A brief introduction about Pharmacology of free radicals, generation of free radicals, Antioxidants, Free radicals causing disorders such as cancer diabetes, neuro degenerative disorders such as Parkisonism's Disease

1. Pharmacology of Free
Radicals
Free radicals causes Disorder & Their Treatment
Generation of free radicals
Antioxidants
Advanced and recent treatment of
Diabetes mellitus,
Alzheimer ‘ s Disease,
Parkinsonism and Cancer
2019
IFTM University, Lodhipur Raput, Moradabad
Prepared by Shivam M. Pharm II Sem Under the Guidance Dr. NA Khan
2019

2. 2
Pharmacology of Free Radicals
Free Radicals
A free radical is defined as any chemical species that contains unpaired electron (s) in its
outer orbit. Because of these unpaired electrons, free radicals are highly reactive and
readily take part in chemical reactions with virtually all cell components (lipids, proteins,
complex carbohydrates and nucleic acids) in the body. These reactions occur through a
chain of oxidative reactions to cause tissue injury. For most biological structures (like lipids,
proteins, and nucleic acids), free radical damage is closely associated with oxidative
damage, causing direct cellular injury by inducing lipid and protein
O2+e−→O−⋅2Superoxide radical
O−⋅2+H2O→HO⋅2+OH−Hydroperoxyl radical
HO⋅2+e−+H→H2O2Hydroperoxide
Types of Free Radicals
• Superoxide Ion Radical ( O 2 ∙ - ) ...
• Hydroxyl Radical (OH∙) ...
• Peroxyl Radical (ROO∙) ...
• Hydrogen Peroxide (H2O2) ...
• Singlet Oxygen (1O2) ...
• Ozone (O3) ...
• Hypochlorous Acid (HOCl) ...
• Nitric Oxide or Nitrogen Monoxide (NO•)
Generation of Free Radicals
Free radicals are unstable, highly reactive molecules which are generated both in the body
and outside the body. ... They travel via cells disrupting the structure of molecules causing
cellular damage. They do serve useful purposes in the human body and under certain
situations have several deleterious effects in the body.

3. 3
Formation of free radicals
• Normally, bonds don’t split to leave a molecule with an odd, unpaired electron. But when
weak bonds split, free radicals are formed.
• Free radicals are very unstable and react quickly with other compounds, trying to capture
the needed electron to gain stability. When the "attacked" molecule loses its electron, it
becomes a free radical itself, beginning a chain reaction , resulting in the disruption of a
living cell.
• Some free radicals may arise normally during metabolism and by immune system’s cells
purposefully to neutralize viruses and bacteria.
Steps involving free radical generation
• free radicals take part in radical addition and radical substitution as reactive
intermediates. Chain reactions involving free radicals

4. 4
can usually be divided into three distinct processes: initiation, propagation, and termination.
• Initiation reactions are those, which result in a net increase in the number of free
radicals. They may involve the formation of free radicals from stable species or they
may involve reactions of free radicals with stable species to form more free radicals.
• Propagation reactions involve free radicals in which the total number of free radicals
remains the same.
• Termination reactions are those reactions resulting in a net decrease in the number
of free radicals.Radicals may also be formed by single electron oxidation or
reduction of an atom or molecule. An example is the production of superoxide by the
electron transport chain.
Causes of free radicals
• Pollution and other external substances:- The pollutants produced by modern
technologies often generate free radicals in the body. The food most of us buy
contains farm chemicals, including fertilizers and pesticides, that produce free
radicals when we ingest them. Prescription drugs often have the same effect, their
harmful side-effects may be caused by the free radicals they generate.
Processed foods frequently contain high levels of lipid peroxides, which produce free
radicals that damage the cardiovascular system. Cigarette smoke generates high
free-radical concentrations , much of the lung damage associated with smoking is
caused by free radicals. Air pollution , Alcohol is a potent generator of free radicals
• Stress:- The body's stress response creating free radicals in abundance. The stress
response races the body's energy-creating apparatus, increasing the number of free
radicals as a toxic by-product The hormones that mediate the stress reaction in the
body - cortisol and catecholamines - will themselves degenerate into particularly
destructive free radicals
• The immune system:-
The body tries to harness the destructive power of the most dangerous free radicals -
the oxy radicals and ROS - for use in the immune system and in inflammatory reactions.
Certain cells in these systems engulf bacteria or viruses, take up oxygen molecules from
the bloodstream, remove an electron to create a flood of oxy radicals and ROS, and
bombard the invader with the resulting toxic shower.This aggressive use of toxic oxygen
species is remarkably effective in protecting the body against infectious organisms.

5. 5
• Energy production:-
The energy-producing process in every cell generates oxy radicals and ROS as toxic
waste, continuously and abundantly Oxygen is used to burn glucose molecules that act as
the body's fuel. The cell includes a number of metabolic processes with the constant
creation of oxy radicals and ROS.
Role of free radicals in Etiopathogenesis
When produced in excess, free radicals and oxidants generate a
phenomenon called oxidative stress, a deleterious process that can
seriously alter the cell membranes and other structures such as proteins, lipids,
lipoproteins, and deoxyribonucleic acid (DNA)
oxidative stress results from an imbalance between formation and neutralization of
ROS/RNS
Cancer and oxidative stress:-
oxidative DNA damage is responsible for cancer development.
Cancer initiation and promotion are associated with chromosomal defects and oncogene
activation induced by free radicals
Oxidative DNA damage also produces a multiplicity of modifications in the DNA structure
including base and sugar lesions, strand breaks DNA-protein cross-links and base-free
sites
For example, tobacco smoking and chronic inflammation resulting from noninfectious
diseases like asbestos are sources of oxidative DNA damage that can contribute to the
development of lung cancer and other tumors
Neurological disease and oxidative stress
Oxidative stress has been investigated in neurological diseases including Alzheimer’s
disease, Parkinson’s disease, multiple sclerosis, memory loss, depression.
In Alzheimer’s, numerous experimental and clinical studies have demonstrated that
oxidative damage plays a key role in the loss of neurons and the progression to dementia .
The production of ß-amyloid, a toxic peptide often found present in Alzheimer’s patients’
brain, is due to oxidative stress and plays an important role in the neurodegenerative
processes
Rheumatoid arthritis and oxidative stress

6. 6
Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of
the joints and tissue around the joints with infiltration of macrophages and activated T cells
The pathogenesis of this disease is due to the generation of ROS and RNS at the site of
inflammation.
Oxidative damage and inflammation in various rheumatic diseases were proved by
increased levels of isoprostanes and prostaglandins in serum and synovial fluid compared
to controls.
Role of Free radicals in Etiopathology of Various Disease
1. Role of free Radicals in Diabetes Mellitus
Diabetes mellitus is a common disorder, caused by hyperglycaemia resulting from a
deficiency in insulin secretion or action. Diabetes mellitus is associated with increased risk
of complications including retinopathy, kidney failure, nerve damage, circulatory problems,
heart disease and stroke. Animal studies have suggested that reactive radicals contribute to
the destruction of pancreatic islet cells in the pathogenesis of insulin dependent diabetes
mellitus. Toxic amounts of reactive oxygen intermediates are released by endothelial cells
and infiltrating macrophages during islet inflammation. Islet cells are thought to have
deficient defense system against free radical attack, making them susceptible to reactive
oxygen intermediates, leading to the destruction of the cells. Impaired ascorbic acid
metabolism has also been implicated in diabetes. Ascorbate is required for the regeneration
of vitamin E in vivo and may be oxidized to dehydroascorbic acid, which can disrupt cell
structures and act as a neurotoxin. In healthy tissues dehydroascorbic acid is generally
recycled back to ascorbic acid. Increased exposure to high levels of dehydroascorbic acid
and low levels of ascorbic acid results in increased susceptibility of the cell to oxidative
damage. Other research suggests that high glucose levels in diabetes interfere with
ascorbic acid uptake, resulting in low levels of ascorbate in cells.
2. Role of free Radicals in Neurodegenerative Disease
Oxidative stress in the brain is likely to occur as the brain uses up to 20% of the body's
inspired oxygen, yet only accounts for 2% body weight. The brain also houses large
concentrations of polyunsaturated fatty acids, which may undergo lipid per-oxidation in such
an oxygen-rich environment. ROS have been implicated in the pathology of a number of
neurological disorders.
Parkinson's Disease
Dopamine is metabolized in the cytosol and can result in the production of hydrogen
peroxide. Increased dopamine turnover has been reported in the cytosol of patients
suffering from Parkinson's disease, which leaves them predisposed to higher levels of
hydrogen peroxide. Hydrogen peroxide can be converted to highly reactive hydroxyl
radicals which are extremely toxic and can cause damage to dopaminergic neurons.
Increased lipid per-oxidation, elevated iron levels, increased production of ROS and

7. 7
decreased levels of reduced glutathione have all been identified in the substantia nigra of
patients suffering from Parkinson's disease.
Down's Syndrome (DS)
Altered antioxidant systems and increased oxidative stress have been implicated in the
etiology of Down's Syndrome. Down’s Syndrome generally results from a trisomy of
chromosome 21, which also encodes SOD. SOD activity is therefore 50% higher in all
tissues in DS patients including the brain. This enzyme converts superoxide radicals to
oxygen and hydrogen peroxide, which can then f highly reactive hydroxyl radicals. DS
patients have increased levels of SOD, GPx and lipid per-oxidation.
Alzheimer's Disease
A. d. is associated with loss of neurons, neurofibrillary tangles, deposition of amorphous
protein, among others. Increased oxidative stress has also been identified in the brain of
these patients. Decreased levels of vitamin E, C and plasmaaluminium have also been
associated with Alzheimer's disease. Increased thought to enhance iron induced lipid
peroxidation.
3. Role of Free Radicals in Cancer
Millions of patients throughout the world suffer from cancer. Recent evidence suggests
regional variance of cancer with lung, breast, colon, uterus and prostate cancers being
prevalent in developed countries compared to cervical, mouth/pharynx, esophageal and
liver cancers being prevalent in the developing world. Evidence suggests that cancer
development occurs in two stages, initiation and promotion. Initiation involves a permanent,
irreversible genetic change in the cell’s DNA. This generally causes DNA strand brakes,
which can lie dormant in the cell but do not alone cause cancer. Promotion elicits the
second stage of carcinogenesis, which stimulates the cell infiltration, transforming it to a
cancerous cell. This process is reversible and may require continued stimulation to promote
mutations. Many components have both initiating and promoting activities, however, free
radicals are thought to act principally as promoting agents. Superoxide radicals and many
peroxides are tumor promoters whereas some antioxidants act as anti-promoters and anti-
carcinogens. Free radicals have been associated with gross chromosomal damage and
also inhibition of the biological natural repair system. Free radicals and ROS can alter gene
expression by mobilization of calcium stores, which activate a variety of cellular kinases,
phosphatases and transcription factors. Lipid peroxidation by free radicals and ROS has
also been implicated as a causative factor in cancer development
Protective Activity of Certain Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules.
Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to
an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals
can start chain reactions.

8. 8
Types of antioxidants:
Mainly Hydrophilic and Hydrophobic
Antioxidant enzymes:
1. Catalase
2. Glutathione peroxidase
3. Glutathione reductase
4. Super oxide dismutase (both Cu-Zn and Mn)
Metals binding proteins:
1. Ceruloplasmin
2. Ferritin
3. Lactoferrin
4. Metallotheinein
5. Transferrin
6. Hemoglobin
7. Myoglobin
Common antioxidants (scavengers)
1. Bilirubin
2. Carotenoids
a. Beta-carotene b. Alpha-carotene
c. Beta-cryptoxanthin d. Lutein
e. Zeaxanthin f. Lycopene
3. Flavonoids
a. Quercetin
b. Rutin
c. Catechin
4. Uric acids 5. Thiols (R-SH)
6. Coenzyme Q10 7. Vitamin A, C, E, D.
Others antioxidants

9. 9
1. Copper 2. glutathione (GSH)
3. Alpha lipoic acid 4.Manganise
5. Selenium 6. Zinc
Mechanism of action of antioxidants
Alpha tocopherol (vitamin E):
Prevent the peroxidation of membrane phospholipids, and avoids cell membrane damage
through its antioxidant action
Ascorbic acid (vitamin C)
Scavenges free radicals and reactive oxygen molecules, which are produced during
metabolic pathways of detoxification
Beta Carotene
Ability to quench singlet oxygen, scavenge free radicals and protect the cell membrane
lipids from the harmful effects of oxidative degradation .
Superoxide dismutase (SOD)
Eliminating ROI by reducing (adding an electron to) superoxide to form H2O2. Catalase and
the selenium-dependent glutathione peroxidase are responsible for reducing H2O2 to H2O.
Catalase and glutathione peroxidase seek out hydrogen peroxide and convert it to water
and diatomic oxygen.
The catalase enzyme
Glutathione peroxidase enzyme
Glutathione peroxidase reduces H2O2 to H2O by oxidizing glutathione (GSH)
Antioxidant System in our body
The enzymatic antioxidants
Superoxide dismutase (SOD)
Catalase
Glutathione peroxidase
The nonenzymatic antioxidants
Vitamins E, C, A or Provitamin A(beta-carotene), GSH
Pro-oxidant activities
Antioxidants that are reducing agents can also act as pro-oxidants. For example, vitamin C
has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,
however, it will also reduce metal ions that generate free radicals through the Fenton
reaction.
2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate
2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH−
Determining Antioxidant Activity
• ORAC, Oxygen Radical Absorbance Capacity method
• TRAP, Total Radical-Trapping Antioxidant Parameter method.
• TEAC, Trolox Equivalent Antioxidant Capacity method
• DPPH
• TOSC, Total Oxyradical Scavenging Capacity method
• PSC, Peroxyl Radical Scavenging Capacity method

10. 10
• FRAP, Ferric Reducing/Antioxidant Power method.
Oxidative stress in disease:
Oxidative stress is thought to contribute to the development of a wide range of diseases
including Alzheimer's disease, Parkinson's disease, the pathologies caused by diabetes,
rheumatoid arthritis, and neurodegeneration in motor neuron diseases
How to measure the oxidative stress
d-ROMs T
This test is used to determine the antioxidant capacity of plasma, mainly due to the level of
hydroperoxides - a subclass of reactive oxygen metabolites (ROM) - amplifiers and
considered markers of cell damage by free
radicals.
BAP Test
This test is used to determine the efficiency of the plasma barrier opposes the attack of free
radicals in terms of iron-reducing activity An increase in the values of d-ROMs Test (> 300
U CARR) and / or a
reduction of the values of the BAP Test (<2200 micromol / L) are indicative of a condition of
oxidative stress
Health effects:
Disease treatment
Disease prevention
Physical exercise
Adverse effects
Benefits of antioxidants:
•Destroy the free radicals that damage cells.
•Promote the growth of healthy cells.
•Protect cells against premature, abnormal aging.
•Help fight age-related macular degeneration.
•Provide excellent support for the body’s immune system, making it
an effective disease preventative.
ALZHEIMER’S DISEASE
“Alzheimer’s disease (AD) is the commonest progressive, dementing neuro-degenerative
disease in the elderly characterised by memory loss, language difficulty and confusion.
▪Alois Alzheimer, a German physician, is credited with being the first to describe AD.
▪In 1906, Dr. Alzheimer observed a patient, Auguste Deter, in a local asylum who
exhibited strange behaviours. He followed her care and noted her memory loss, language
difficulty and▪ After her death at the age of 51, he examined her brain tissue. The
slides showed what are now known as plaques and tangles.
▪ In 1911, Doctors were using Dr. Alzheimer’s research to base diagnosis.

11. 11
▪ In the 1960’s British pathologists determined that AD was not a rare disease of the young
but rather
what had been termed “senility.”
▪ In the 1990’s researchers identified that the beta amyloid protein was a factor in AD.
Epidemiology
▪ MC cause of dementia, > 65yr.
▪ Risk at the age of 80 years is around 15 to 20%.
▪ About 7.7 million new cases of dementia each year. A new case detected in every 4
seconds somewhere in world.
Protective factors
▪ Physical activity
▪ Caffeine consumption
▪ Antioxidants – VITAMIN C, E, B6 and B12
▪ Folate
▪ Omega 3 fatty acid intake
▪ Speaking > 2 languages
Pathogenesis and pathophysiology
AD is characterized by generalized cerebral cortical atrophy, neuronal loss, widespread
cortical neuritic plaques and neurofibrillary tangles. Following mechanisms have been
attributed for the development of Alzheimer’s dementia:
▪ Amyloid cascade theory
▪ Cholinergic hypothesis
▪ Excitotoxicity
▪ Genetic factors
Amyloid cascade theory

12. 12
▪ Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in the brain
from APP (amyloid precursor protein).
▪ APP is normally found in the cell membranes of neurons and normally metabolised by a
protease enzyme α-secretase.
▪ In AD, the metabolism of APP is altered by two other enzymes β and γ-secretase and is
called β amyloid (Aβ).
Pharmacotherapy
Drugs for the treatment of alzheimer’s
Cholinesterase inhibitors
▪ Tacrine (1993)
▪ Donepezil (1996)
▪ Rivastigmine (2000) and
▪ Galantamine (2001)
Tacrine:
It is the first centrally acting anti-ChE to be introduced for AD. In clinical trials tacrine
produced significant improvement in memory, attention, praxis, reason and language.
Frequent side effects and hepatotoxicity have restricted its use.
Donepezil:
This is a cerebroselective and reversible anti-AChE drug. Because of long t½ (~70 hr),
donepezil is
administered once daily at bed time; a distinct advantage over rivastigmine and
galantamine which need twice daily dosing. Moreover, it can be used even in relatively
severe case of AD.
Rivastigmine:
This carbamate derivative of physostigmine inhibits AChE . The carbamyl residue
introduced by
rivastigmine into AChE molecule dissociates slowly resulting in inhibition of cerebral AChE
for upto 10 hours despite the 2 hr plasma t½ of the drug.
Recent Therapy
Classification
Cholinesterase inhibitor
β-secretase inhibitors
γ-secretase inhibitors/modulators
α-secretase activators/modulators
Aβ-aggregation inhibitors
• M1 muscarinic agonists
• Aβ-degrading enzymes
• Apolipoprotein E (ApoE)
• Drug development based on the metals hypothesis

13. 13
• HMG-CoA reductase inhibitors
• MAO inhibitors
• Treatments based on tau pathology
• Estrogens, Nicotine, Melatonin
• Cell transplantation and gene therapy
• Docosahexaenoic acid (DHA), Clioquinol,
Cholinesterase inhibitor
▪ Phenserine: Phenserin treatments increased cognition and regional cerebral metabolic
rate for glucose in AD patients.
▪ Dimebon: A cholinesterase inhibitor and also a NMDA-antagonist, showed improved
cognitive and self-service functions while diminishing the psychopathic symptoms in AD
patients.
▪ Huperzine A: A Chinese herb with reversibly and selectively acetylcholinesterase
inhibition activity.
▪ Ladostigil : A multimodal drug, combined neuroprotective effects with monoamine
oxidase (MAO) -A and -B and cholinesterase inhibitory activities in a single molecule, was
tested and now in Phase II clinical trial.
▪ PMS777: A new cholinesterase inhibitor with anti-PAF activity is also in clinical trial.
Β-Degrading Enzymes
▪ Neprilysin (NEP),
▪ Insulin degrading enzyme (IDE),
▪ Plasmin,
▪ Endothelin converting enzyme (ECE) 1
▪ Angiotensin-converting enzyme.
▪ Imatinib: A tyrosine kinase inhibitor, cause increase of NEP protein, mRNA levels, and
activity.
▪ Valproic acid: A widely used drug in the treatment of epilepsy, was capable of up-
regulating NEP expression, seen in experimental rats. Estrogen and green tea all could
increase NEP activity and suggest their potential in AD treatment but there is a long way
before their final clinical application.
Apolipoprotein E
Apolipoprotein E (ApoE) promotes Aβ clearance. The ApoE activates microglia and/or
astrocyte to degrade Aβ. It decreased brain amyloid plaque burden and improved behaviour
functions in AD
transgenic mice.
Drugs Development Based On The Metals Hypothesis:

14. 14
▪ There is increasing evidence that metal (mainly Cu, Zn and Fe) metabolism is involved in
the major pathophysiological events of AD: APP processing and tau hyperphosphorylation.
▪ Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in vivo.
▪ A phase II clinical trial with clioquinol, a metal-protein-attenuating compound that inhibits
zinc and copper ions from binding to Aβ.
DIABETES MELLITUS
It is a metabolic disorder characterized by hyperglycaemia, glycosuria,
hyperlipaemia, negative nitrogen balance and sometimes ketonaemia. A widespread
pathological change is thickening of capillary basement membrane, increase in vessel wall
matrix and cellular proliferation resulting in vascular complications like lumen narrowing,
early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and
peripheral vascular insufficiency. Enhanced nonenzymatic glycosylation of tissue
Introduction
• 250 BC- Apollonius of Memphis coined the name "diabetes” meaning “siphon- to
pass through”
• Thomas Willis in 1675 added "mellitus" to the word "diabetes”
• 1869- Paul Langerhans, a German medical student, discovered islet cells in the
pancreas
• 1910- Sharpey-Shafer of Edinburgh suggested a single chemical was missing from
the pancreas. He proposed calling this chemical "insulin.”
• 1922, Leonard Thompson became the first human to be successfully treated for
diabetes using insulin.
• 1921- Frederick G. Banting and Charles H. Best successfully purified insulin from a
dog's pancreas
• 1923- 1st Nobel prize for insulin
• 14th November of every year: to mark the birthday of Frederick Banting.
Current Therapy for DM
• Non-Pharmacological
• Insulins
• Oral Hypoglycemic Agents
Non-Pharmacological
• Weight Loss
• Regular Physical activity
• Medical Nutrition Therapy
• Lifestyle Changes

15. 15
Therapy of DM type 1: Insulins
• Rapid Acting:
• Lispro
• Aspart
• Glulisine
• Short Acting:
• Regular
• Intermediate Acting:
• Neutral Protamine Hagedorn (NPH)
• Lente
• Long/Slow Acting:
• Ultralente
• Protamine zinc
• Glargine

16. 16

17. 17
• NPL and NPA
• “NPL” (Neutral Protamine Lispro) and “NPA” (Neutral
• Protamine Aspart): Isophane complexes of protamine with insulin lispro and insulin
aspart
• Intermediate acting insulins
• Detemir vs NPL- achieved similar glycaemic control
• Weight gain and nocturnal hypoglycaemia rate were statistically higher with NPL
• NPL(75/25) vs NPH(30/70)- Improved glycaemic profile
• Hypoglycaemia rate was low
• FDA has approved NPL/insulin lispro(50-50 and 75-25) and NPA/insulin aspart(70-
30) premixed formulations.
• Hexyl-insulin monoconjugate 2 (HIM2)
• Modified oral human insulin
• Single amphiphilicoligomer is covalently linked to the free
• amino acid group on the Lys-β29 residue of recombinant human
• insulin via an amide bond.1
• Phase II( type 1 ) & III(type 2) trials
• Has enhanced stability and resistance to intestinal degradation1
• Significantly absorbed from GIT, directly into portal circulation1
• HIM2 insulin v/s Humulin R2.
• Hexyl-insulin monoconjugate 2 (HIM2)
• Modified oral human insulin

18. 18
• Single amphiphilic oligomer is covalently linked to the free amino acid group on the
Lys-β29 residue of recombinant human insulin via an amide bond.1
• Phase II( type 1 ) & III(type 2) trials
• Has enhanced stability and resistance to intestinal degradation1
• Significantly absorbed from GIT, directly into portal circulation1
• HIM2 insulin v/s Humulin R2.
• Absorbed through the mucous membranes lining the mouth and begins lowering
blood glucose levels in 5 mins
• Peaks at 30 mins and works till 2 hrs
• Unlike inhaled insulins (Exubera), Oral-lyn does not enter the lungs, both because of
the design of the device used to take it, and because users are instructed not to
inhale as they spray
• An earlier short-term study, in which Oral-Lyn was compared with short-acting
subcutaneously injected pre-prandial insulin (Humulin) showed similar efficacy.
Inhalational Insulin
Inhalable insulin is a powdered form of insulin, delivered with a nebulizer into the lungs
where it is absorbed
Advantages and Disadvantages of nasal route
PK:
Depends hugely on properties of inhaler device, breathing maneuver & local
pathology/physiology
Bioavailability: 9-22%
Tmax: 7 to 90 minutes
High clearance: less incidence of hypoglycemia.
Afrezza
• Approved FDA in 2014
• Meal time insulin
• Rapid-acting inhaled insulin
• Starts to work immediately after inhalation, peaks in about 12 mins, and wanes off by
3 hrs
• Monomeric formulation is reputed to more closely mimic the natural insulin response
of healthy individuals
• Decreases the risk of hypoglycemia and weight gain
• C/I- asthma, active lung cancer or COPD.
• Newer Insulin delivery systems
• Insulin Pumps: CSII
• Pen devices
Continuous Subcutaneous Insulin
INFUSION(CSII)

19. 19
• Portable infusion devices with S.C cannula
• Only rapid or regular insulins are used
• Programmed to deliver at low basal rates ( 1U/hr) & premeal bolus (4-10 times of
basal rate)
• No definite advantage over multidose S.C inj has been seen in the trials
Therapy for Type 2 Diabetes
Newer Drugs in DM TYPE 2
• Newer Insulins
• Incretin-based therapy:
• GLP-1 analogues: Exenatide, Liraglutide
• DPP 4 inhibitors: Sitagliptin, Vidagliptin
• Amylin analogue: Pramlintide
• Dual PPAR agonists: Aleglitazar, Muraglitazar, Tesaglitazar
• SGLT2 inhibitors: Dapagliflozin, canagliflozin, empagliflozin
• Others:
• Bromocriptine.
Incretins

20. 20
Incretins: GIT Hormones produced in response to incoming nutrients that contribute to
glucose homeostasis
• The Incretin Effect
• Two hormones:
• Gastric inhibitory polypeptide [also known as Glucose-dependent Insulinotropic
Polypeptide] (GIP)
• Glucagon-like peptide-1 (GLP-1).
GLP-1
• 30-amino acid peptide secreted by L cells in ileum & colon.
• GLP-1 receptors seen in islets and CNS
• Increases glucose-dependent insulin secretion.
• Inhibits glucagon secretion
• Increases satiety
• Slows gastric emptying.
• In animal studies shown to increase beta-cell mass.
GLP-1 Analogues: Exenatide
• Naturally occurring peptide from the saliva of the Gila Monster.
• PK:
• Injectable, SC
• Resistant to DPP4 inactivation
• Plasma T ½ of 10 hrs; Renal clearance
• Therapeutic dose: 5-10 mcg twice daily before meals
• Adverse effects: nausea, vomiting, diarrhea, weight loss; necrotizing and
hemorrhagic pancreatitis.
Contraindications: severe renal impairment (creatinine
clearance <30 mL/min) or ESRD
Safety in pregnancy not studied.
Newer GLP-1 Analogues
• Liraglutide:
• Approved by the European Medicines Agency (EMEA) on July 2009; FDA in 2015
• Adjuctive therapy
• Longer T ½ (11 hrs): Once daily, SC
• 0.6 mg SC OD for 1 week initially then increase to 1.2 mg OD & can increase to 1.8
mg OD.
Albiglutide
• FDA approved in 2014
• GLP-1 dimer fused with albumin
• T ½ of 6-7 days
• 30-50 mg SC once weekly

21. 21
• No dose adjustments in renal failure
• Black Box Warning– Risk of thyroid C-cell tumors
• Cautions
• MEN-2
• Acute pancreatitis
• Hypersensitivity
• Hypoglycemia.
Sitagliptin
• Approved by FDA as a monotherapy and in combination with Metformin or TZD
• Oral, 87% bioavailable.
• T ½ 8-14 hrs; Hepatic clearance
• Therapeutic dose: 100 mg Once daily
• Weight-neutral
• A/E- Nasopharyngitis, Diarrhea, Headache, Peripheral edema, Osteoarthritis
• Contraindications: ESRD
• Safety in children<18 yrs & pregnancy not established
• Dose to be reduced in renal failure.
Vildagliptin
• Less protein bound, less T ½ than Sitagliptin
• Therapeutic dose:
• 25-100 mg, twice a day
• Current Status:
• FDA approval pending
• Has been approved by EU in Feb’08 as a combination therapy with SU, TZD or
Metformin
• FDC with Metformin is also EU-approved
• Headache, nasopharyngitis, cough, constipation & increased sweating
• C/I in liver/ renal failure.
Other DPP4 inhibitors
• Saxagliptin:
• Therapeutic dose: 2.5-5 mg once a day
• Approved by FDA in July’09 as Monotherapy or in combination with
SU/TZD/Metformin
• Alogliptin: FDA approved in 2013, risk of heart failure ( FDA 2016)
• Linagliptin: Phase III trials
• Anagliptin- phase III
• Dutogliptin- Phase III trials.
Amylin
• Also known as IAPP
• Secreted from Beta cells in response to meals
• Actions:
• Suppresses endogenous glucagon production

22. 22
• Reduces postprandial hepatic glucose production
• Delays gastric emptying
• Induces satiety: Centrally mediated
• Amylin secretion is diminished (or even absent) in patients with Diabetes.
Pramlintide
• Synthetic Analogue of Amylin
• FDA approved 2005
• PK:
• SC, T ½ around 50 min
• Metabolised in kidney: active metabolite
• Therapeutic dose:
• T2DM: 60-120 mcg
• T1DM: 15-60 mcg
• To be given immediately prior to meals
• Adverse effects:
• Nausea
• Hypoglycemia.

23. 23
ADVENCED AND RECENT TREATMENT OF CANCER
Definition
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or
spread to other parts of the body. These contrast with benign tumors, which do not spread
to other parts of the body. Possible signs and symptoms include a lump, abnormal
bleeding, prolonged cough, unexplained weight loss and a change in bowel movements.
While these symptoms may indicate cancer, they may have other causes.Over 100 types of
cancers affect humans.
Causes
• Chemicals
• Diet and exercise
• Infection
• Radiation
• Heredity
• Physical agents
• Hormones
• Autoimmune diseases

24. 24
Types of Cancer Treatment
There are many types of cancer treatment. The types of treatment that you receive will
depend on the type of cancer you have and how advanced it is.
Some people with cancer will have only one treatment. But most people have a
combination of treatments, such as surgery with chemotherapy and/or radiation therapy.
When you need treatment for cancer, you have a lot to learn and think about. It is normal to
feel overwhelmed and confused. But, talking with your doctor and learning about the types
of treatment you may have can help you feel more in control.
1. Surgery
When used to treat cancer, surgery is a procedure in which a surgeon removes cancer from
your body. Learn the different ways that surgery is used against cancer and what you can
expect before, during, and after surgery.
2. Radiation Therapy
Radiation therapy is a type of cancer treatment that uses high doses of radiation to kill
cancer cells and shrink tumors. Learn about the types of radiation, why side effects happen,
which ones you might have, and more.
3. Chemotherapy
Chemotherapy is a type of cancer treatment that uses drugs to kill cancer cells. Learn how
chemotherapy works against cancer, why it causes side effects, and how it is used with
other cancer treatments
4. Immunotherapy to Treat Cancer
Immunotherapy is a type of treatment that helps your immune system fight cancer. Get
information about the types of immunotherapy and what you can expect during treatment.
5. Targeted Therapy
Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that
help them grow, divide, and spread. Learn how targeted therapy works against cancer and
about common side effects that may occur.

25. 25
6. Hormone Therapy
Hormone therapy is a treatment that slows or stops the growth of breast and prostate
cancers that use hormones to grow. Learn about the types of hormone therapy and side
effects that may happen.
7. Stem Cell Transplant
Stem cell transplants are procedures that restore blood-forming stem cells in cancer
patients who have had theirs destroyed by very high doses of chemotherapy or radiation
therapy. Learn about the types of transplants, side effects that may occur, and how stem
cell transplants are used in cancer treatment.
8. Precision Medicine
Precision medicine helps doctors select treatments that are most likely to help patients
based on a genetic understanding of their disease. Learn about the role precision medicine
plays in cancer treatment, including how genetic changes in a person's cancer are identified
and used to select treatments.
Radiation therapy
Radiation therapy (also called radiotherapy) is a cancer treatment that uses
high doses of radiation to kill cancer cells and shrink tumors. At low doses, radiation is used
in x-rays to see inside your body, as with x-rays of your teeth or broken bones
How Radiation Therapy Works Against Cancer
At high doses, radiation therapy kills cancer cells or slows their growth by damaging
their DNA. Cancer cells whose DNA is damaged beyond repair stop dividing or die. When
the damaged cells die, they are broken down and removed by the body.
Radiation therapy does not kill cancer cells right away. It takes days or weeks of treatment
before DNA is damaged enough for cancer cells to die. Then, cancer cells keep dying for
weeks or months after radiation therapy ends.
Types of Radiation Therapy
There are two main types of radiation therapy, external beam and internal.
The type of radiation therapy that you may have depends on many factors, including:
• The type of cancer
• The size of the tumor
• The tumor’s location in the body
• How close the tumor is to normal tissues that are sensitive to radiation
• Your general health and medical history
• Whether you will have other types of cancer treatment
• Other factors, such as your age and other medical conditions

26. 26
External Beam Radiation Therapy
External beam radiation therapy comes from a machine that aims radiation at your cancer.
The machine is large and may be noisy. It does not touch you, but can move around you,
sending radiation to a part of your body from many directions.
External beam radiation therapy is a local treatment, which means it treats a specific part of
your body. For example, if you have cancer in your lung, you will have radiation only to your
chest, not to your whole body.
Learn more about external beam radiation therapy.
Internal Radiation Therapy
Internal radiation therapy is a treatment in which a source of radiation is put inside your
body. The radiation source can be solid or liquid.
Internal radiation therapy with a solid source is called brachytherapy. In this type of
treatment, seeds, ribbons, or capsules that contain a radiation source are placed in your
body, in or near the tumor. Like external beam radiation therapy, brachytherapy is a local
treatment and treats only a specific part of your body.
With brachytherapy, the radiation source in your body will give off radiation for a while.
Chemotherapy
Chemotherapy works by stopping or slowing the growth of cancer cells, which grow and
divide quickly. Chemotherapy is used to:
• Treat cancer
Chemotherapy can be used to cure cancer, lessen the chance it will return, or stop or
slow its growth.
• Ease cancer symptoms
Chemotherapy can be used to shrink tumors that are causing pain and other problems.
Who Receives Chemotherapy
Chemotherapy is used to treat many types of cancer. For some people, chemotherapy may
be the only treatment you receive. But most often, you will have chemotherapy and other
cancer treatments. The types of treatment that you need depends on the type of cancer you
have, if it has spread and where, and if you have other health problems.
How Chemotherapy Is Used with Other Cancer Treatments
When used with other treatments, chemotherapy can:
• Make a tumor smaller before surgery or radiation therapy. This is called neoadjuvant
chemotherapy.
• Destroy cancer cells that may remain after treatment with surgery or radiation therapy.
This is called adjuvant chemotherapy.

27. 27
• Help other treatments work better.
• Kill cancer cells that have returned or spread to other parts of your body.
Chemotherapy Can Cause Side Effects
Chemotherapy not only kills fast-growing cancer cells, but also kills or slows the growth of
healthy cells that grow and divide quickly. Examples are cells that line your mouth
and intestines and those that cause your hair to grow. Damage to healthy cells may cause
side effects, such as mouth sores, nausea, and hair loss. Side effects often get better or go
away after you have finished chemotherapy.
The most common side effect is fatigue, which is feeling exhausted and worn out. You can
prepare for fatigue by:
• Asking someone to drive you to and from chemotherapy
• Planning time to rest on the day of and day after chemotherapy
• Asking for help with meals and childcare on the day of and at least one day after
chemotherapy
There are many ways you can help manage chemotherapy side effects. For more
information, see the section on side effects.
How Much Chemotherapy Costs
The cost of chemotherapy depends on:
• The types and doses of chemotherapy used
• How long and how often chemotherapy is given
• Whether you get chemotherapy at home, in a clinic or office, or during a hospital stay
• The part of the country where you live
Talk with your health insurance company about what services it will pay for. Most insurance
plans pay for chemotherapy. To learn more, talk with the business office where you go for
treatment.
If you need financial assistance, there are organizations that may be able to help. To find
such organizations, go to the National Cancer Institute database, Organizations that Offer
Support Services and search for "financial assistance." Or call toll-free 1-800-4-CANCER
(1-800-422-6237) to ask for information on organizations that may help.
What to Expect When Receiving Chemotherapy
How Chemotherapy Is Given
Chemotherapy may be given in many ways. Some common ways include:

28. 28
• Oral
The chemotherapy comes in pills, capsules, or liquids that you swallow
• Intravenous
The chemotherapy goes directly into a vein
• Injection
The chemotherapy is given by a shot in a muscle in your arm, thigh, or hip, or right
under the skin in the fatty part of your arm, leg, or belly
• Intrathecal
The chemotherapy is injected into the space between the layers of tissue that cover the
brain and spinal cord
• Intraperitoneal
The chemotherapy goes directly into the peritoneal cavity, which is the area in your
body that contains organs such as your intestines, stomach, and liver
• Intra-arterial
The chemotherapy is injected directly into the artery that leads to the cancer
• Topical
The chemotherapy comes in a cream that you rub onto your skin
Chemotherapy is often given through a thin needle that is placed in a vein on your hand or
lower arm. Your nurse will put the needle in at the start of each treatment and remove it
when treatment is over. IV chemotherapy may also be given through catheters or ports,
sometimes with the help of a pump.

29. 29

30. 30
Parkinsonism
Extrapyramidal disorder due to dysfunction in the basal ganglia, comprising four cardinal
features:
◦ Bradykinesia
◦ Muscle Rigidity
◦ Resting Tremors
◦ Loss of postural reflexes
Causes:
◦ Parkinson’s disease: 85%
◦ Neuroleptic induced Parkinsonism: 7-9%
◦ Multiple system atrophy: 2.5%
◦ Progressive supranuclear palsy: 1.5%
◦ Vascular parkinsonism: 3%
◦ Postencephalitic parkinsonism rare Parkinson’s Disease
AKA: Primary, Idiopathic Parkinsonism – Paralysis Agitans – Shaking Palsy
The most common movement disorder
2nd most common neurodegenerative diseaseafter Alzheimer disease.
Epidemiology:
◦ Incidence: 0.2/1000
◦ Prevalence: 1.5/1000
History of Parkinson's disease
1817: description of symptoms by James Parkinson
1862: Coined the name “Parkinson’s Disease” by Jean-Martin Charcot
1919: Degeneration of substantia nigra
1968: L-dopa was introduced
1979: MPTP was found to cause Parkinsonism
1997: PARK1 gene mutation was discovered
Advanced Parkinson’s Disease
Staging of PD:
Hoehn & Yahr
Stage 1: unilateral symptoms
Stage 2: symptoms on both sides without impairment of balance.
Stage 3: Balance impairment, Mild or moderate disease
Stage 4: Sever disability, but still able to walk or stand unassisted
Stage 5: weel-chair bound or bed ridden
Braak Pathological staging:
◦ Stage 1; medulla oblongata
◦ Stage 2; medulla oblongata and pontine tegmentum
◦ Stage 3; midbrain
◦ Stage 4; basal prosencephalon and mesocortex
◦ Stage 5; neocortex
◦ Stage 6; neocortex
UPDRS:
◦ Part I: evaluation of Mentation, behavior, and mood;
◦ Part II: self-evaluation of the activities of daily life (ADLs)
◦ Part III: clinician-scored motor evaluation
◦ Part IV: complications of therapy
◦ Part V: Hoehn & Yahr staging of severity of Parkinson disease.
Management

31. 31
Motor complications:
◦ Wearing off: refers to the recurrence of motor and non-motor symptoms preceding the
scheduled dose of L-Dopa
◦ On-off fluctuations: are sudden unpredictable shifts between “well-” treated status (on)
and an undertreated state with severe Parkinsonism symptoms (off)
Management of wearing off and On-Off is focused on prolonging the effect of individual
L-Dopa doses:
Fragmentation of dosing: up to 6-7 times a day at about 3-hour intervals
Substitution of regular with controlled-release Ldopa
COMT inhibitor (entacapone and tolcapone)
MAO inhibitor (selegiline and rasagiline)
Dopamine agonists: is generally contraindicated in late-stage disease.
Continuous dopaminergic stimulation (CDS)
Continuous infusion of levodopa/carbidopa gel through portable duodenal systems
(Duodopa)
The liquid effervescent levodopa formulation of melevodopa (methyl-ester levodopa)
Duodopa Gel 2000/500mg (20+5/ml)
Price: 7 x 100ml = $1,375.00 Duodopa® is approved in all 30 countries of the European
Economic Area (EEA = EU plus Norway, Iceland and Liechtenstein), Croatia, Switzerland,
Canada and Australia.
The morning bolus dose is usually 5-10ml (100-200mg levodopa).
The continuous maintenance dose can be adjusted in steps of 0.1ml/hour and is usually
2-6ml/hour.
Majority of patients need less than 2000mg levodopa (1 cassette) daily.
Dyskinesias
◦ Involuntary choreiform and twisting movements occurring in patients undergoing long-
term L-Dopa treatment.
◦ There are different types of levodopa-induced
dyskinesias, such as the “peak-dose dyskinesias”,“biphasic dyskinesias” and “wearing-off”
dyskinesias
◦ Usually occur in “on” state, as chorea, myoclonus or dystonic movement.
◦ In end-stage patients dyskinesia may appear in off state as dystonic posture, especially in
the lower limbs.
◦ Management:
Lower the single L-Dopa dose
Amantadine
Clozapine: particularly useful when hallucinations are also present
High-frequency subthalamic DBS (DBS-HFS)
Drug Failure Response:
The efficacy of L-Dopa progressively decreases and patients may not respond at all to
administered doses.
May be related to
◦ Degeneration of dopaminergic neurons
◦ poor gastric emptying and insufficient intestinal absorption.
Management:
◦ Domperidone
◦ Low-protein dietary regimens
shifting protein intake to the evening is an effective strategy
Autonomic complications:

32. 32
◦ Constipation: in late stage can become particularly severe due to the combination of
anti-PD medications, slowed intestinal motility, immobility, and
dehydration.
◦ Constipation should be well managed in order to avoid bowel occlusion and in order to
ensure proper absorption of L-dopa.
Dietary supplementation of fibers
Increased fluid intake
Macrogol (polyethylene glycol)
Urinary urgency or frequency
◦ Overactive bladder is the result of loss of normal inhibition by the basal ganglia and the
frontal cortex to the sacral spinal cord
◦ Anticholinergics: are commonly used, although their use should be discouraged in late-
stage patients due to cognitive and other anticholinergic adverse effects.
◦ Trospium (Trospikan 20mg) : Newer generation of peripheral anticholinergics, better
tolerated and can be used even in advanced patients.
◦ Botulinum toxin injections in the detrusor muscle
Orthostatic Hypotension (OH)
Fall in systolic blood pressure below 20 mmHg and diastolic pressure below 10 mmHg
within 3 minutes of standing
Presents in severe cases with lightheadedness or
syncope, exposing the patient to high risk of fall.
Management:
◦ Avoiding rapid changes of position or straining during micturition or defecation
◦ Fluid intake, particularly in the morning, should be maintained at around 2L of water daily
and at least 8g of sodium chloride
◦ Elastic stocking and abdominal binders can be helpful
◦ Plasma volume expander, like fludrocortisone, and vasoactive agents, like midodrine
Dysphagia:
Severe dysphagia may cause weight loss, malnutrition, dehydration, and increasing the
risk of aspiration pneumonia and death.
◦ Thickening agents, gelling agents, forming a gel that can be swallowed by patients.
◦ Supraglottic swallow maneuver, Super supraglottic swallow maneuver and Mendelsohn
maneuver
◦ PEG: (Percutaneous endoscopic gastrostomy) to guarantee to patients' adequate food
and fluid intake as well as dopaminergic therapy through infusion
Sialorrhea:
caused by impaired or infrequent swallowing, rather than hypersecretion.
◦ Anticholinergics (glycopyrrolate and scopolamine)
◦ Botulinum Toxin: Intraglandular injection of botulinum toxin type A.
◦ Surgery to denervate the salivary glands: performed through the middle ear, where the
tympanic plexus and chorda tympani travel before entering the major salivary glands. The
procedure is relatively simple and fast, Unfortunately, salivary function returns
within six to 18 months, when nerve fibers regenerate
◦ Radiation to the salivary glands: a reasonable treatment option in elderly patients who are
not candidates for surgery and cannot tolerate medical therapy.
Cognitive dysfunction:
Cognitive difficulties may occur in up to 80% of PD patients, and dementia in
approximately 30%, making this condition a very frequent non-motor complication.
Management:

33. 33
Begins with an evaluation to rule out other potential causes including depression,
infection, dehydration, and sleep disturbances.
Rivastigmine and Donepezil, both were found to be moderately effective in PD dementia
Memantine has not been shown to be effective in PD dementia and may worsen both
the motor and cognitive functions in PD
Behavioral Dysfunction:
Depression:
Depression is the most common psychiatric manifestation in Parkinson’s disease
patients with 40% prevalence.
• Diagnosing depression in Parkinson’s disease is often a challenge, as the clinical
symptoms of depression may bemistaken for those of Parkinson’s disease, such as
flat affect, psychomotor slowing, sleep disturbance, fatigue, and decreased libido.
◦ SSRIs are most frequently used as first line therapy.
◦ Tricyclic antidepressants can aggravate orthostatic hypotension and its anticholinergic
side effects can worsen cognition.