ADRs

Introduction to ADRs

Adverse drug reactions (ADRs), also known as ‘side effects’, ‘adverse
drug events’, or ‘drug misadventures’, are a frequent cause of morbidity in hospital and the community. They have a significant cost both financially and in terms of quality of life. 
Few studies of ADRs have been carried out in the community so the effect on primary care is harder to assess, but studies in the hospital environment have shown the following.

• ADRs occur in 10–20 % of patients in hospital.
• ADRs are responsible for 5 % of admissions to hospital.
• ADRs might be responsible for 1 in 1000 deaths in medical wards.
• ADRs are the most common cause of iatrogenic injury in hospital
patients.

The World Health Organization (WHO) defines an ADR as follows:
‘ a drug-related event that is noxious and unintended and occurs at doses used in
humans for prophylaxis, diagnosis or therapy of disease or for the modification
of physiological function .’

However, this definition does not take into account the following
scenarios, all of which can also cause ADRs:
• overdose (including prescribing or administration errors)
• therapeutic failure
• drug interactions
• drug withdrawal.

Pharmacists have an important role in identifying, reporting, and preventing
ADRs.

Terminology in liver disease

Hepatocellular injury
Damage to the main cells of the liver (hepatocytes)

Hepatitis
 Inflammation of the liver, a type of hepatocellular injury. Could
be caused by viruses, drugs, or other agents, or could be
idiosyncratic.

Cirrhosis
 Chronic, irreversible damage to liver cells, usually caused by
alcohol or hepatitis C. If the remaining cells cannot maintain
normal liver function (compensated disease), ascites, jaundice,
and encephalopathy can develop (decompensated disease).

Cholestasis 
Reduction in bile production or bile fl ow through the bile
ducts.

Liver failure 
Severe hepatic dysfunction where compensatory mechanisms
are no longer suffi cient to maintain homeostasis. Could be
acute and reversible, or irreversible (e.g. endstage cirrhosis).

Anaphylaxis

Symptoms and signs of anaphylaxis

Anaphylaxis is defined as an immediate systems hypersensitivity event produced

by IgE-mediated release of chemicals from mast cells and basophils.
Theoretically, prior exposure to the agent is required and the reaction is
not dose- or route-related, but in practice anaphylaxis to injected antigen
is more frequent, severe, and rapid in onset than following exposure to
oral or topical antigen.
Agents which commonly cause anaphylaxis include:
• drugs — e.g. penicillins, aspirin
• insect stings — e.g. wasp and bee venoms
• food — e.g. nuts.
Urticaria and angioedema are the most common symptoms
and absence of these suggests that the reaction may not be anaphylaxis.
Airways oedema, bronchospasm, and shock are life-threatening and
immediate emergency treatment is usually required.
The onset of symptoms following parenteral antigen (including stings) is
usually within 5–30min. With oral antigen, there is often a delay. Symptoms
usually occur within 2h, but may be immediate and life-threatening.
A late-phase reaction may also occur with recrudescence of symptoms
after apparent resolution. Recurrence is a fairly frequent phenomenon
and healthcare workers should be aware of this. Patients should not be
discharged too quickly as they may require further treatment.
End-of-needle reactions
Some patients may experience an anaphylactic-like reaction during rapid
intravenous (IV) drug administration. This is known as an end-of-needle
reaction. Initial symptoms may suggest anaphylaxis, but in fact this is a
vasopressor effect and can be distinguished from anaphylaxis as bradycardia
occurs which is rare in anaphylaxis. Skin symptoms are also rare
in end-of-needle reactions. Stopping or slowing down the infusion or
injection usually leads to resolution of symptoms,and administration at a
slower rate usually avoids a repeat event.
Signs and symptoms of anaphylaxis
F Urticaria
R Angioedema
E Dyspnoea, wheeze
Q Nausea, vomiting, diarrhoea, cramping abdominal pain
U Flush
E Upper airway oedema
N
T
R Headache
A Rhinitis
R Substernal pain
E Itch with no rash
Seizure

ATOMIC EMISSION SPECTROSCOPY

ATOMIC EMISSION

Technique is also known as OPTICAL EMISSION SPECTROSCOPY (OES)

- The study of radiation emitted by excited atoms and
monatomic ions
- Relaxation of atoms in the excited state results in
emission of light
- Produces line spectra in the UV-VIS and the
vacuum UV regions
Used for qualitative identification of elements present
in the sample
- Also for quantitative analysis from ppm levels to percent
- Multielement technique
- Can be used to determine metals, metalloids, and some
nonmetals simultaneously
Emission wavelength and energy are related by
ΔE = hc/λ
- Does not require light source
- Excited atoms in the flame emit light that reaches the detector
(luminescence)
Techniques Based on Excitation Source
- Flame Photometry (flame OES)
- Furnace (Electrical Excitation)
- Inductively Coupled Plasma (ICP)

FLAME ATOMIC EMISSION SPECTROSCOPY

- Known as Flame OES

- Also called flame photometry

- Solutions containing metals (or some nonmetals) are

introduced into a flame

- Very useful for elements in groups 1A and 2A

INSTRUMENTATION OF FLAME OES

- No external lamp is needed

- Flame serves as both the atomization source and the

excitation source

Main Components

- Burner assembly

- Flame

- Wavelength selection device

- Detector

Burner Assembly

- The most commonly used is the Lundegarth or the premix burner

- Is the heart of the emission spectrometer

- Nebulizer introduces sample aerosol into the base of the flame

- Free atoms are formed and excited in flame

- Excited free atoms emit radiant energy

- Only about 5% of the aspirated sample reach the flame

General Process in Flame

- Liquid samples enter nebulizer

- Sample droplets of liquid enter flame

- Fine solid particles form

- Particles decompose to free atoms

- Excited atoms form

- Excited atoms relax and emit radiation

- Oxidation of atoms occur

Nebulizers commonly used

- Pneumatic

and

- Cross-flow

Wavelength Selection Device

Two wavelength selectors used

- Monochromators

and

 - Filters

Monochromators

- Diffraction grating is used as the dispersion element

Filters

- Good for detection of alkali metals due to simple spectrum

- Material is transparent over a narrow spectral range

- Desired radiation passes through filter and others are absorbed

- One element is determined at a time (single channel)

Multichannel Flame Photometers

- Two or more filters are used simultaneously

- Each filter transmits its designated radiation

- Detector is PMT

- Permits the use of internal standard calibration

Detectors

- PMT

- Solid-state detectors (CCD, CID)

- PDA

Flame Excitation Source

- Two gases (fuel and oxidant) are used

- Oxidant: air or nitrous oxide

- Fuel: acetylene (commonly used), propane, butane, natural gas

- Increase in flame temperature increases emission intensity

of most elements (exception: Na, K, Li)

Each element emits different characteristic wavelength of light

- Emission lines are characterized by wavelength and intensity

Emission intensity depends on

- Analyte element concentration in sample

- Rate of formation of excited atoms in flame

- Rate of introduction of sample into flame

- Flame composition

- Flame temperature

S = kN

S = intensity

k = proportionality constant

N = number of atoms in the excited state

- Increasing temperature increases N

- Atomic emission spectrometry is very sensitive to temperature

- Temperature must be carefully controlled for quantitative analysis

Elements with emission lines at shorter wavelengths give weak

emission intensity at low temperature

- High-temperature nitrous oxide-acetylene flame is used for

such elements

- High-energy electrical or plasma excitation sources may

also be used

- Ratio of fuel to oxidant also affects emission intensity

- The highest temperature is achieved when stoichiometric

mixture is used

INTERFERENCE

Two Classes

- Spectral interference

and

- Nonspectral interference

Spectral Interference

Two types

Background Radiation

- Broad band emission by excited molecules and radicals in flame

Overlapping emission lines

- Emission by different elements of the same wavelength as

the analyte element

Nonspectral Interference

Chemical Interference

- Occurs if anions that combine strongly with analyte element

are present in sample

Excitation Interference

- Result of collisions between unexcited atoms of an element with

excited atoms of a different element in sample

Ionization Interference

- Occurs when atoms ionize in flame and cannot emit atomic λs

APPLICATIONS OF FLAME OES

- For measurement of alkali metals in clinical samples such as

serum and urine

- Excellent method for qualitative determination of multiple

elements in sample

- Characteristic emission lines of analyte are compared

with literature (appendix 7.1)

- Also used for quantitative analysis (application of Beer’s Law)

- Deviation from linearity is generally observed at

high concentrations

- More free atoms are liberated in organic solvents than

in aqueous solutions

- Implies emission intensity is relatively higher in

nonaqueous solutions

- Atomization is exothermic and rapid in organic solvents

- Atomization is endothermic and relatively slow in aqueous

solutions

- External calibrations and standard addition methods are used

Biopharmaceutics

Biopharmaceutics: 

the study of how the physicochemical properties of drugs, dosage forms and routes of administeration affect the rate and extent of the drug absorption.

Thus, biopharmaceutics involves factors that influence the: 1) protection and stability of the drug within the  product; 2) the rate of drug release from the product; 3) the rate of dissolution of the drug at the absorption site; and 4) the availability of the drug at its site of action . 

nADME: is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism.

nPharmacokinetics: The study and characterization of the time course (kinetics) of drug absorption, distribution, metabolism and elimination (ADME).

nAbsorption: is the process of a substance entering the body.
nDistribution: is the dispersion  of substances throughout the fluids and tissues of the body.
nMetabolism: is the irreversible transformation of parent compounds into daughter metabolites.
nExcretion: is the elimination of the substances from the body.

nBioavailability: The rate and extent of drug absorption.

nBioavailable dose: The fraction of an administered dose of a particular drug that reaches the systemic circulation intact. 

nPlasma level-time curve:

nThe plasma level-time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered.

nThe concentration of drug in each plasma sample is plotted against the corresponding time at which the plasma sample was removed.

nDrug Product Performance Parameters:

1- Minimum effective concentration (MEC): The minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect.

2- Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect.

3- Onset time: The time required for the drug to reach the MEC.

4- Duration of action: The difference between the onset time and the time for the drug to decline back to the MEC.  

5- The time of peak plasma level: The time of maximum drug concentration in the plasma and is proportional to the rate of drug absorption.

6- The peak plasma level: The maximum drug concentration, usually related to the dose and the rate constants for absorption and elimination of the drug.

7- Area under the curve: It is related to the amount of drug absorbed systemically.

Pharmaceutical Aerosol

Pharmaceutical Aerosol

Definition

Pharmaceutical aerosols are dosage systems

containing one or more active ingredient which 

upon actuation emit a fine dispersion of liquid / or 

solid materials in a gaseous medium. 

Classification

Space Sprays

▫These are used o provide an airborne mist.

▫These have Particle size is less than 50 mm.

▫Contain 70-80% propellant

▫Examples are: Room disinfectants, room deodorizers, space sprays, air fresheners etc.

Surface Sprays

▫Used to carry an active ingredient to a surface.

▫Larger particle size

▫Contain usually 30-70% propellant.

▫Examples are: Dermatological aerosols, Non-pharmaceutical aerosols e.g. cologne sprays etc. 

Drug Discovery Pipeline