1. PHARMACOLOGY OF PEPTIDES
Gastric Inhibitory Peptide
It is an inhibitory hormone of the secretin family of hormones.
Also known as GASTRIC INSULINOTROPIC POLYPRPTIDE.
• The discovery of gastric inhibitory polypeptide during the time 1969-1971 can be related histologically to the
recognition that food substances ,when introduced into the small intestine trigger a humoral reflex leading to the
inhibition of gastric acid secretion.
Chemical structure of GIP.
• Gastric insulinotropic polypeptide is a polypeptide hormone containing 42 amino acids.
2. ,
Synthesis and Metabolism of GIP
GIP is synthesized by k-cells, which are found in the mucosa of the duodenum
and jejunum of the gastrointestinal tract.
Transported by blood like all other endocrine hormone.
Both GIP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4,DPP-4
and DPP-4 inhibitors which potentiate their effects on glycaemic control,are
now used to treat type 2 diabetes.
3. .
Physological roles and Effects
1. It inhibits gastric secretion and mortily.
It stimulates insulin secretion i.e.it is considered as an important physiological regulator of insulin
secretion. Though other hormones like gastrin, cck, secretin and glucagon also stimulate insulin
secretion ,plasma insulin level of insulin in response to GIP resembles the concentration o insulin
attained following oral glucose ingestion.
Main effect of GIP is stimulating insulin secretion in response to a meal.
4. • Factors Influencing GIP.
Intake of glucose i.e. it stimulates secretion of GIP which passes to the pancreas causing the B-
cells to secrete insulin.
• Mechanism of action of GIP.
GIP directly stimulates insulin secretion through the B-cell GIPR and indirectly potentiates a cell
activity to enhance alpha to beta cell communication through the GLP-1R .
Thus ,GIP indirectly stimulates insulin secretion through alfa cells.
5. • Storage and release.
GIP is sercretd by eneroendocrine k-cells that are present in high density in the
duodenum and upper jejunum but are present throughout the small intestine.
• Receptors.
Tirzepatide is a dual gastric inhibitory peptide/glucagon-like peptide-1 receptor
agonist formulated as a synthetic linear peptide,based on the native GIP
sequence.It has a prolonged half-life of 5 days,which enables once-weekly
dosing.
6. Agonist and Antagonist.
An ideal antidiabetic medication should present proven efficacy in lowering
elevated levels, promote weight loss ,have low risk of hypoglycemia and offer
cardiovascular benefits.
• Diabetes drugs in the GLP-1 agonists class are generally taken by an
injection gien daily or weekly .Examples are
i. Dulaglutide – taken weekly
ii. Exenatide extended relaese –taken weekly
iii. Exenatide –twice daily
iv. Semaglutide –weekly
v. Victoza,saxenda -daily
The hormone antagonistic to GIP is GIP3-30NH2 which is a potent
competitive antagonist of the GIP receptor and effectively inhibits GIP-
mediated insulin ,glucagon and somatostatin release.
7.
8. PHARMACOLOGY
ASSIGNMENT
STUDENT`S NAME: KELVIN B KIWALE
REG. NUMBER: BPH/18965/2101/DT
QUESTIONS;
TO DISCUSS PHARMACOLOGY OF PEPTIDES - OPIOIDS : what are opioids,history, chemical
structure and properties, types of opioids, synthesis and metabolism, storage and
release, physiological roles and effects of opioids, factors influencing opioids, (if
possible with diagrams)
9. what are opioids
Opioids are compounds resembling opium in addictive, properties or physiological
effects.
Are substances that act on opioid receptor to produce morphine- like effect.
Medically the are primarily used for pain relief including f, including anesthesia.
Other medical uses include suppression of diarrhea, replacement therapy for
opioid use disorder, reversing opioid overdose, and suppressing cough.
History f opioids
The use of opioids to treat pain first became prevalent in the United States in the
early 1860s as a way to treat wounded soldiers. These soldiers were treated with
morphine, and many developed dependencies and addictions to the drug in the
years following the war
chemical structure and properties of opioids
What is the structure of opioids?
Structure. Opioid receptors belong to the class A of G protein-coupled receptors
(GPCR) which share some common features. They possess seven transmembrane
domains linked by three intracellular and three extracellular loops, an extracellular
amino-terminus and an intracytoplasmic C-terminus tail.
10. Properties of opioids
Opioids are highly addictive, in large part because they activate powerful
reward centers in your brain. Opioids trigger the release of endorphins,
your brain's feel-good neurotransmitters. Endorphins muffle your
perception of pain and boost feelings of pleasure, creating a temporary
but powerful sense of well-being.
Types of opioids
Common types are;
oxycodone (OxyContin)
hydrocodone (Vicodin)
morphine
methadone.
11. Synthesis and metabolism of opioids
How are opiates synthesized?
Opiates such as morphine and codeine are mainly obtained
by extraction from opium poppies. Fermentative opiate
production in microbes has also been investigated, and
complete biosynthesis of opiates from a simple carbon source
has recently been accomplished in yeast.
How are opioids metabolized in the body?
Most opioids are metabolized via CYP-mediated oxidation and have
substantial drug interaction potential. The exceptions are morphine,
hydromorphone, and oxymorphone, which undergo glucuronidation.
12. Storage and release of opioids
All opioids should be stored in their original packaging. Don't store them in places
medicines are usually kept, such as in a bathroom or kitchen cabinet. Instead, place
them in a locked cabinet, lockbox, or other location where people can't easily access
them.
What part of the brain releases opioids?
The locus ceruleus (LC) is an area of the brain that is critically involved in the
production of opioid dependence and withdrawal.
Physiological roles and effects of opioids
What are the physiological effects of opioids on the body?
People who use prescription opioids can feel relaxed and happy, but also
experience drowsiness, confusion, nausea, constipation, and slowed breathing.
Prescription opioids have effects similar to heroin.
13. Factors influencing opioids
Poverty.
Unemployment.
Family history of substance abuse.
Personal history of substance abuse.
Young age.
History of criminal activity or legal problems including DUIs.
Regular contact with high-risk people or high-risk environments.
Refference;
“The Opioid Diaries” by David J. Herzog, M.D. ...
“The Hidden Epidemic” by Kathryn Boor. ...
“A Higher Power: My Journey from Addiction to Faith” by David Oltman.
14. PHARMACOLOGY ASSIGNMENT
Samwel samwel bph/18968/2101/dt
PHARMACOLOGY OF PEPTIDES - OPIOIDS :
mechanism of action of opioids ,
opioid receptors,
agonist and antagonist of opioids,
clinical indications,
side effects,
toxicity
15. Mechanism Of Action
Opioids have actions at two sites, the presynaptic nerve terminal and the
postsynaptic neuron.
The postsynaptic actions of opioids are usually inhibitory.
The presynaptic action of opioids is to inhibit neurotransmitter release,
and this is considered to be their major effect in the nervous system
17. Agonist And Antagonist Of Opiods
Partial agonist opioids activate the opioid receptors in the brain, but to a much lesser degree
than a full agonist. Buprenorphine is an example of a partial agonist.
An antagonist is a drug that blocks opioids by attaching to the opioid receptors without
activating them.
18.
19. Clinical Indicator
Opioid analgesia is indicated for the treatment of moderate to severe pain.
An opioid is a medication that relieves pain by binding to opioid receptors in
the central nervous system spinal cord and peripheral nervous system.
20. Side Effects Of Opiods
Include; Sedation, Dizziness, Nausea, Vomiting,
Constipation, Physical Dependence, Tolerance, And
Respiratory Depression.
21. Opiods Toxicity
Slow, shallow or complete cessation of breathing
Vivid dream / hallucinations
Drop of blood pressure
Pinpoint pupils
Slow, erratic pulse
Vomiting
Un responsiveness when shaken or to painful stimuli
Awake but
22. CGRP-calcitonin gene related peptide
Kelvin C Osward BPH/18978/2101/DT
Introduction
• 37 amino acid vasoactive neuropeptide
• Derived from CT gene localized in chromosome 11
• Widely distributed in CNS and PNS
• 2 forms α and β CGRP
• α-CGRP found in neuronal tissue and a potent vasodilator
23. History and Discovery
Canadian scientist Copp postulated the existence of calcium lowering peptide-CT. In 1961 regulation
of parathyroid hormone was studied and two calcium regulating hormone was discovered. In 1980-
CT gene was cloned and in 1982 CGRP was discovered by molecular cloning of CT gene.
CGRP has a molecular weight of 3790,has hydrogen bond donor and acceptor 57 and 58
respectively, topological surface area of 1670A square and formal charge of zero.
24. Chemical
structure of
CGRP
i. It has 37 amino acid
ii. Has N terminus which act as receptor activation.
iii. It contain disulphide bonded ring
iv. Has four clear domain
v. α- CGRP and β- CGRP has similar structures
25. Synthesis and metabolism
The two isoform of CGRP are synthesized from two distinct genes at different site on
chromosome 11 in the human. Gene Ι can undergo alternative splicing to produce either
calcitonin or alpha CGRP where β-CGRP is transcribed from its own distinct gene ΙΙ.Theses two
forms differ by only three amino acid in the human, thus it is perhaps not surprising that they
share similar biological activities. Alpha form is found in CNS and beta form is mainly found in
enteric nervous system.
CRGP is metabolized by an endopeptidase hydrolyzing substance. Endopeptidase are group of
hydrolyses which catalyze the hydrolysis of peptide bond and thus hydrolyze protein.
After synthesis CGRP is stored in a large dense-core vesicles within the sensory nerve terminal.
Following neuronal depolarization, CGRP is released from terminal via calcium-dependent
exocytosis mediated by classical exocytotic pathway.
CGRP is highly potent vasodilator,posess protective mechanism that are important for
physiological and pathological conditions such as cardiovascular system and wound healing.
26. Receptors
Heteromeric receptor composed of G protein coupled receptor called calcitonin-like
receptor(CALCRL) and a receptor activity-modifying protein(RAMP1).
CGRP are found throughout the body
May modulate a variety of physiological functions in all major system
respiratory,endocrine,gastrointestinal,immune and cardiovascular.
Function
In CNS modulate acetylcholine receptor
In PNS potent inhibitor of gastric acid secretion
Block tolerance to morphine
27. Mechanism of action
CGRP appears to work on several ways. For example
1. Increase local blood flow enhancing hemodynamic proficiency.
2. Protect heart muscle cells from the damage due to lack of oxygen(Ischemia).
3. Modulates the immune system by boosting anti-inflammatory cytokine expression.
All these actions are meant to minimize heart muscle damage and subsequent scar tissue formation
while promoting the healing process.
28. CGRP-Agonist and Antagonist receptor
CGRP receptor Antagonists; Its
mechanism of action is blocking
CGRP receptor of nerve cell.
When released in excess CGRP
causes intense inflammation in
the covering of the
brain(meninges).Excess CGRP
release account the pain of a
migraine attack.CGRP receptor
antagonist work by binding to
receptor and not allow the
binding of CGRP.Antagonists are
used for prevention of migraine
in adults which are administered
subcutaneously
e.g.Fremanezumab and
Galcanezumab. Agonist is rare
used in CGRP
.
29. Factors affecting CGRP
1. High concentration of calcium in bone.
2. In case of renal failure calcitonin accumulate in serum.
3. Ginger reduce CGRP.
4. Frequent activation of trigeminal nerves cause initial
release of CGRP
.
5. Dietary reasons.
Foods like spinach(dark green leafy is rich in magnesium),
fatty fish, dark chocolate and avocados can help migraine go
away.
31. NEUROPEPTIDE
are chemical messengers made up of small
chains of amino acids that are synthesized
and released by neurons. For example
vasopressin and oxytocin
32. Properties of neuropeptide
(1)Should be small-size protein molecule
(2)Should be produced and secreted by cells of the nervous system
(3)Must play a specific role in the regulation of neuronal cells
Synthesis
Neuropeptides are exclusively produced inside the cell and In most
instances, several different neuropeptides are encoded by a single
continuous messenger RNA (MRNA), which is translated into large
protein precursor (polyprotein).
33. Metabolism
Neuropeptides are broken down by enzymes, such as peptidases,
that cleave the peptide bonds between amino acids. These
enzymes are found in various locations, including the blood, liver,
and kidneys. Once the neuropeptides have been broken down,
they are eliminated from the body through urine or feces.
Additionally, some neuropeptides can also be reabsorbed by the
body, which helps to regulate their overall levels and activity.
34. Storage
Neuropeptides are stored in dense core vesicles, which
are larger and functionally distinct from the small,
clear synaptic vesicles.
35. Release
Neuropeptides are synthesized in the cell body of nerve cells and
are then transported to the axon terminal, where they are stored
in vesicles. Release of neuropeptides occurs in response to an
appropriate stimulus, such as the arrival of an action potential at
the axon terminal.
This process is called exocytosis, where the vesicles containing
the neuropeptides fuse with the plasma membrane of the axon
terminal, releasing the neuropeptides into the extracellular
space.
36. Effects
They can have a wide range of effects on the body, depending on
the specific neuropeptide and the area of the brain or nervous
system where it is active. Some examples of the effects of
different neuropeptides include:
Oxytocin: Promotes feelings of bonding and social connection
Vasopressin: Regulates water balance in the body and also
involved in pair bonding and social behavior
Endorphins: Reduce pain and increase feelings of pleasure
Melanin-concentrating hormone: Involved in regulating appetite
and body weight
37. There are several factors that can influence the
activity of neuropeptide receptors in the brain
and nervous system:
Gene expression
Receptor density
Receptor desensitization
Interaction with other neurotransmitter
Hormonal state
38. Agonistic
An agonist is a compound that mimics the activity of a
naturally occurring neurotransmitter or neuropeptide by
binding to and activating receptors. Agonists can have
similar effects to the natural neurotransmitter or
neuropeptide, such as increasing or decreasing the
activity of a particular neural pathway.
39. Antagonistic
An antagonist is a compound that blocks or reduces the
activity of a naturally occurring neurotransmitter or
neuropeptide by binding to and blocking receptors.
Antagonists can have opposite effects to the
neuropeptide, such as decreasing or inhibiting the
activity of a particular neural pathway.
40. Examples of agonists and antagonists for specific
neuropeptides include:
Oxytocin receptor agonists, which can promote
feelings of social bonding and trust.
Vasopressin receptor antagonists, which can be
used to reduce water retention and treat certain
medical conditions related to fluid balance.
41. ANGIOTENSIN
Angiotensin is a protein hormone that causes vasoconstriction and increase in blood
pressure
History
Pressor action of kidney extracts was know since the turn of the 19th century . The active
material was termed ‘ Renin ”
In the 1940s renin was shown to be enzyme which acted indirectly by producing pressor
principle from plasma Protein subsequently it became clear that the product of renin
action was inactive decapeptide angiotensin I which was converted to the active
octapeptide
42. CHEMICAL STRUCTURE
Angiotensin II is octapeptide with molecular formula 𝐶50𝐻71 𝑁13𝑁13
TYPES
Angiotensin I , II, III, IV , angiotensin II is the man and active form of hormone
Angiotensin I - kidney
Angiotensin II - with kidney
Angiotensin II - bloody vessel
Cortex and outer stripe of the outer medulla of the kidney
Angiotensin IV : Cerebral cortex
Basal card and several peripheral tissues including kidney , bladder , heat ,
spleen etc .
43. SYNTHESIS
The Lives creates and release a protein called Angiotensinogen . It is then
broken up by renin an enzymes produced in the kidney to form Angiotensin
I this is important precursor for Angiotensin II
44. METABOLISM
Angiotensin II acts through the Angiotensin types 1 and 2 receptors ( AT IR and AT2R
) AT – II is metabolized in different tissues by various enzyme to generate two
heptapeptide A – III and Angiotensin 1-7 , which can then catabolized into the
smaller peptides
45. STORAGE
It is stored in blood vessels , cortex and outer stripes of the outer medulla
of the kidney and adrenal medulla and cortex
RELEASE
When the blood pressure fall , your kidneys release the enzyme renin into you blood
stream - renin split angiotensinogen a protein made in your Liver and release the
pieces one piece is the hormone angiotensin I
