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Master File - Chronic
Master File - Chronic
Master File - Chronic
RPGLS
THE HUMAN BODY
Overview of Anatomy &
Physiology
2 Cellular level
Cells are made up of molecules
1 Chemical level
Atoms combine to
form molecules
3 Tissue level
Tissues consist of
similar types of
cells
6 Organismal level
Connective The human organism is
tissue made up of many organ
systems
4 Organ level
Organs are made up of 5 Organ system level
different types of tissues Organ systems consist of different
organs that work together closely
Figure 1.1
Levels of Structural Organization
• Chemical – atoms combined to form
molecules
• Cellular – cells are made of molecules
• Tissue – consists of similar types of cells
• Organ – made up of different types of tissues
• Organ system – consists of different organs
that work closely together
• Organismal – made up of the organ systems
Chemical organization
• All forms of matter living or nonliving are made
of limited no. of building blocks called
elements.
• Human body is made of 26 different element.
• C,H,O,&N --------96%
• Ca,P,K,S,Na,Cl,Mg,Fe----3.8%
• Additional 14 trace element—0.2%
What is your body made of?
99% of the mass of the human body:
• oxygen (65%)
• carbon (18.6%)
• hydrogen (9.7%)
• nitrogen (3.2%0
• calcium (1.8%)
• phosphorus (1.0%)
Chemical organization
• Carbohydrate:
– C,H,O—3%(Energy)
• Lipids:
– C,H,O---25%--Protection & energy storage.
• Proteins:
– C,H,O,N---18%--(Structural frame work).
Molecular Level
– Carbohydrates
• Sugars and starches
– Lipids
• Fats and oils
– Proteins (formed from amino acids)
• Enzymes, hormones, antibodies
• Basis of life
– Nucleic acids (formed from nucleotides)
• DNA, RNA
• Determine what proteins are made
Cell
◆ The cell is the basic
structural and functional
unit of the body.
◆ About 200 different type
of cells are basic unit of
human body.
• Cytology – study of the
cell
Basic Cell Functions
• Obtain nutrients and oxygen from surrounding
environment
• Perform chemical reactions that provide energy
for the cell
• Eliminate carbon dioxide and other wastes to
surrounding environment
• Synthesize needed cellular components
Basic Cell Functions
• Reproduction
– Exception - nerve cells and muscle cells
lose their ability to reproduce during their
early development
• Sensing and responding to changes in
surrounding environment
• Control exchange of materials between cell
and its surrounding environment
Cell
• Cytoplasm : It consists of
all the cellular content in
between plasma
membrane & nucleus.
• Cytosole : Fluid portion.
• Organelles : several type
of organ having specific
shape & function like
Cytoskeleton, Ribosome,
E.R, Golgi complex,
Lysosome,Mitochondria.
Cell
• Cell Membrane: It is a
selective barrier that
regulates the flow of
materials into and out
the cell.
Cell
• Cytoskeleton :
Provides a structural
framework for the
cell & gives a
particular shape to
cell. Helps in the
movement of
organelles in side
the cell.
Cell
• Ribosome :
Ribosome's are site
for protein synthesis.
• Mitochondria : since
they generate most
of the ATP hence
called power house.
Cell
• Endoplasmic
Reticulum : ER is an
extensive network of
folded membranes
that extends from
nuclear membrane
through out the
– steroid synthesis
– detoxification
– storage
Cell
• Golgi complex :
– Receives protein from
ER and remakes them
into enzymes in
lysosomes
– Synthesizes
polysaccharides,
glycolipids,
glycoproteins,
lipoproteins, mucous
and secretes many of
them from the cell
Cell
• Lysosomes :
Lysosome are
membrane enclosed
vesicles that form
from the golgi
complex & contains
60 type of digestive
& hydrolytic enzyme
Cell
• Nucleus : Contains
most of the cell’s
gene which are
located on
chromosome.
Controls cellular
structure, directs
cellular activity
Tissue
• Tissues:
– groups of cells which are similar in
structure and which perform common
or related functions.
• Histology:
– the study of tissues.
Basic kinds of tissues
• Epithelial Tissue Locations: Epithelial tissue
consists of cells arranged in continuous
sheets, in single layer or multiple layers.
– Covers the body
– Lines the cavities, tubes, ducts and blood
vessels inside the body
– Covers the organs inside body cavities
–
Basic kinds of tissues
• Classification: Based on arrangements of cells epithelial
tissue is of three types :
1. Simple epithelial – Single layer-
Filtration,Absorption,Secretion
2. Stratified epithelial- Multiple layer-Protection.
3.Pseudostratified epithelium- one layer but appear as
multiple layer- Secretion & Movement.
THE LUNGS
LIVER
THE STOMACH
THE BLADDER
Nervous System
• Fast-acting control system
• Responds to internal and external changes
Integumentary System
• Forms external body
covering
• Protects deeper tissues
from injury
• Synthesizes vitamin D
• Site of cutaneous
receptors
(pain, pressure, etc.) and
sweat
and oil glands
Skeletal System
• Protects and supports
body organs
• Provides a framework for
muscles
• Blood cells formed within
bones
• Stores minerals
Muscular System
• Locomotion
• Facial expression
• Maintains posture
• Produces heat
Endocrine System
• Glands secrete
hormones that
regulate:
– Growth
– Reproduction
– Nutrient use
Cardiovascular System
• Blood vessels
transport blood
– Carries oxygen and
carbon dioxide
– Also carries nutrients
and wastes
• Heart pumps blood
Lymphatic System/Immunity
• Disposes of debris in
the lymphatic system
• Houses white blood
cells (lymphocytes)
• Mounts attack against
foreign substances in
the body.
Respiratory System
• Keeps blood supplied
with oxygen
• Removes carbon dioxide
• Gas exchange occurs
through walls of air sacs
in the lungs
Digestive System
• Breaks down food into
absorbable units
• Indigestible foodstuffs
eliminated as feces
Urinary System
• Eliminates
nitrogenous wastes
• Regulates water,
electrolyte, and acid-
base balance
Male & Female Reproductive Systems
• Overall function is to
produce offspring
• Testes produce
sperm and male sex
hormones
• Ovaries produce
eggs and female
sex hormones
• Mammary glands
produce milk
Orientation and Directional
Terms
Orientation and Directional Terms
Orientation and Directional Terms
LIFE PROCESSES
❋ Oral
❋ Parenteral
❋ Local
Oral administration
It is simple to use
Can be done at home
Does not require any medical assistance
can be taken at a convenient time
painless and safe
Oral drugs disadvantages
Trans-cutaneous
Trans-mucosal
INJECTIONS
Intra-dermal
Subcutaneous
Intramuscular
Intravenous
Intra-arterial
Intra-thecal
Intra-peritoneal
Intra-medullary
Intra-articular and intra-lesional
Other Pharmaceutical Preparations
• Creams - o/w
• Ointments - w/o
• Gels, lotions
• Vaginal/rectal suppositories
• Nasal drops/aerosols
• Inhalers/sublingual
• Otic/opthalmic preparations
Injectable drugs – advantages
IM/IV
Liver
Pharmacokinetics
❋ Pharmacokinetics is the detailed study of how
the body absorbs, distributes, metabolizes and
excretes a drug
Pharmacodynamics
❋ Pharmacodynamics is the detailed study of
effects of the drugs on the body
Dissolution
• Dissolution is the amount of drug substance
that goes into solution per unit time under
standard conditions of solid/liquid interface,
temperature, and solvent composition.
Dissolution
• Drug Absorption from a solid oral dosage depends
on the release of the drug substance from the drug
product (dissolution), the solubility, and the
permeability across the gastrointestinal tract. The
first aspect of the tablets is determined by the
manufacture of the product. The next two aspects
are determined by the properties of the active
pharmaceutical. All solid oral dosage forms can be
characterized according to these three properties.
PHARMACOKINETICS
Site
Blood stream
Process of Absorption
• In order for a drug to have its effect after oral
administration it must go into solution and then
diffuse through the gut wall into the body. The first
step in that process is the disintegration of the
dosage form followed by dissolution of the active
ingredient.
Process of Absorption
• One way to increase dissolution rate of poorly
soluble drugs is to increase the surface available
for dissolution. This is done by reducing particle
size or by dividing the dosage form into two smaller
tablets or capsules, with a larger combined surface
area. Other ways include increasing the
disintegration rate and deaggregation.
Where are oral drugs absorbed
Administration
Absorption
Portal circulation
Liver
Metabolites
The end result of the metabolic process is termed
a metabolite. A metabolite is usually inactive, but
some metabolites retain some activity of the
parent compound.
Need of Metabolism
C
o
n
c
T max time
Half life
It is the time needed for the plasma
concentration to fall to half the C max value
40 mcg
30mcg
20 mcg
10 mcg
0 1 2 3 4 5 6 7 8
PHARMACODYNAMICS
DRUG TARGETS
❋ Receptors
❋ Enzymes
❋ Nucleic acids
❋ Carrier molecules
❋ Ion channels
Receptors
Effect
Drug receptors
microorganisms
Efficacy of a drug
Dose-response quantitation
Potency of drug
100
Drug A Drug B
Biological effect
50 Drug A is more
potent than B,
but both have
same efficacy
Antagonistic drugs
Good affinity
Poor intrinsic activity
Antagonism can be reversible and irreversible and may be for
the same receptor (competitive) nor different receptor (non-
competitive)
Therapeutic window
Sex
Route of administration
Emotional factors
Genetic factors
FACTORS MODIFYING THE
EFFECTS OF A DRUG (Contd.)
Presence of disease
Cumulation
Additive effect
Synergism
Antagonism
Additive Effect
1+1=2
OD - Once daily
BD - twice daily
TD - Thrice daily
QD - Four times daily
SOS - During emergency use
HS - At bed time
Stat - immediately
ADVERSE DRUG REACTIONS
(ADR)
Any undesirable and unwanted effect that goes
along with the therapeutic effects of the drug
Side effects
Untoward effects
Toxic effects
•Cells (45%)
• Artery
• Vein
• capillary
Blood vessels
Blood Vessels: Anatomy
• Three layers (tunics)
• Tunica intima
• Endothelium
• Tunica media
• Smooth muscle
• Controlled by sympathetic nervous
system
• Tunica externa
• Mostly fibrous connective tissue
Artery/Vein differences
– Pericardium
– Myocardium
– Endocardium
Heart
Left
ventricle
Right ventricle
Heart chambers
Separation of chambers
• Interatrial septum
separates atria
• Intraventricular
septum separates
ventricles
• Both composed of
connective tissue as
well as muscle
A-V Valves
• Pulmonary valve:
Between right ventricle
and pulmonary artery
• Aortic valve: Between left
ventricle and aorta
Path of blood through the heart
Coronary artery circulation
Coronary Circulation
• Blood in the heart chambers does not nourish the
myocardium
• The heart has its own nourishing circulatory system
• Coronary arteries
• Cardiac veins
• Blood empties into the right atrium via the
coronary sinus
Slide
Intrinsic Cardiac Conduction
System
75/min
40-60/min
30/min
Intrinsic Conduction System
Function: initiate & distribute impulses so heart depolarizes
contracts in orderly manner from atria to ventricles .
SA node
AV node
Bundle of His
Bundle Branches
Purkinje fibers
Extrinsic Control of Heartbeat
• A cardiac control center in the medulla
oblongata speeds up or slows down the heart
rate by way of the autonomic nervous system
branches.
– Sympathetic Stimulates heart rate
• Systolic - Systole, or
contraction, of the heart is
initiated by the electrical
cells of the sinoatrial
node, peak arterial
pressure. Averages about
120 mm Hg in healthy
adults.
• Diastolic - Cardiac
Diastole is the period of
time when the heart
relaxes after contraction
in preparation for refilling
with circulating blood..
Averages between 70 -
80 mm Hg in healthy
adults.
Heamodynamics
• VENOUS RETURN : The amount of blood reaching
back to the heart per minute.
• Velocity of blood
• Viscosity of blood
• Elasticity of vessel walls
• Diameter of vessel
The Electrocardiogram
• .
ECG Deflection Waves
1st Degree
Heart
Block = P-
Q interval
longer
than 0.2
seconds.
ECG Deflection Wave
Irregularities
Enlarged QRS =
Hypertrophy of
ventricles
ECG Deflection Wave
Irregularities
Prolonged
QT Interval
=
Repolarization
abnormalities
increase
chances of
ventricular
arrhythmias.
ECG Deflection Wave
Irregularities
Elevated
T wave :
Hyperkalemia
ECG Deflection Wave Irregularities
Flat T
wave :
Hypokalemia
or ischemia
Blood Pressure
“Blood pressure (BP) is the
pressure (force per unit area)
exerted by circulating blood on the
walls of blood vessels”
B.P = CO*PR
Blood Pressure
Measurement
Arterial pressure is most commonly
measured via a sphygmomanometer.
BP is always measured in the ratio of
systole vs diastole.
Units
The predominantly used unit for blood
pressure measurement is mmHg (millimeter
of mercury).
Angiotensinogen
Renin
(Kidney)
Angiotensin I
ACE
(Lungs)
Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
HYPERTENSION
Normal 120 80
Pre hypertension 120-139 80-89
Other factors:
Bradykinin
Endothelin
EDRF or nitric oxide
ANP (atrial natriuretic peptide)
Low birth weight
Renin Angiotensin Aldosterone System
Brain-Stroke
Angiotensinogen
Heart-
Renin Fibrosis
(Kidney)
LVMI
Angiotensin I BV-
ACE Endothelial
(Lungs) dysfunction
Arterial
stiffness
Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
Other factors
Bradykinin : Bradykinin is a potent vasodilator that is
inactivated by angiotensin converting enzyme.
Endothelin : Endothelin is a powerful, vascular, endothelial
vasoconstrictor, which may produce a salt sensitive rise in blood
pressure. It also activates local renin-angiotensin systems.
Endothelial derived relaxant factor : EDRF now
known to be nitric oxide, is produced by arterial and venous
endothelium and causes vasodilatation.
• Lifestyle Changes
– Don’t smoke
– Limit alcohol
– Manage stress
Follow a Healthy Eating Plan
• Smoking damages
blood vessel walls and
causes early hardening
of the arteries
• Nicotine narrows your
blood vessels and
forces your heart to
work harder
Limit Alcohol
• Causes of obstruction -
– Atheroma - Deposition of fatty materials in the walls of the
arteries
– Thrombosis - Formation of a clot.
– Spasm - Sudden constriction of a portion or multiple
portion of artery
– Embolism - A moving clot or atheroma.
Symptoms of IHD
• Heartburn,
• Nausea,
• Vomiting,
• Shortness of breath, and
• Heavy sweating.
.
Types of Angina
Variant or Prinzmetal’s angina:
Treatment
Symptoms
common symptoms
Changes in vision,
Speech, and comprehension;
Weakness;
Vertigo;
Loss of sensation in a part of the body; or
changes in the level of consciousness,
Transient Ischemic Attack (TIA )
– shortness of breath
– edema (pooling of fluid in lungs and body)
Classification of heart failure
• Left Heart Failure - The inability of the left side
of the heart to pump into the systemic
circulation. Clinical symptoms due to poor
blood flow to the body:
– difficulty exercising
– fatigue
– dizziness (due to low blood pressure)
The leading causes of heart failure are
diseases that damage the heart. These
include:
– Coronary artery disease (CAD),
– High blood pressure, and
– Diabetes
Cause of Heart failure
• Heart failure is caused by many conditions
that damage the heart muscle, including:
– Coronary artery disease
– Arrhythmias
– Cardiomyopathy — damage to the heart muscle from
causes other than artery or blood flow problems.
– High blood pressure (hypertension)
– Valve disease Heart defects present at birth
– Diabetes Mellitus
– Chronic kidney disease
How does heart failure develop?
The physiological
unit of the
kidney used for
filtration of
blood and
reabsorption and
secretion of materials
Functions of Nephron
Structures
• Afferent Arteriole
– Transports arterial blood to the
glomerulus for filtration
• Efferent Arteriole
– Transports filtered blood from the
glomerulus , through the peritubular
capillaries and the vasa recta, and to the
kidney venous system
Functions of Nephron
Structures
• Glomerulus
– The site for blood filtration
– operates as a nonspecific filter; in that, it will remove both
useful and non-useful material
– the product of the glomerulus is called filtrate.
• Bowman’s Capsule
– A sac that encloses Bowman’s Capsule and transfers
filtrate from the glomerulus to the Proximal Convoluted
Tubule (PCT)
Functions of Nephron
Structures
• Proximal Convoluted Tubule (PCT)
– A thick, constantly actively segment of the nephron that
reabsorbs most of the useful substances of the filtrate:
sodium (65%), water (65%), bicarbonate (90%),
chloride (50%), glucose (nearly 100%!), etc.
– The primary site for secretion (elimination) of drugs,
waste and hydrogen ions.
• Glomerulus
– the Glomerulus is the site of filtration
– the filtration mechanism is sieve-like and consists of
fenestrated glomerular capillaries, podocytes and a
basement membrane that allows free passage of water
and solutes smaller than plasma proteins
Helps in
Aldosterone
Cathepsin D
Ang II
Inactive
peptides
Effects of Aldosterone
The classic concept
Secreted by zona glomerulosa of adrenal gland
– Stimulated by angiotensin-2, K,ACTH
Regulates K & Na transport
Causes Na & water retention
causes K excretion
Increases volume overload & causes HTN
Effects of Aldosterone
The new concept
Aldosterone also
MR receptors
synthesized by:
identified in:
Endothelial cell
kidney
Vascular smooth
muscle heart
Locally in blood blood vessels
vessels, brain & brain
myocardium
Circulation:2003
Role of Aldosterone
Aldosterone
MR
The “Aldactone”
Aldactone
• It is a synthetic 17-lactone drug that is a
aldosterone antagonist in a class of
pharmaceutical called Mineralocorticoid receptor
antagonist, used primarily to treat heart failure,
ascites in patients with liver disease, as well as
high blood pressure
Mechanism of action
MR
MR
Indication:
CHF
Hepatic cirrhosis with ascites
Nephrotic Syndrome
Dosage:
• Pharmacokinetic data :
– Bioavailability : 80-90%
– Protein binding: 99%
– Metabolism :80%(hepatic)
– Half life :3.5hr
:7-8hr in cirrhosis
• Therapeutic considerations :
– Catogery :C
– Routes : Oral/ I.V
Is it time for a newer and
better loop diuretic?
• The degree of kaliuresis that the drug
(Frusemide) induces can lead to
potentially fatal consequences, especially
in metabolically deranged states such as
congestive heart failure and renal failure.
– Outcme:
• Mortality was significantly lower in the torsemide (2.2%)
than in the frusemide/other diuretics group (4.5%).
• Torsemide treatment was associated with a significantly
lower total mortality and cardiac mortality. Also, a
significantly greater proportion of patients in the torsemide
group showed improvement in the NYHA class compared to
patients treated with frusemide or other diuretics.
References
1. J Cardiovasc Pharmacol 1993; 22 (suppl 3): S59-S70
Benefits beyond frusemide
• in ascites :
– Torsemide and frusemide have been compared in
cirrhotic patients receiving spironolactone and sodium-
restricted diets. Torsemide induced a remarkably higher
natriuretic and diuretic effect than frusemide. Body
weight loss was also significantly higher with torsemide
(2.5 + 1.6 vs 0.2 + 1.3 kg).
• Torsemide in hypertension :
– Thiazides are recommended as first-line drugs for
hypertension. Loop diuretics such as frusemide have
proven to be less effective in controlling blood
pressure than thiazides. In contrast, torsemide has
been found to be as effective as thiazides
(hydrochlorothiazide and a combination of
hydrochlorothiazide and a potassium sparing diuretic)
in small doses for the therapy of hypertension without
changes in serum electrolytes or metabolic indicators.
• Hypertension
– The usual initial dose is 5 mg once daily. If the 5 mg
dose does not provide adequate reduction in blood
pressure within 4 to 6 weeks, the dose may be
increased to 10 mg once daily. If the response to 10 mg
is insufficient, an additional antihypertensive agent
should be added to the treatment regimen.
Side effects
• Dizziness
• Headache
• Nausea
• Weakness,
• Vomiting,
• Hyperglycemia
• Excessive urination,
• Hyperurecemia
• Hypovolemia
• Impotence
• Esophageal hemorrhage, and dyspepsia
DRUG INTERACTIONS
Indications
• Hypertension
• Chronic stable / vasospastic Angina
Dosage
• Hypertension
• 5-10mg OD
• 2.5mg OD (elderly, hepatic failure)
• Chronic stable / vasospastic Angina
• 10 mg OD
How does Topdip Act?
What are the key pharmacokinetic
features of Amlodipine?
Composition
• Atenolol 50 mg + Amlodipine 5 mg
Indications
• Hypertension, prophylaxis of chronic stable
angina.
Dosage
• 1 tablet once daily
What is Topdip AT?
• Atenolol
– Beta blocker, Selective, Water- soluble
• Amlodipine
– Long acting CCB with Sustained and smooth
pharmacodynamics
• Pharmacokinetic compatibility
• Low ADR profile of each
• Patient compliance
Pharmacokinetic features of
Amlodipine & Atenolol in Topdip AT
Amlodipine Atenolol
Angina
Initial 50 mg OD, Increase to 100 mg OD
In MI and SVA : intravenous formulations used
What are the advantages of
Atenolol?
∀ ↓ BP & oxygen demand by blocking +ve inotropic
& chronotropic action of catecholamines
• Cardioselective ( B1); No unwanted (B2)
bronchoconstrictor effects, can be used in
asthmatics
• Water soluble beta-blocker. Hence low incidence of
CNS side effects
• No ISA unlike metoprolol
• No effect on glucose metabolism : Useful in
diabetic hypertensives
• Effective in elderly
Topdip AT
Advantages
COMPOSITION
Lisinopril 5 mg + Amlodipine 5 mg
• Hypertension
• Resistant Hypertension
• Diabetic Hypertension
• 1 tablet once daily
ACEDIP
RATIONALE
IN RESISTANT HYPERTENSION
SUMMARY
•Synergistic action - Superior BP control than
monotherapy
•1 tablet daily in hypertension
( Resistant,Diabetic,Obese)
– Diabetic hypertensives : Improves insulin sensitivity,
Antiproteinuric effects
– Obese / Hyperlipidemic hypertensives : Lipid neutral
•Aids patient compliance - OD dosing Lesser cough,
edema
Mathew JAG et al, Indian Pract,
1998: 51(6): 441-447.
ACEDIP
ADVANTAGES
Synergism of antihypertensive effect
Lower doses of each drug required leading
to better clinical response with lesser side
effect
Due to their long elimination of half-life,
they can be administered once daily,
hence improved patients’ compliance and
better clinical response.
Amlodipine activates sympathetic nervous
system. Lisinopril counterbalances this
effect by decreasing sympathetic outflow.
Vasoprotective and cardioprotective
effects
Fewer tablets to be administered, this
leads to increased patients’ convenience
Avoiding Cardiovascular Events through
COMbination Therapy in Patients
LIving with Systolic Hypertension
• Objective: To determine if amlodipine besylate /
benazepril will confer reduction in cardiovascular
morbidity and mortality in high-risk hypertensive subjects
when compared with the combination of benazepril and
HCTZ.
• Design :
– Multinational, double-blind clinical trial
– Patient - 11,508 subjects (550 centers)
– Duration: 5-year
Conclusions
Renin Fibrosis
(Kidney)
LVMI
Angiotensin I BV-
ACE Endothelial
(Lungs) dysfunction
Arterial
stiffness
Aldosterone
Angiotensin II (adrenal gland)
Kidney-
Water & Na
Aldosterone Retention
Acts on MR Albuminuria
AT-2 AT-1
Vasoconstriction
Vasodilatation
Apoptosis ↑ Blood Pressure
Wound Healing
Effect of Angiotensin - ii at AT1 &
AT2 receptor
Mechanism of action
LOSARTAN
AII receptor (AT1) blocker
Vasodilation
Afterload
Reduction in BP
Pharmacokinetics
• Absorption: Losatec is well absorbed on oral
administration.
• Bioavailability - 33%.
• Protein Binding: 99%.
• Half-life: 6-9 hours respectively.
• Excretion: Following oral administration of
Losatec, approximately 35% of the radioactivity
is recovered in the urine and about 60% in the
faeces.
Losatec
• Indications
– Losatec is indicated for the treatment of hypertension; it may
be used alone or in combination with other antihypertensive
agents. Losatec is indicated in diabetic nephropathy.
• Dosage
– Usual starting dose is 50 mg once daily.
– Losatec can be administered with or without food once or
twice daily with total daily doses ranging from 25 to 100 mg.
– If the antihypertensive effect measured at trough using once
daily dosing is inadequate, a twice daily regimen at same total
daily dose or an increase in dose may give a more
satisfactory response.
Losatec
The USPs of Losatec
– First angiotensin II receptor blocker
– Selective A II receptor (Type AT1) antagonist
– Patients with/ susceptible to cough on ACEIs
– Unresponsive/ Intolerant to current therapy
– No rebound hypertension on abrupt withdrawal unlike Beta
blockers
– No change in heart rate unlike Calcium Channel blockers
– No effect on glomerular filtration rate, renal plasma and
filtration fraction
– Reduction of mortality and left ventricular mass
– Reduction in the risk of stroke
– Reno – protection in diabetics
Losartan Intervention for Endpoint
Reduction in Hypertension Study
(LIFE Study)
Objective- Double-blind, randomized trial to
compare the effects of losartan and atenolol on
cardiovascular morbidity and mortality in high-risk
patients with hypertension and left ventricular
hypertrophy (LVH).
• Population
9,193 patients (55 to 80 years old) from 945 sites in 7
countries
previously treated or untreated essential
hypertension (systolic BP 160–200 mmHg or
diastolic BP 95–115 mmHg)
1,195 patients (13%) had diabetes at baseline
LIFE Study
Summary
• Losartan-based compared with atenolol-based
antihypertensive therapy was associated with:
– A reduction in the combined primary endpoint
of cardiovascular death, stroke or MI (-13%)
– Fewer strokes (-25%)
– similar blood pressure reduction
– Losartan reduced the rate of new-onset diabetes (-25%)
• In the diabetic subgroup, losartan reduced the rate
of:
– Combined endpoint of cardiovascular death,
stroke and MI (-25%)
– All-cause mortality (-39%)
LIFE Study
• Conclusions
– Losartan reduced the combined risk of
cardiovascular morbidity and mortality compared
to atenolol with benefits not explained by blood
pressure reduction
– Losartan reduced the rate of new-onset diabetes
– `Losartan was significantly better tolerated than
atenolol
– Among diabetics, losartan reduced
cardiovascular morbidity and mortality
Reduction of Endpoints in Non-insulin dependent
diabetes mellitus with the Angiotensin II
Antagonist Losartan(RENAAL)
The question addressed by this study is: does taking
losartan reduce the progression of kidney disease in
patients with type 2 diabetes and established kidney
disease?
• Results-
– Losartan treatment was associated with:
– 28% risk reduction of ESRD over a mean of 3.4 years (P
= 0.002)
– 25% risk reduction of a doubling of the serum creatinine
concentration (P = 0.006)
– 35% decrease in the level of proteinuria (P < 0.001)
Reduction of Endpoints in Non-insulin dependent
diabetes mellitus with the Angiotensin II
Antagonist Losartan(RENAAL)
– 32% risk reduction in the rate of first
hospitalization for heart failure (P < 0.005)
– The benefits exceeded those attributable to
changes in blood pressure. Morbidity from
cardiovascular causes was similar in the two
groups, as was all-cause mortality.
• Conclusion---Losartan conferred
significant renal benefits in patients with
type 2 diabetes and was generally well
tolerated.
LOSATEC- H
Composition:
Losartan 50 mg + Hydrochlorothiazide 12.5 mg
tablet
Complementary actions
• First of a new class of AII receptor blockers
+ diuretic (thiazide)
Dosage
• 1 tablet OD
• Can be increased to 2 tablets OD
(Max.)
Mechanism of action
LOSARTAN HYDROCHLOROTHIAZIDE
AII receptor (AT1) Diuretic
blocker (inhibits sodium
reabsorption)
Vasodilation Preload
Reduction in BP
Pharmacokinetics
• Compatible
– No interaction between Losartan &
Hydrochlorothiazide
– No difference between young and elderly
• Losartan Hydrochlorothiazide
T ½ 2h (6-9h) 5.6 – 14.8h
• Dosing frequency
OD OD
PHARMACODYNAMICS –
COMPATIBLE
• Brain
• Spinal cord
Introduction to the Brain
• 100 billion neurons
• A typical neuron has about
1,000 to 10,000 synapses (that
is, it communicates with 1,000 –
10,000 other neurons,muscle
cells, glands, etc.).
• 100 trillion synapses
– Structures
• Divided into 3 general
areas
– Functions
• Controls the bare
necessities of life
• Location for primal
drives and emotions
• Intellectual thought,
imagination, perception,
interpretation, etc.
Protections and Coverings
• Cranial bones- Hard bony structure which
protects the brain called cranium.
• Meninges – Meninges are three layers of
connective tissue which encircles the entire
spinal cord & brain.
– Cranial meninges – encircles the brain.
– Spinal meninges – encircles the spinal
cord.
Meninges has three layers:
1. Dura mater- External
2. Arachnoid mater- Middle
3. Pia mater- Inner
Protections and Coverings
• Cerebrospinal Fluid- CSF is a
clear, colorless liquid found in
between pia mater & arachnoid
mater which protects the brain
against injury. It also carries
oxygen, glucose & other chemical
required by neurons & neuroglia.
• CSF has three main function:-
– Mechanical protection- serves as
shock absorber & protects the
delicate tissue of CNS.
– Chemical protection- provides an
optimal environment for accurate
neuronal signaling.
– Circulation- CSF is a medium for
exchange of nutrients & waste
products between the blood &
nervous tissue.
Protections and Coverings
• Blood-Brain
Barrier
– A function of glial cells
• Secrete chemicals
that maintain the BBB
• Absorb materials from
blood
• Extract materials from
brain
– Cells of capillaries form
tight junctions
– Differential rates of
passage of certain
materials
UT-GSM 2008
Adult Brain
– Forebrain
• Cerebrum
• Thalamus & hypothalamus
– Midbrain
– Hindbrain
• Cerebellum & pons
• Medulla oblongata
Cerebrum
(seat of intelligence)
Hemispheric Specialization
• Right side processes:
• Creativity
• Patterns
• Spatial Awareness
• Context
• It Recognizes:
• Faces
• Places
• Objects
Hemispheric Specialization
Left side processes:
• Speech
• Analysis
• Time
• Sequence
It Recognizes:
• Letters
• Numbers
• Words
Senses and integrates Hearing,
Its primary function
sensation's) Organization
is the processing, Spatial awareness and of language
Memory Formation
Emotions integration, Perception Information
Decision making interpretation, (Awareness of body/ Retrieval
Reasoning etc. of VISION body parts (Memory and
Personality in space and in Memory
and visual stimuli.
relation to each other) Formation)
FUNCTIONAL AREAS OF
CEREBRUM (Basal Ganglia)
• Amygdala
– Involved in anger, &
fear
• Hippocampus
– Is important in the
formation of memories
– Korsakoff’s syndrome
Anatomy of
Limbic System
• Thalamus
– Relay sensory information to
the cerebral cortex
• Hypothalamus
– Important to metabolic
behaviors, eating, drinking,
sexual behaviors, and
regulating emotions
Mid-Brain
• Location
– The midbrain extends from the pons to the
lower portion of thalamus.
– Mid-brain contains several nuclei & right &
left substantia Nigra which are large darkly
pigmented substance.
– Neurons that releases dopamin extends
from the sbbstantia nigra to the basal
ganglia & helps control subconscious
muscle activities.
Hindbrain
• Pons
– Relay station
Medulla Oblongata
• The lowest part of the brain stem
• Merges into the spinal cord
• Includes important fiber tracts
• Contains important control centers
• Heart rate control
• Blood pressure regulation
• Breathing
• Swallowing
• Vomiting
Spinal cord
• Link between brain and body organs
• Situated in vertebral canal
• Covered by Meninges and CSF
• Central gray matter - H.shaped
• Peripheral white matter
Spinal cord
Parts of Neuron:
Cell Body
Dendrites
Axon
UT-GSM 2008
Neurons
dendrites
cell
axon with body
myelin sheath
Schwann
cell
synapses
Moore’s COA5 2006
Dendrites (receptors)
Cell Body (processing Take in excitatory & inhibitory
center) stimuli
Inside is called the SOMA
Dendrites
Dendrites are the "receiving"
surface of the neuron.
The soma
soma (cell body) of a
neuron contains the nucleus
(DNA) of the cell & cytoplasm
cytoplasm
that
that includes
includes organelles
organelles such
such as
as
lysosome,
lysosome, mitochondria,
mitochondria, &
& golgi
golgi
complex..
complex. It also manufactures
neurotransmitters.
neurotransmitters
• Myelin- The axon of most neurons are surrounded by lipid &
protein covering called Myelin sheath that is produced by
neuroglia. Axon without such cover is known as
unmyelinated & those covered known as myelinated axons.
e.g., skin
e.g., muscle
multipolar neurons conducting impulses
from the CNS to effector organs (muscles & glands)
Gray’s Anatomy 38 1999
Chemicals that cross the synapse between
two neurons & can cause either excitation
or inhibition of postsynaptic neurons.
Neurotransmitter
NT can be divided into two classes based on
size. They are:
1. Small Molecule NT-
1. Acetylcholine- Ach is excitatory at some synapse
such as neuromuscular junction & it is also inhibitory
at other synapse as it slows the heart rate.
2. Amino acids- Glutamate & Aspartate have powerful
excitatory effect. Half of the excitatory neurons in
CNS communicate via Glutamate. Inactivation of
Glutamate occurs via reuptake.
3. GABA- Gamma amino butyric acid & Glycine are
important inhibitory NT. GABA is mainly found in CNS
& in Spinal cord half of the synapse use GABA & half
uses Glycine
Neurotransmitter
• Biogenic Amines- Certain amino acids are modified & decarboxylated
to produce Biogenic amine. They are also known as catecholamine.
– Nor epinephrine- plays role in arousal, dreaming & regulating the
mood.
– Dopamine- plays role in emotional responses, addictive behavior
& pleasure experience. Dopamine also help in maintaining the
muscle tone.
Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tubero infundibular pathway
Mesolimbic pathway
This pathway originates in the ventral
tegmental area and innervates several
structures of the limbic system, including the
nucleus accumbency.
Olfactory hallucinations
• Phantosmia is the phenomenon of smelling odors
that aren't really present. The most common odors
are unpleasant smells such as rotting flesh, vomit,
urine, feces, smoke, etc.
Tactile hallucinations
• This type of hallucination is often associated with
substance use, such as someone who feels bugs
crawling on them (known as formication) after a
prolonged period of cocaine or amphetamine use.
Delusions
Dopamine
Receptors
D3 D5
D4
Dopamine Hypothesis
of
Mesocortical
Schizophrenia
pathway
Nigrostriatal
pathway
Hypoactivity: (part of EP system)
negative
symptoms
Mesolimbic
pathway
Tuberoinfundibular pathway
Hyperactivity:
(inhibits prolactin release)
positive
Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.
symptoms
Pathways Symptom Neuro- Remarks
s Transmitters
1) MESOLIMBIC +ve DA > 5HT Hallucination,
Delusions seen
2) MESOCORTICAL -ve 5HT > DA Apathy,
social withdrawal
seen
3) NIGROSTRIATAL SIDE- ACH > DA E.P.S.
EFFECT
4) TUBERO- SIDE- PROLACTIN Gynaecomastia
INFUNDIBULAR EFFECT >DA
Dopamine theory:
dopaminergic systems in CNS
Dopamine tract Innervation Function D-antagonist
effects
Typical
Atypical
or
Conventional
Chlorpromazine Thioridazine Clozapine, Olanzapine
Trifluoperazine, Haloperidol Risperidone
Atypical antipsychotics
Serotonin- Dopamine
Antagonists (SDA’s)
Metabolism Hepatic
Absolute
• Preexisting coma, acute stroke
• Severe intoxication with alcohol or other
central depressant drugs
• Known allergy against haloperidol or other
butyrophenones or other drug ingredients
• Known heart disease; when combined will
tend towards cardiac arrest
Contraindications
Special caution needed
• Preexisting Parkinson's disease
• Patients at special risk for the development of QT
prolongation
• Compromised liver-function (as haloperidol is metabolized
and eliminated mainly by the liver, dose reductions and/or
spaced intervals may be needed)
• Patients with hyperthyreosis; the action of haloperidol is
intensified and side-effects are more likely. Initiate an
effective therapy of hyperthyreosis.
• IV injections: inject slowly to avoid hypotension or
orthostatic collapse. Avoid IV injections in cardiovascular
unstable patients (preexisting hypotension, shock,
concomitant antihypertensive therapy, heart insufficiency).
Prefer in these cases moderate oral or IM doses.
Adverse effects
• Extrapyramidal side-effects
• Tardive dyskinesia
• Akathisia
• Dry mouth,
• Lethargy,
• Restlessness of akathisia,
• Muscle-stiffness,
• Muscle-cramping, restlessness, tremors,
• weight-gain;
Section IV
Product
Information
FAQ
• Q1: What is Serenace? (Which group does it belong
to? What is the composition?)
• Q2: What are the indications?
• Q3: How do we define the indications?
• Q4: What is EPS?
• Q5: How to handle EPS question?
• Q6: How to handle Atypical antipsychotics question?
• Q7: Why do doctors use liquid and injection?
• Q8: How does haloperidol differ from
chlorpromazine?
• Q9: What is the recommended dose of Serenace ?
Q1: What is Serenace?
[Others: Atypical]
– Chemical group Butyrophenone
[Others:Phenothiazines,
Thioxanthines]
Q1: What is Serenace? (Contd.)
• Acute Psychosis
– Symptoms of schizophrenia for less
than 6 months
– DSM IV diagnosis based on symptom
duration
• < 1 month Brief psychotic disorder
• 1-6 months Schizophreniform disorder
• > 6 months Schizophrenia
Q3: How do we define the
indications? (Contd.)
• Impairment of consciousness
• Marked distortion of perception of world
- Hallucinations - Illusions
- Delusions - Mood changes
Q3: How do we define the indications?
(Contd.)
• Kinds of EPS
Acute dystonia
• Sudden tonic contraction of muscles of
tongue, neck, back, mouth & eyes.
• Young males, early in treatment, 10%
Parkinsonism
• Rigidity (stiff muscles), Bradykinesia (shuffling
gait), tremors
• Women, > 40 years, early in treatment, 15%
Q4: What is EPS? (Contd.)
• Postural hypotension.
• Weight gain and fluid retention.
• Soporific effects
• Hypothermia
Q9: What is the recommended dose of
Serenace ?
• Acute cases
5-10 mg/day short-term
• Early (1st 6 mo)
5-20 mg/day
• Maintenance
Reduce dose by 50% over 3-6 months
Recommended optimal dose 6-12 mg (Am Psych
Assoc1997)
Haloperidol v/s Olanzapine
Pathways HALOPERIDOL OLANZAPINE
1) MESOLIMBIC ++ +
2) MESOCORTICAL _ +
3) NIGROSTRIATAL ++ +
4) TUBERO- + _
INFUNDIBULAR
Conclusion :
Diabetes
Hyper
Glycemia
Weight
Gain
Insulin
Insulin CVD Dyslipidemia
Resistance
Resistance
Hyper-
QTc Hyper- lipidemia
glycemia EPS QTc
Schizophrenia Acute
Psychosis
Effectiv
e in Delirium
Manic
episodes in Mania,&
Bipolar Anxiety
What is the recommended dose of
Serenace ?
• Acute cases
5-10 mg/day short-term
• Early (1st 6 mo)
5-20 mg/day
• Maintenance
Reduce dose by 50% over 3-6
months
Recommended optimal dose 6-12 mg (Am Psych
Assoc1997)
Adverse Effects of Antipsychotic Medication
Adverse Haloperid Pericyazine Risperido Olanzapin Clozapine
ne
effects ol (Low pot) e
(High pot)
Sedation + +++ + ++ ++++
Postural + ++ ++ + +++
Hypotension
Tardive +++ ++ + + ** + **
Dyskinesia
**
* Typically at doses over 6mg but may be lower in some patients
** Results extrapolated from shorter term trials
Adaopted from “Using the new antipsychotic agents” by Louric K Aust. Doc. No. 25, June 1999
Drug Daily oral Sedation Postural Anticholinergi Extrapyramid Weight gain
dose range hypotensio c al
(mg) n
Newer agents
pimozide 2-12 ++ + + ++ +
ApoA -I
Lipoproteins
• As lipids are hydrophobic hence only the
smallest lipid can dissolve in blood plasma.
Proteins (apoproteins)
Cholesterol
Non polar lipids in
core
(TAG and
H O
HO
cholesterol esters)
Apoprotein
phospholipid
Cholesterol ester
Cholesterol
TAG (86%)
Function is to transport dietary TAG to the adipose tissues where
it can be stored as fat or to muscles where the constituent fatty
acids can be used for energy.
This animation shows how chylomicrons are metabolised
once they enter the circulation from the lymphatic system
B48
B48 Tissues
CM
CM CII
E Lipoprotein
B48 lipase
Taken up by CII
E CMR
liver (via LDL receptors)
E CII
B48
HDL
E CMR CII Capillary wall
(endothelial surface)
Chylomicron summary
• Synthesised in intestine.
Function:
•Function is to transport endogenously synthesised TAG in
fasting state to the extra hepatic tissues where it can be stored
as fat or to muscles where the constituent fatty acids can be
used for energy. The cholesterol is delivered to extra hepatic
tissues once VLDL has been metabolised to LDL.
This animation shows how VLDL are metabolised
once they enter the circulation from the liver
B100 Tissues
VLDL B100
LDL Lipoprotein
Some LDL taken up lipase
E CII
by liver (LDL receptors)
apoproteins
HDL receptor mediated HDL
HDL endocytosis by liver
HDL
Liver
some cholesterol
ester transferred to
“used” cholesterol circulating VLDL
transferred to HDL and
converted to cholesterol
VLDL
ester
Cholesterol can be
LDLreceptor converted to bile salts
Peripheral mediated for excretion or
tissues LDL endocytosis LDL repackaged in VLDL
for redistribution
High density lipoprotiens
summary
• HDL carries “used” cholesterol (as CE) back to the
liver. Also donate some CE to circulating VLDL for
redistribution to tissues.
TG in food
Absorbed by cell
Hydrolysis of TG by LPL to
Free fatty acid
LIPID TRANSPORT - Overview
Reverse Cholesterol Transport and HDL
Cause :
1. Increased LDL
2. Decreased HDL
3. Increased remnants lipoprotein like IDL & CM
remnants.
Type:
a. Primary- Due to genetic defects
b. Secondary- Metabolic disturbance
Fredrickson’s classification of
hyperlipidemia
• Type-1- elevation in CM & TG
• Type-2A- Elevation in LDL
• Type-2B- Elevation in both LDL & TG
• Type-3 - defect in VLDL remnant
clearance.
• Type-4 - TG level (250-500mg/dl)
• Type-5 - elevated level of CM & VLDL
Arpitor
Arpitor is Atorvastatin. Atorvastatin is a potent
synthetic HMG CoA-reductase inhibitor. It
lowers plasma cholesterol levels by inhibiting
endogenous cholesterol synthesis.
Atorvastatin also has additional beneficial
effects on arterial structure and function i.e.,
anti-atherosclerotic and antithrombotic effects.
MOA
HMG CoA Reductase
HMG CoA Reductase
Inhibitor
Arpitor
Mevalonic Acid
Cholesterol
• ↓ Platelet activation
• ↓ Coagulation
• ↑ Endothelial function
• ↓ Reactive oxygen species
• ↑ NO bioactivity
• ↓ AT1 receptor
• ↓ Effects on collagen
• ↓ MMPs
• ↓ Endothelin
Side effects
% P a t i e n t a c h 7i e8 %v e d 6
How is Atorvastatin superior to
Lovastatin ?
• Effect seen from starting dose
• The maximum gain in life expectancy was
achieved with Atorvastatin
• 36 % reduction in cardiovascular complication
in CAD patient compared to patients
undergoing angioplasty.
• Ensures patients compliance
• Cost effective therapy
How is Atorvastatin superior to
Simvastatin?
S ta tin
R o su v a sta t
Effect of lipid-modifying therapies on
lipids
Therapy
Bile acid
sequestrants
Summary of Drug Choice
L ip id
abnorm
What we will learn?
Proteins
Carbohydrate
Fats
Most common energy
sources
• Carbohydrates
• Fats
Most common energy sources
• Proteins
Gasoline for human being
– Glucose (Carbohydrate)
– Fatty acids (Fats)
What is a Carbohydrate?
Carbohydrates are compounds which
have the following basic composition:
I
(CH2O)n or H - C - OH
I
Classified as –
Monosaccharides
Disaccharides
Oligosaccharides
Polysaccharides
Simple Sugars:Mono and
Disaccharides
• Monosaccharides – single sugar
unit
– Glucose
• Found in fruits, vegetables,
honey
• used for energy
– Fructose
• “fruit sugar”
• Found in fruits, honey, corn
syrup
– Galactose
• Found as part of lactose in milk
Disaccharides – two
linked sugar units
– Sucrose: glucose + fructose
• “table sugar”
• Made from sugar cane and sugar
beets
– Lactose: glucose + galactose
• “milk sugar”
• Found in milk and dairy products
– Maltose: glucose + glucose
• Found in germinating cereal
grains
• Product of starch breakdown
Complex Carbohydrates
• Oligosaccharides
– dried beans, peas, lentils
• Rafinose (gal-glu-fru)
• Stachyose (gal-gal-gal-fru)
• Metabolized by intestinal bacteria
• Gaseous effects
Complex Carbohydrates
• Polysaccharides
– contain 100’s or 1000’s of
monosaccharide units
– starch-digestible
– fiber-indigestible
– Glycogen
Glycogen
• Importance
– Stored form of glucose.
– Major sites – Muscles and Liver; 75% is stored in
muscles.
– Liver: major site for glycogen synthesis
• ~10% of wet weight of liver
– Muscles
• Glycogen < 1% weight
• Used as energy when body requires energy.
• Important for “instant” energy
Glycogen Storage
• Skeletal muscle
– Function: serve as fuel reserve for
synthesis of ATP during muscle contraction
• Liver
– Function: maintain blood glucose
concentration in times of fasting
Also known as
a-glucosidase
enzymes
Metabolism of Carbohydrates
Glycolysis Glycogenesis
Gluconeogenesis Glycogenolysis
Glycolysis (glucose pyruvate)
• Derived from the Greek stem glyk-,
"sweet," and the word lysis,
"dissolution."
• Glycolysis: sequence of reactions that
metabolizes one molecule of glucose to
2 molecules of pyruvate (triose sugar)
• Also produce 2 molecules of ATP
• Anaerobic
– Pyruvate to lactate
• Aerobic
– Pyruvate to acetyl-CoA
Gluconeogenesis
– Controls blood
glucose levels by
secreting hormones
into the blood
1. α -cells (20-30% of
islet cells)
- Glucagon
1. β -cells (60-70% of
islet cells)
- Insulin
1. δ -cells (2-8% of islet
cells)
- Somatostatin
Insulin
• First hormone
identified
(1920’s) by
Banting and
Best
• Released when
glucose is
abundant
(elevated plasma
glucose) and
stimulates:
How insulin is synthesized?
Preproinsulin
NH2
S S
S S
HOOC
S S
How insulin is synthesized?
Proinsulin
NH2
S S
S S
HOOC
S S
How insulin is synthesized?
Insulin
HOOC NH2 β -
chain
S S
S S
HOOC NH2 α -
S S chain
C - peptide ESR11-08
Role of C-Peptide
• Insulin is difficult to measure
• Half-life is only 5 mins
• Rapidly inactivated by various
enzymes.
• C-Peptide has 30 mins half life
• Synthesized in equimolar conc to
that of insulin
• Determines amount of insulin
secreted from b-cell
How insulin is secreted?
• Insulin is secreted in 2 phases –
1. First phase
– Sharp peak
– Within 3-5 mins of glucose intake
– Completed within 10 mins
– Release of mature granules.
2. Second phase
– Release of secretory
granules that are mobilized
within the beta cell for
release.
– Granules contain newly
synthesized insulin.
– Second Phase helps to
attain normoglycemia.
Insulin – the “hormone of
plenty”
• Increases glucose uptake by muscle and adipose
cells
• Helps in increasing cells to breakdown glucose,
releasing its energy in the form of ATP
• The liver and muscle to store glucose as glycogen
(short-term energy reserve)
• Adipose tissue to store glucose as fat (long-term
energy reserve)
• Glycogen synthesis and protein synthesis
Muscles Liver
Glucose Glycogenolysis
Uptake
Gluconeogenesis
Adipose cells
Glycolysis
Glycogenesis Lipogenesis
K+ Depolarization
Voltage
ATP
dependent Ca+
sensitive K+ +
channels
channels
Binds and open
closes
Ca++
Glucose ATP
Secretary
granules
GLUT-2
Insulin
High
Glucose
Insulin
Insulin
Receptor
Seri
es o
f e nz
reac
tion
GLUT 4
Mode of action of Insulin
Glucose
Insulin enters
Insulin GLUT-4
Receptor
Translocation
of GLUT-4
Series of
reaction
Glucose
Glycogen Glycolysis
Mode of action of insulin
Sources of blood glucose in the various nutritional states
40 Exogenous
(glucose
Glucose 30 from diet)
glucose from
Used gluconeogenesis
g/hr glucose from (lactate + amino acids) glucose from
20 liver glycogen gluconeogenesis
(mostly lactate)
10
0
4 8 12 16 2 7 42
HOURS DAYS
Hyperglycemia & Hypoglycemia
Hyperglycemia – too
little insulin
Insulin
Non esterified Fatty acid (NEFA or FFA)
Hence insulin -
•Decreases lipolysis
•Increases lipogenesis
•Decreases ketoacidosis
Insulin on Protein metabolism
Amino acid
Insulin
Protein
Insulin –
•Increases protein synthesis
•Decreases proteolysis
Summary of insulin action
Increases –
– Glucose uptake
– Glycolysis
– Glycogenesis
– Lipogenesis
– Protein synthesis
Decreases –
•Gluconeogenesis
•Glycogenolysis
•Lipolysis
•Ketogenesis
•Proteolysis
Diabetes Mellitus
Disease, Pathogenesis &
Management
Definition
A group of metabolic disorders comprising
of abnormal carbohydrate, fat and protein
metabolism and characterized by chronic
or persistence hyperglycemia
Due to lack of insulin hormone
OR
Improper insulin secretion
Risk Factors for Diabetes
• Family history of diabetes
• Obesity (> 20% over desired body weight or BMI > 27 kg/m2
• Age > 45 years
• Sedentary life style
• Some ethnic groups ( Indians, African-Americans and native
Americans, asian americans)
• Gestational diabetes or delivering a baby weighing more than 9
pounds (4kg or more)
• High blood pressure ( > 140/90mmHg)
• High blood levels of triglycerides (> 250mg/dl)
• low HDL cholesterol level (<35mg/dl)
Symptoms of diabetes
• Frequent urination - Polyuria
• Excessive thirst - Polydypsia
• Excessive hunger - Polyphagia
• Fatigue
• Weight loss
• Blurred vision.
– Gestational diabetes.
Type-1 Diabetes mellitus
Abnormal
Insulin β -cell
resistance function
Type 2 diabetes
Insulin resistance
Healthy
600
500
400
300
200
100
-20 -10 0 10 20 30
Years of diabetes
Hyperglycemia
Types of Diabetes Type-2
• Obese
– Very high degree of insulin resistance
compared to b-cell impairment
• Non-obese
– Very high degree of b-cell impairment
compared to insulin resistance
Diagnosis of Type-2 Diabetes
• Normal value 4 - 6%
• Chronic complications
• Vascular
• Non-vascular
Diabetic Ketoacidosis (DKA)
Coma or death
Diabetic Ketoacidosis (DKA)
Symptoms are –
• Nausea and vomiting.
• Thirst / polyuria.
• Abdominal pain.
• Altered mental function.
• Shortness of breath.
Treatment – Insulin
injection
Non-Ketotic Hyperosmolar
State (NKHS)
• reported in all age groups, but it most frequently affects
older patients with type 2 diabetes
• initiating event in hyperosmolar hyperglycemic state is
glucosuric diuresis
• Decreased intravascular volume or underlying renal
disease decreases the glomerular filtration rate, causing
the glucose level to increase.
• The loss of more water than sodium leads to
hyperosmolarity
Non-Ketotic Hyperosmolar
State (NKHS)
Symptoms are –
• Polyuria.
• Orthostatic hypotension.
• Neurological symptoms like - altered
mental status,
lethargy, seizure and possibly coma.
Treatment
1. Vigorous intravenous rehydration,
2. Electrolyte replacement
3. Administration of intravenous insulin,
Chronic Complications
• Vascular
– Microvascular
– Retinopathy
– Neuropathy
– Nephropathy
– Marcovascular
– Cardiovascular disease
– Cerebrovascular disease
– Peripheral vascular disease
Layers of blood vessels
Hyperglycemia damages only a particular
subset of cell types:
capillary endothelial cells in the retina,
mesangial cells in the renal glomerulus,
and neurons and Schwann cells in peripheral
nerves.
• AGE pathway
• PKC pathway
• Hexosamine pathway
PAI-1
Microvascular Complications
Retinopathy
• Leading cause of blindness
• Starts with a small areas of
balloon-like swelling in the
retina's tiny blood vessels.
Hemorrhages in non-proliferative diabetic
• As the disease progresses, retinopathy
blood vessels that nourish
the retina are blocked.
Neuropathy
• Damage to the nerves that helps to feel sensations such as
pain
• Two types
1. Peripheral Neuropathy
• Nerve damage in the feet can result in a loss of
foot sensation, increasing risk of foot problems.
Symptoms include –
• Tingling
• Numbness (severe or long-term numbness
can become permanent)
• Burning
Microvascular Complications
Neuropathy
2. Autonomic Neuropathy
Diabetic Nephropathy
• Most common cause of
kidney failure.
• Five stages in the progression to
kidney failure in people with
diabetes
• Stage 4 (late-stage
diabetes). "advanced clinical
nephropathy." GFR < 75
milliliters per minute. Almost all
patients have hypertension at
stage 4.
• Stage 5 (end-stage renal disease, ESRD) -
GFR <10 mL/min) and renal
replacement therapy (i.e., hemodialysis, peritoneal
dialysis, kidney transplantation)
is needed
Macrovascular Complications
Cardiovascular
complications
• More than 60% of DM patients dies
due to CAD
• Most common CVD includes –
• Hypertension
• CAD
• Heart Failure
Macrovascular Complications
Cardiovascular
complications
Hypertension
Category SBP DBP
Normal < 120
and < 80
Pre hypertension 120- 139 and / or
80-89
Hypertension
Stage 1 140 - 159 and / or
90-99
Stage 2 Sustained increase
>160 in “Systolic
and“/ Blood
or
>100 Pressure > 140 mmHg and / or
“Diastolic” Blood Pressure > 90
Macrovascular Complications
Cardiovascular
complications
Hypertension
Cardiovascular
complications
• Causes of Obstruction
Atheroma (Atherosclerosis)
Thrombosis
Embolism
Spasm
Macrovascular Complications
Cardiovascular
complications
Symptoms
Angina Pectoris
– Stable
– Unstable
– Variant or Prinzmetal’s
Heart attack
• Death of muscle tissue
due to lack of oxygen
Macrovascular Complications
Cardiovascular
complications
Manageme
nt
Life Style Modifications
Drug Therapy
• Drugs
• Nitrates
• Beta blockers
• Calcium channel blockers
• Potassium channel openers
• Metabolic modifier
Macrovascular Complications
Cardiovascular
complications
Surgical Procedures
• Bypass surgery
• Balloon angioplasty
Macrovascular Complications
Cardiovascular
complications
Heart Failure
Inability of the heart to pump sufficient blood to
meet the body’s metabolic requirement
Cerebrovascular
complications
Stroke
Blood supply is interrupted,
resulting in tissue death and loss of
brain function
Transient Ischemic
Attack (TIA)
A brain disorder caused by
temporary
disturbance of blood supply to an
area of the brain, resulting in a
sudden, brief decrease in brain
Macrovascular Complications
Peripheral vascular disease
• Blocking of an artery
in the peripheral
region of the body
• Major cause -
atherosclerosis
Non Vascular Complications
•Galucoma, Cataract
•Diabetic foot ulcer
•Gastroparesis
•Sexual dysfunction
•Skin changes
Biochemical mechanism of
the development of diabetic
complications
Hypothesis 1
Damage to cells
Hypothesis 2
Glycation
Increased glucose level
Oxidative stress
High glucose
Polyol Pathway
Hyperglycemia
Cellular damage
Management of Diabetes Type-2
Goals
• Pharmacological therapy.
Importance of achieving tight
glycemic control
• Various landmark studies have confirmed that
by decreasing glucose level there is a
significant reduction in risk of microvascular
and macrovascular complications.
– DPP
UKPDS
Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)
• Primary failure
• No response with a drug given for
the first time
• Secondary failure
• Gradual lose of action of a drug
when used for a prolonged period.
E.g., Sulfonylureas.
BENCLAMET
(Metformin)
BENCLAMET (Metformin)
Decreases gluconeogenesis
Variables Effects
Bodyweight Decrease
BPNo effect
Triglycerides Decrease to neutral
Total Cholesterol Decrease to neutral
LDL Decrease to variable
HDL Increase to variable
Lipoprotein(a) Decrease
Hypercoagulability Decrease
C-Reactive Protein Decrease to variable
Endothelial function Improve
Cardiovascular Events Decrease
Indication
• Drug of first choice in obese with type-2
diabetes mellitus.
• USFDA approved in children > 10 years of
age with type-2 DM.
• Metabolic Syndrome.
• Renal disease.
COMPOSITION
Each tablet contains :
Glipizide 5 mg/10 mg in a SR form
INDICATION
• Type 2 Diabetes Mellitus
GLYTOP-SR
RATIONALE
• Longer acting agents like
glibenclamide are efficacious but have
1) Higher rates of hypoglycemia
PHARMACOKINETICS
• Tmax : 6-12 h
• Steady state : 5th day
6-7 days in elderly
• Effect of food : None
• Metabolism : Liver (90%)
• Excretion : Urine and feces
GLYTOP-SR
DOSAGE
Initial
No fixed dosage regimen
Recommended starting dose : 5mg OD with breakfast
Maximum : 20mg OD
Switch from conventional Glipizide
Nearest equivalent dose
Switch from other SUs
Start with 5mg OD
Type 2 DM Patients on Insulin
<20 units - discontinue insulin, start with 5mg OD Glytop-
SR
>20 units -Reduce insulin dosage by 50% and start
5mgOD Glytop-SR.
GLYTOP-SR
COMPETITION
vs. Conventional Glipizide
COMPETITION
vs. Glibenclamide