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It is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment.
Symptoms-wheezing, breathlessness, cough, chest tightness
Prevalence-10-12% adults, 15% children Developed country>Developing countries
Genetic predisposition Atopy
Indoor allergens Outdoor allergens occupational sensitizers Passive smoking Respiratory infections
Allergens-Dermatophagoides species(dust mite), environmental exposure, grass pollen, ragweed, tree pollen, fungal spores, pets furs, cockroaches etc
Virus infection-upper respiratory tract virus such as rhinovirus, respiratory syncytial virus, coronavirus etc
Pharmacological agents-beta blockers, ACE inhibitors, aspirin
Exercise(may exacerbate )
Physical factors-cold air, hyperventilation
Air pollutants-sulfur dioxide, irritant gases
Irritants-household sprays paint fumes
Hormonal factors-fall in progesterone thyrotoxicosis
Types of asthma-
Atopic asthma-classical type I IgE mediated hypersensitivity, allergen sensitization, seen from childhood, +ve history of asthma in family, skin test +ve
Non-atopic asthma-no allergen sensitization, no
such history, skin test –ve, virus infection?
Drug induced asthma-sensitive to certain drugs like aspirin, NSAIDS etc
Occupational asthma-stimulants such as fumes, organic and chemical dusts(wood, cotton), gas(toluene), penicillin products etc
Exercise induced asthma-begins after exercise and stops after 30 minutes, worsen in cold and dry climate
Effects of inflammation
Chronic inflammation of lower airways
Mucosal infiltration of activated eosinophils and T lymphocytes
Thickening of basement membrane
Goblet cell metaplasia
Smooth muscle hypertrophy and thickening
Shedding of epithelium
Occlusion of airway by mucosal plug
Allergic type of inflammation occurs
From trachea to terminal bronchiole
Predominantly in bronchi
Cells involved in inflammation-mast cell macrophages dendritic cell eosinophils neutrophils T lymphocytes and structural cells
Early phase reaction-mediated by granules release from mast cell, bronchoconstriction, vasodilation and increase permeability
Late phase reaction-inflammation with recruitment of eosinophils, T lymphocytes, neutrophils, macrophages etc and subsequent release of mediators.
Mast cell-activated by IgE dependant mechanism, initiate acute bronchoconstriction action by releasing histamine, prostaglandinD2,leukotrienes etc
Macrophage-activated by low affinity IgE receptor, produce various inflammatory mediators
Dendritic cell-macrophage like major APC in airways, TSLP(Thymic stromal lymphopoietin) by epithelial cell induced chemokine release for TH2 cells
Eosinophils-infiltration is characteristic feature of asthma, activated by IL-5, causes exacerbation of asthma by producing mediators
Neutrophil-activated and infiltration
T cell-release cytokines, causes recruitment of eosinophils, also causes maintenance of mast cells, in asthma TH2 cell produce IL- 5(eosinophil recruitment) IL-4, IL-13(increase IgE production and mucus secretion).CD4+ cell also involved
Structural cells-epithelial cells(TSLP),
Histamine, prostaglandin D2, cysteinly leukotrienes-cause smooth muscle contraction, increased microvascular leakage, increased mucus secretion, act as chemoattractant for inflammatory cells
Cytokines- IL-4, IL-5, IL-13-causes allergic inflammation, IL-1beta, TNF-alpha-amplification of inflammation, TSLP(Tymic stromal lmphopoietin)- from epithelial cells act as chemoattractant for TH2 cells, IL-10, IL-12-anti inflammatory
Chemokines-attract inflammatory cells, Eotaxin(CCL11) attract eosinophil via CCR3 receptor, TARC(CCL17) and MDC (CCL 22) from epithelial cell attract TH2 cell via CCR4.
Oxidative stress-increase in ROS production
NO-act as relaxant but mainly causes
vasodilatation leading to leakage
Transcription factor-NF-kB, activator protein-
Effects of inflammation-
Epithelium-dysfunction, damage, loss of enzyme, loss of relaxant factors, loss of barrier functio
Fibrosis- subepithelial fibrosis, basement membrane thickening, deposition of III and V collagen(by factors release from eosinophil)
Smooth muscle- increased responsiveness to constrictor mediators, in chronic cases hypertrophy/hyperplasia by growth factors released by inflammatory mediators
Vascular response-vasodilation, angiogenesis, microvascular leakage
Mucus hypersecrection- by goblet cell hyperplasia, increase in mucus plug, leading to blocking of airway
Neural effect-reflex cholinergic bronchoconstriction by increased muscarinic action
Several changes can be seen
Irreversible narrowing of lumen
Decline in lung function
Smooth muscle hyperplasia
Asthma is chronic inflammatory disorder with airway hyperresponsiveness and airway obstruction.
various risk factors and triggers
Types-atopic and non-atopic
Eosinophilic infiltration and thickening of B.M.
Hyperplasia of gland and vasodilatation
IgE dependant mast cell activation and release of
Early and late phase reactions with dendritic cell and TH2 cell
Various mediators-cytokine, chemokines, PGs etc
Epithelium shedding, fibrosis, hypertrophy of muscle
and increased permeability
Phases of Clinical Trials
preclinical Drug Development
Before clinical drug development can begin, many years of preclinical development occur.
Basic research teams consisting of chemists. pharmacologists, biologists, and biochemists.
This team identify promising therapeutic categories and classes of compounds.
Compounds are selected for secondary pharmacology evaluations and toxicology testing in animal models.
Compound that is pharmacologically active and safe in at least two nonhuman species may then be selected for study in humans.
Investigational New Drug (IND):
Before the drug can be tested in humans, an Investigational New Drug (IND) application must be filed with an appropriate regulatory agency.
IND contains supporting preclinical information and the
proposed clinical study designs.
Phases of clinical trials
Development of a new drug in humans is divided into four phases.
Different phases refer to different types of studies rather than a specific time course of studies.
The generalized sequence of studies may be tailored to each new drug during development.
Pre-approval segments (Phases 1 through 3).
Post-approval segment (Phase 4).
Studies that involve normal subjects, are included in Phase 1.
Phase 1 of the clinical program begins After the regulatory agency has approved the drug for testing in humans.
To demonstrate safety in humans.
To collect sufficient pharmacokinetic/pharmacological information for determination of the dose strength and regimen for Phase 2 studies.
Typically conducted in healthy adult subjects.
Other Evidences obtained:
Adverse events associated with increasing dosages.
Evidence of efficacy.
Pharmacokinetic profile…includes information
about absorption (initial studies has an oral formulation).
Assessment of bioequivalence of various formulations.
Dose range and route of administration.
Dosing/Sampling (Phase 1)
The initial dose may be based on animal pharmacology or toxicology data.
Doses are increased gradually until an adverse event is observed.
Sampling is done by collecting Blood and urine.
First Study (single dosing)
Second Study (Multiple dosing).
Study Design (Phase 1)
Placebo controlled, double-blind(so that the drug effects, such as drug induced can be distinguished from the nondrug effects)
Escalating single-dose study is initiated.
Healthy volunteers are recruited.
Sometimes patients are used (e.g testing anticancer drug that may be too toxic to administer to healthy volunteers).
Include two or three cohorts, with six or eight subjects receiving the active drug and two subjects receiving placebo.
The groups may receive alternating dose levels which allow assessment of dose response (i.e., adverse events) relationship.
Study Setting (Phase 1)
Participants in the first study are usually hospitalized or enrolled in a clinic.
Clinical measurements can be performed under controlled conditions.
Any medical emergency can be handled in the most expeditious manner.
Maximum Tolerated Dose(MTD)
The first study in humans is usually not considered successfully completed until an MTD has been reached.
Relationship between a clinical event (e.g., emesis) and a particular dose level observed under controlled conditions can provide information that will be extremely useful when designing future trials.
A multiple-dose safety study typically is initiated once the first study in humans is completed.
To define an MTD with multiple dosing before to initiating well-controlled efficacy testing.
Should simulate actual clinical conditions in as many ways as possible.
The inclusion of a placebo group is essential to allow the determination of drug-related versus nondrug-related events.
Dosages, frequency, dose escalations, and dose tapering, should simulate the regimen to be followed in efficacy testing.
dosing in the second study lasts for 2 weeks.
length of the study may be increased depending on the pharmacokinetics of the drug.
if the drug is to be used to treat a chronic condition, a 4-week study duration may be appropriate.
minimum enrollment of 24 subjects should be anticipated.
subjects would be hospitalized for the duration of the study.
Blood and urine.
whether the pk parameters obtained in the 1st study accurately predicted the multiple dose pharmacokinetic behavior of the drug.
verification of pharmacokinetic linearity (i.e., dose proportionality of C,,, and AUC)observed in the 1st study.
whether the drug is subject to autoinduction of clearance upon multidosing.
Existence and accumulation of metabolites that could not be detected in the previous single-dose study
Demerits of ADR clinical Trials
Pre-marketing trials cannot detect important reactions that occur at rates of 1 in 10,000.
Only pharmacologically predictable ADRs may be identified in clinical trials.
ADRs are only assessed by the clinicians who run them so rare/potentially serious ADRs often remain undetected.
ADR’s and Clinical Trials
Evidence of safety must be demonstrated for regulatory authorities to permit marketing.
The degree of exposure of the drug is an important factor in understanding the toxicologic results of the study.
However, it is not possible to discover the complete safety profile of a new drug prior to its launch.
These involves on average 2500 patients.
Patient selected for ADR detection should be without the multiple disease states or complex drug histories.
Focus on efficacy.
Pharmacokinetic information obtained in Phase 1 studies is used to optimize the dosage regimen.
Not as closely monitored as Phase 1 studies.
Conducted in patients.
These studies are designed to obtain information
Efficacy trials (Phase 2)
Efficacy trials should not to be initiated until the MTD has been defined.
On completion of the efficacy trial, a therapeutic
window for plasma drug concentrations can be defined by reviewing the correlation between plasma drug concentrations and key safety and efficacy parameters.
To improve efficacy and safety of the drug.
By individualizing the dosage based upon previous plasma drug concentration profiles in the same patient.
Study Design (Phase 2)
Pharmacokinetic information obtained in healthy volunteers (during phase 1) is key to the design of successful efficacy trials.
During the planning stage of an efficacy trial, the focus is on the dosage regimen and its relationship to efficacy measurements.
Following information obtained earlier must be considered when choosing an optimal dosage regimen for the study.
Disease or physiological states of the test patients
(e.g., organ dysfunction as a function of age).
concurrent medications (e.g., enzyme inducers or inhibitors).
Phase 3 clinical trials will be initiated if:
earlier clinical studies establishes:
Drug’s therapeutic properties.
Cinical pharmacologic properties.
and if it is still considered to be a promising drug.
Phase 3 studies enroll many more patients.
conducted both in a hospital or controlled setting and in general practice settings.
to confirm the therapeutic effects.
to establish dosage range and interval.
to assess long-term safety and toxicity.
to identify less common side effects and AEs that develop latently.
to evaluate/quantify specific effects of the drug, such as drowsiness.
to establish a place for the drug in its therapeutic class.
to identify the most appropriate population or subpopulation for the study drug.
Relative safety profiles:
to establish better safety profile of the investigative
compound as compared to its already available/existing alternative.
Drug Interactions (Phase 3)
Polytherapy ….high risk of drug-drug interactions,both from pK and pD perspectives.
Closer inspection of drug interactions is warranted in Phase 3 clinical trials.
The likelihood of drug interactions and may be predicted from in vitro data.
Evaluation of Drug Interactions :
The potential for interactions needs to be evaluated from two perspectives:
potential that the new drug may affect the pharmacokinetics of other drugs
(depends on the ability of the new drug to affect various enzyme and carrier-mediated clearance processes).
the potential that other drugs may affect the pharmacokinetics of the new drug.
(requires knowledge of the components of clearance
General practitioners (phase 3)
Early clinical trials are conducted at university medical centers with specialized physicians.
General physicians are exposed to study drugs during this phase because they will be the one writing most of the prescriptions post marketing.
Phase 1, 2, and 3 studies depends on strict inclusion and exclusion criteria.
Phase 4 emphasizes on collection of safety information.
Phase 4 studies employ mainly observational study designs.
Post marketing surveillance and any additional studies requested by the regulatory agency are conducted during Phase 4.
Data collection (Phase 4)
Is an extensive, scientific exercise.
Detailed blood work.
Special laboratory tests.
Careful physiologic monitoring.
Post marketing studies, however, are often targeted for much larger patient populations (5000- 10,000 or more).
Groups in Clinical Trials
Comparative groups to assess the efficacy and safety of the investigational drug relative to other drugs currently marketed.
The control groups take either placebo or active medication.
Sometimes more than one control group is used in a study.
group taking the investigational drug.
Placebo & Active Medication
Placebo Should be as similar as possible to the drug being investigated.(e.g., same color. taste. and shape).
Active medication taken by the control group also should be as similar as possible to the drug being investigated (e.g.. same color, taste, and shape).
To maintain the blind:
If the formulations cannot be made with similar appearances a placebo of each formulation could be made.
So subjects would take one active formulation and the placebo of the other formulation.
A medication error is:
“Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional , patient or consumer .
an estimated 7000 deaths per year are caused by medication errors.
• More Americans die of medication errors annually than from workplace injuries.
• Medication harm have a cost, calculated at as much as $2 billion annually.
Second report,Crossing the quality chasm;A New Health System for the 21st centurey
Three problem categories introduced.
–failures to execute clinical care plans and procedures properly.
–use of health care resources and procedures in the absence of evidence.
failure to employ health practices of proven benefit.
TYPES OF ERRORS.
A. Wrong drug error.
B. Extra dose error.
C. Omission error.
D. Wrong dose/wrong strength error.
E. Wrong route error.
F. Wrong time error.
G. Wrong dosage form error.
Wrong drug error
A drug that was not ordered for a patient was administered.
for example, a patient accidentally received furosemide 40 mg orally.
Extra dose error.
A patient receives more doses of a drug than were ordered
a patient received a medication with breakfast for 5 days instead of 3 days
drug was not administered as ordered but was skipped.
patient was supposed to receive digoxin 0.25 mg orally but did not receive the dose.
Wrong dose or wrong strength error
wrong dose of a medicine or the wrong strength is administered
patient was supposed to receive warfarin .5 mg but received 5 mg instead.
Wrong route error
patient receives a dose of a medication by a route that was not ordered by the physician.
patient was supposed to receive
prochlorperazine 10 mg IM but was administered IV.
Wrong time error
patient does not receive a dose of medication at the time at which it was to be administered.
hospitalized patient with diabetes is scheduled to receive insulin immediately before breakfast but the dose is given 2 hr after breakfast .
Common Error Hazards
U, IU: unit (s)
The letter U can easily be misinterpreted as a number (e.g. , 0 or 4) .
results in serious harm with insulin and heparin
patient received 66 units of insulin instead of 6 units.
“6U” of regular insulin was misread as 66.
QD, Q.D,qd, q.d. (daily)
misinterpreted as “QID” or “qid” (four times daily
resulting in overdoses
When a dose is ordered and followed with a decimal point and a zero, such as 2.0 mg .
Decimal point may be missed and an overdose can occur .
warfarin 2.0 mg may be
misinterpreted as 20 mg
Lack of leading zero
drug's dose less than 1 mg.
dose is written without a leading zero.
digoxin .25 mg instead of digoxin 0.25 mg.
abbreviations for morphine sulfate and magnesium sulfate are quite similar and can be confused
confusing symbols, abbreviations
cc. instead of mL.
HCT for hydrocortisone
misinterpreted as a 0.
mistaken for mg.
misinterpreted as hydrochlorothiazide
Sound-a- like or look-a- like drug names
Amitriptyline and aminophylline
Cisplatin and carboplatin
What's New ?
Two vaccines have been approved by the Food and Drug Administraion (FDA) for use against COVID-19: The Pfizer vaccine and Moderna Vaccine.
These vaccines are being shipped across the U.S. and each state develops its own plan for who will receive the vaccine and when.
Healthcare workers and patients in long-term care facilities are receiving the vaccine now.
The vaccines are safe
Both vaccines were tested on up to 40,000 Volunteers of different races, ethnicities, and health conditions including kidney disease, diabetes, and cancer.
Both vaccines have gone through a full safety review with no short cuts taken, What has allowed the process to move more quickly is the research community working together on a single goal and the speedy shipment of the vaccines.
The vaccines are effective. Both vaccines are approximately 95% effective at preventing COVID-19
When and where can i get the COVID-19 Vaccine?
Order is :
Phase 1a - Healthcare workers and long term care facility residents
Phase 1b - People 75 and older and essential workers
Phase 1c - People 65 to 74 and people 16 to 64 with high risk health condition.
Where dialysis patients can receive the vaccine is still being determined.
How many doses of the vaccines are needed to be effective?
The vaccines requires 2 doses, 21-28 days apart. You need both doses.
You may not be fully protected against COVID-19 until 7 days after the second dose.
What side effects can i expect after receiving the Pfizer or Moderna vaccine?
Both vaccines may result in mild side effects such as pain at the injection site and feeling tired, which are normal and expected with vaccination.
Who should NOT get a COVID-19 Vaccine?
The Pfizer vaccine is recommended for most people 16 and older.
The Moderna vaccine is recommended for most people 18 and older.
Talk to your doctor if you have had an allergic reaction to a vaccine before.
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