is available as an online calculator at NIH site of http://cvdrisk.nhlbi.nih.gov/calculator.asp. According to D.C.’s clinical presentation, he will has a CV risk of  14% in a next 10-year period of expectation before we intervention, which means in a population cohort such as D.C., 14 in 100 individuals will develop CV diseases after a period of 10-year, if we don’t treat these CV risk factors (if these risk factors worsen, the incidence of developing CV diseases would be higher). If we treat D.C.’s current hypertension target the BP goal, with other interventions that target D.C.’s rest risk factors like habit of smoking, etc., the incidence of developing CV diseases would be attenuated (In D.C.’s example, the incidence would decrease to 5%, that is 5 in 100 of individuals will develop CV diseases in a period of 10-year). Compare the results without/with interventions to D.C.

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The intervention above does not include the management of dyslipidemia. According to the latest AHA guideline, four types of patients need the intervention for dyslipidemia, including: 1.secondary prevention in individuals with clinical ASCVD; 2. primary prevention in individuals with primary elevations of LDL-C >=190 mg/dL; 3.primary prevention in individuals with diabetes 40 to 75 years of age who have LDL-C 70 to 189 mg/dL; and 4.primary prevention in individual without diabetes and with estimated 10-year ASCVD risk>=7.5%, 40 to 75 years of age who have LDL-C 70 to 189 mg/dL. (References: http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/). So we need to calculate D.C.’s ASCVD risk from another tool developed by ACC/AHA (American College of Cardiology/American Heart Association), which is available as iOs apps. So the result of ASCVD risk of D.C. is 9.7% (>=7.5%) without any intervention, whereas ASCVD risk is 8.6% (still >=7.5%) with interventions of antihypertensive therapy and smoke cessation. Therefore, the dyslipidemia should be treated for D.C.

PS: ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.

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Pharmacokinetics Series – Clearance and Maintenance Dose

March 14, 2015 Pharmacokinetics, Pharmacotherapy, Therapeutics No comments , , , , ,

UCSFClearance and Maintenance Dose

Clearance can be thought of as the intrinsic ability of the body or its organs of elimination (usually the kidneys and the liver) to remove drug from the blood or plasma. Clearance is expressed as a volume per unit of time. It is important to emphasise that clearance is not an indicator of how much drug is being removed; it only represents the theoretical volume of blood or plasma which is completely cleared of drug in a given period. The amount of drug removed depends on the plasma concentration of drug and the clearance.

As steady state, the rate of drug administration (RA) and the rate of drug elimination (RE) must be equal, so that, RA = RE. Because RA can be described as (S)(F)(Dose/τ), and the RE equals to (Cl)(Css ave), we get the formula for Cl as Cl = (S)(F)(Dose/τ)/(Css ave) [Equation 1].

If an estimate for clearance is obtained from the literature, the clearance formula of [Equation 1] can be rearranged and used to calculate the rate of administration or maintenance dose that will produce a desired average plasma concentration of (Css ave) at steady state: Maintenance Dose = (Cl)(Css ave)(τ)/[(S)(F)] [Equation 2].

Attention must be paid that the units of all factors in these formulas must be consistent.


Factors Affecting Clearance

Body Surface Area/Weight

Most literature values for clearance are expressed as volume/kg/time or as volume/70 kg/time. There is some evidence, however, that drug clearance is best adjusted on the basis of BSA rather than weight. BSA can be calculated using BSA in m2 = (Patient’s Weight in kg/70 kg)0.7(1.73 m2) [Equation 3] or it can be obtained from various charts and nomograms. The value of a patient’s weight divided by 70 taken to the 0.7 power is an attempt to scale or size a patient as a fraction of the average 1.73 m2 or 70-kg individual. Weight divided by 70 taken to the 0.7 power has no units and should be thought of as the fraction of the average-size person.

As an example, a 7-kg patient has a weight ratio relative to 70 kg of 0.1 and, therefore, may be thought of as having a size and thus a metabolic and renal capacity that is one-tenth of the average 70-kg person (7 kg/70 kg = 0.1). If the same weight individual was compared to the 70-kg standard using weight to the 0.7 power, the ratio becomes 0.2 or 20%, (7 kg/70 kg)0.7 = 0.2. Therefore in these two examples, the difference between  0.1 and 0.2 is large. However, when patients do not differ significantly from 70 kg, the difference between using weight versus weight to the power 0.7 (BSA) becomes less significant.

The underlying assumption in using weight or surface area to adjust clearance is that the patient’s liver and kidney size (and hopefully function) vary in proportion to these physical measurements (weight or BSA). However, this may not always be the case; therefore, clearance values derived from the patient population having a similar age and size should be used whenever possible. When a patient’s size is substantially greater or less than the standard 70 kg, or 1.73 m2, a careful assessment should be made to determine if the patient’s body stature is normal, obese, or emaciated. In obese and emaciated patients, neither weight nor surface area is likely to be helpful in predicting clearance, since the patient’s body size will not reflect the size or function of the liver and kidney.

Plasma Protein Binding

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentrations (total of unbound plus free drug) for any given dose that is administered. According to Equation 1, a decrease in the denominator, (Css ave), increases the calculated clearance. This actually would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated of drug per unit of time has increased. Equation 1 assumes that when (Css ave) changes, the free drug concentration, which is available for metabolism and renal elimination, changes proportionately. In actuality the free or unbound fraction of drug in the plasma generally increases with diminished plasma protein binding. As a result, the amount of free drug eliminated per unit of time remains unchanged. This should be apparent if one considers that at steady state, the amount of drug administered per unit of time (RA) must equal the amount eliminated per unit of time (RE). If RA has not changed, RE must remain the same.

In summary, when the same daily dose of a drug is given in the presence of diminished protein binding, an amount equal to that dose will be eliminated from the body each day at steady state despite a diminished steady-state plasma concentration (Css ave) and an increase in the calculated clearance (Cl). This lower plasma concentration (C bound + C free) is associated with a decreased C bound, no change in C free, and as a result there is an increase in the fraction of unbound drug (fu). Therefore, the pharmacologic effect achieved will be similar to that produced by the higher serum concentration observed, under normal protein binding conditions. This example re-emphasizes the principle that clearance alone is not a good indicator of the amount of drug eliminated per unit of time (RE).

Extraction Ratio

The direct proportionality between calculated clearance and fraction unbound (fu) does not apply to drugs that are so efficiently metabolised or excreted that some (perhaps all) of the drug bound to plasma protein is removed as it passes through the elimination organ. In this situation the plasma protein acts as a “transport system” for the drug, carrying it to the eliminating organs, and clearance becomes dependent on the blood or plasma flow to the eliminating organ. To determine whether the clearance for a drug with significant plasma binding will be influenced primarily by blood flow or plasma protein binding, its extraction ratio is estimated and compared to its (fu) value.

The extraction ratio is the fraction of the drug presented to the eliminating organ that is cleared after a single pass through that organ. It can be estimated by dividing the blood or plasma clearance of a drug by the blood or plasma flow to the eliminating organ. If the extraction ratio exceeds the (fu), then the plasma proteins are acting as a transport system and clearance will not change in proportion to (fu). If, however, the extraction ratio is less than (fu), clearance is likely to increase by the same proportion that (fu) changes. This approach does not take into account other factors that may affect clearance such as red blood cell binding, elimination from red blood cells, or changes in metabolic function.

Renal and Hepatic Function

Drugs can be eliminated or cleared as unchanged drug through the kidney and by metabolism in liver. These two routes of clearance are assumed to be independent of one another and additive. A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination. However, as the major elimination pathway becomes increasingly compromised, the “minor” pathway becomes more significant because it assumes a greater proportion of the total clearance. For example, a drug that is usually 67% eliminated by the renal route and 33% by the metabolic route will be 100% metabolised in the event of complete renal failure; the total clearance, however, will only be one-third of the normal value.

Cardiac Output

Cardiac output also affects drug metabolism. Hepatic or metabolic clearances for some drugs can be decreased by 25% to 50% in patients with CHD. For example, the metabolic clearances of theophylline and digoxin are reduced by approximately one-half in patients with CHD. Since the metabolic clearance for both of these drugs is much lower than the hepatic blood or plasma flow (low extraction ratio), it would not have been predicted that their clearances would have been influenced by cardiac output. The decreased cardiac output and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.

Inflammation Mediators

March 9, 2015 Infectious Diseases, Pharmacology, Pharmacotherapy, Physiology and Pathophysiology No comments , , , , , , ,

The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important inflammation mediators include vasoactive amineslipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.

The inflammation mediators have some common characteristics, like

  • Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesised de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Plasma derived mediators (e.g., complement proteins) are produced mainly in the liver and are present in the circulation as inactive precursors that must be activated. When activated a series of proteolytic and protein-protein interactions are initiated that ultimately to acquire their biologic properties.
  • Ative mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signalling pathways.
  • Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions.
  • One mediator can stimulate the release of other mediators. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying or, in certain instances, counteracting the initial action off a mediator.

Vasoactive Amines: Histamine and Serotonin

The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. The richest sources off histamine are the mast cells that are normally present in the connective tissue adjacent to blood vessels. It is also found in blood basophils and platelets. Histamine is stored in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli, including 1.physical injury, such as trauma, cold, or heat, by unknown mechanisms;2.binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions; and 3.products of complement called anaphylatoxins (C3a and C5a). Antibodies and complement products bind to specific receptors on mast cells and trigger signalling pathways that induce rapid degranulation. In addition, leukocytes are thought to secrete some histamine-releasing proteins but these have not been characterised. Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) may also trigger release of histamine.

Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered to be the principle mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. Histamine also causes contraction of some smooth muscles.

Serotonin is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It is also a vasoconstrictor, but the importance of this action in inflammation is unclear.


Arachidonic Acid Metabolites

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation. AA does not occur free in the cell but is normally esterified in membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A2. The biochemical signals involved in the activation of phospholipase A2 include an increase in cytoplasmic Ca2+ and activation of various kinases in response to external stimuli. AA-derived mediators, also called eicosanoids are synthesised by two major classes of enzymes: cyclooxygenases (for prostaglandins) and lipoxygenases (for leukotrienes). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation, including vasodilation (PGI2, PGE1, PGE2 PGD2), vasoconstriction (TxA2/Thromboxane A2, leukotrienes C4/D4/E4), increased vascular permeability (Leukotrienes C4/D4/E4), Chemotaxis, leukocyte adhesion (Leukotrienes B4/HETE or Hydroxyeicosatetraenoic acid).

  • Prostaglandins

Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are generated by the actions of two cyclooxgenases, called COX-1 and COX-2. COX-1 is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX-2 is induced by inflammatory stimuli and thus generates the prostaglandins that are involved in inflammatory reactions, but it is low or absent in most normal tissues. Prostaglandins include many subtype PGs, such as TxA2, PGI2, PGD2, PGE2, PGF2a etc. These subtype prostaglandins are derived by the action of different enzymes on an intermediate in the pathways, respectively.

TxA2, a potent platelet-aggregating agent and vasoconstrictor is derived by the enzyme thromboxane synthase which locates in the platelets. Prostacyclin synthase in vascular endothelium catalyze the production of PGI2 and PGI2 has functions as vasodilator,  a potent inhibitor of platelet aggregation, and markedly potentiates the permeability-increasing and chemotactic effects of other mediators. PS: a thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels. PGD2 is the major prostaglandin made by mast cells; along with PGE2 (which is more widely distributed), it causes vasodilation and increases the permeability of post capillary venules, thus potentiating edema formation. Also it has a function of chemoattractant for neutrophils. PGF2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles.

In addition to their local effects, the prostaglandins are involved in the pathogenesis of pain and fever in inflammation. PGE2 is hyperalgesic and makes the skin hypersensitive painful stimuli, such as intradermal injection of suboptimal concentrations of histamine and bradykinin. It is also involved in cytokine-induced fever during infections.

  • Leukotrienes

Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. There are three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme converts AA (arachidonic acid) to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is the precursor of the leukotrienes. Among leukotrienes, LTB4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to ventral endothelium, generation of ROS (reactive oxygen species), and release of lysosomal enzymes. The LTC4, LTD4, and LTE4 cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Leukotrienes are more potent than is histamine in incresing vascular permeability and causing bronchospasm.

  • Lipoxins

Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They are also unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.


Cytokines and Chemokines

  • Cytokines

Cytokines are proteins produced by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions. They include TNF (tutor necrosis factor) and Interleukin-I (IL-1). These cytokines are produced mainly by activated macrophages and dendritic cells; TNF is also produced by T lymphocytes and mast cells, and IL-1 is produced by some epithelial cells as well. The most important roles of these cytokines in inflammation are the following:

Screen Shot 2015-11-11 at 7.40.44 PM1.Endothelial activation. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly E- and P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and cheekiness, growth factors, and eicosanoids; and increased procoagulant activity of the endothelium.

2.Activation of leukocytes and other cells. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages, in part by inducing production of NO. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial and other mesenchymal cells. IL-1 also stimulates TH17 responses, which in turn induce acute inflammation.

3.Systemic acute-phase response. IL-1 and TNF induce the systemic acute-phase responses associated with infection or injury, including fever. They are also implicated in the syndrome of sepsis, resulting from disseminated bacterial infection. TNF regulates energy balance by promoting lipid and protein mobilisation and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterised by weight loss and anorexia that accompanies some chronic infections and neoplastic disease.

  • Chemokines

Cheekiness are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. Inflammatory chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and they stimulate migration (chemotaxis) of leukocytes in tissue to the site of infection or tissue damage. Also, some chemokines are produced constitutively in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues.


Complement System

The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defines against microbes and in pathologic inflammatory reactions. This system of complement functions in both innate and adaptive immunity for defines against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization.

Complement system acts as the bridge between innate and adaptive immune system. This concept is due to the fact that complement proteins can be activated directly by antigen-antibody complexes.

Primary Functions

There are three main effects of complement: 1.lysis of cells such as bacteria, allografts, and tumor cells; 2.generation of mediators that participate in inflammation and attract neutrophils; and 3.opsonization – enhancement of phagocytosis.

C3b is the central molecule of the complement cascade. It has two core functions: 1.it combines with other complement components to generate C5 convertase, the enzyme that leads to the production of the  membrane attack complex (first it adhere to the surface of the targets); and 2.it opsonises bacteria because phagocytes have receptors for C3b on their surface.

How to activate?

In the classic pathway, antigen-antibody complexes activate C12 to form a protease and thereafter the complement cascade starts. In the lectin pathway,  MBL (mannas-binding lectin/mannose-binding protein) binds to the surface of microbes bearing mannan. This activates proteases associated with MBL that activates complement cascade. In the alternative pathway, many unrelated cll surface substances can initiate the process by binding C3 and factor B. This complex is cleaved by a protease and finally the complement cascade initiates.


Other Mediators

  • Platelet-Activating Factor (PAF)

PAF is a phospholipid-derived mediator that was discovered as a factor that caused platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF, in both recreated and cell-bound forms. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased ventral permeability.

  • Products of Coagulation

Protease-activated receptors (PARs) are activated by thrombin (converting fibrinogen to fibrin), and are expressed on platelets and leukocytes.

  • Kinins

Kinins are vasoactive peptides derived from plasma proteins called kininogens, by the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin, a substance that increases vascualar permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase.

  • Neuropeptides

Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, such as substance P and neurokinin A, are produced in the central and peripheral nervous systems. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and increasing vascular permeability.