Autacoids Pharmacology

Sabah Elkheir
John
Lecturer,
Autacoids
• The word autacoid comes from the Greek "auto" (self) and "akos"
(healing substance or remedy).
• Autacoids or "autacoids" are biological factors (molecules) which
act locally (with in inflammatory cells) at the site of synthesis
and release.
• The autacoid known as tissue hormones or local hormones.
• They differ from the hormones in two way:
• Acts as mediator in physiological and pathological processes, reaction
to injury and immunological insult
• Serve as transmitter or modulator in nervous system.
Classification of autacoids
• Amine autacoids: Histamine & 5-hydroxytryptamine (serotonin),
are two important amine.
• Other autacoids, which produce paracrine type effects, include:
• Lipid-derived substances: prostaglandins, leukotrienes and platelet-
activating factor
• Peptides autacoids: plasma kinins (bradykinin and kallidin)
angiotensin, in addition to Cytokines (interleukins, TNF alpha, etc)
• Several peptides: Gastrin, somatostatin, vasoactive intestinal peptide.
Classification of Autacoids
 Histamine
 Histamine means tissue amine
• Present mostly in:
• Mast cells: skin, lungs, GIT mucosa, liver and placenta
• Non- mast cell histamine: brain, epidermis, and growing regions gastric
mucosa------ ‘neurotransmitter’
• Also presents in body secretions, venoms and pathological fluids.
• Histamine is a biologic amine present in many animal and plant tissues.
• Implicated as mediator in hypersensitivity and tissue injury reactions,
present almost and stored in mast cell.
• It’s formed by decarboxylation of amino acid histidine, a major portion
stored in mast cells and basophils.
• Histamine has no valid therapeutic use currently, but it plays very important
role in anaphylaxis and other forms of allergic reactions.
Histamine releasers:
• Variety of mechanical, chemical and immunological stimuli are capable of
releasing histamine from mast cell. These include;
• Tissue damage: trauma, stings and venoms, proteolytic enzymes,
phospholipase A.
• Polymers like dextrans, polyvinyl pyrrolidone.
• Basic drugs: tubocurarine, morphine, atropine, pentamidine, polymyxin,
vancomycin.
Histamine receptors
Histamine Antagonists
Pharmacological Actions
Pathophysiological Roles
Pharmacological actions
• Antihistamines are drugs which treat hay fever and other allergies.
• Used to relieve from nasal congestion, sneezing, or hives caused
by pollen, dust mites, or animal allergy with few side effects.
• Antihistamines are usually for short-term treatment.
• Chronic allergies increase the risk of health problems which
antihistamines might not treat, including asthma, sinusitis, and
lower respiratory tract infection.
Pharmacological Actions
1. Antihistaminic Actions: block histamine effects at various sites.
2. Other Effects: are independent of the antihistaminic effects and
vary widely according to the drug used.
• Most of them produce; CNS depression resulting in sedation,
drowsiness, inability to concentrate, and disturbances of
coordination.
• Anticholinergic actions: dryness of mouth, blurring vision,
constipation and urinary retention.
• Anti-motion sickness effects are exhibited by promethazine,
Diphenhydramine. Promethazine and mepyramine have
significant tranquilizer effect.
 • Local anaesthetic:
• BP: smooth muscle relaxation/ alpha adrenergic blockage
• Antiemetic: promethazine
• Antiparkinsonism: Diphenhydramine, orphenadrine,
promethazine
• Antivertigo: cinnarizine
Pharmacokinetics:
• They are well-absorbed following oral and parenteral
administration.
• Mainly metabolized by the liver and degradation products are
removed in the urine.
Therapeutic Uses
• 1. Allergic Disorders:- Including;
• Allergic rhinitis & common cold
• Allergic dermatitis, itching urticaria, seasonal hay fever
• Mild blood transfusion reactions
• Wasp stings/ bite: pain and itching decreases
• Allergic conjunctivitis.
• 2. Other uses:
• Motion sickness:
• Diphenhydramine and promethazine are used for prevention and
treatment of motion sickness and other vomiting disorders, as well as
nausea and vomiting associated with pregnancy.
• Morning sickness: primarily linked to hormonal changes in early
pregnancy (promethazine).
• Vertigo: is a specific type of dizziness characterized by a sensation of
spinning or the world spinning (cinnarizine).
• Chronic urticarria
• Appetite stimulant: cyproheptadine
• Carcinoid syndrome: cyproheptadine (block serotonin).
• Drug induced parkinsonism: diphenhydramine
• Diphenhydramine is frequently used in the treatment of cough as
combination preparation with other agents.
Adverse effects of histamine antagonists
 Eicosanoids
• Eicosanoids are fatty acid derivatives. Prostaglandins and related
compounds are collectively known as eicosanoids.
• Eicosanoids are important regulatory molecules.
• Most are produced from arachidonic acid, a 20- carbon
polyunsaturated fatty acid.
• The eicosanoids are considered “local hormones.”
• They have specific effects on target cells close to their site of formation.
• They are rapidly degraded, so they are not transported to distal sites
within the body
• There is evidence for involvement of eicosanoids in intracellular signal
cascades.
 Classes of Eicosanoids
• The are two classes of eicosanoids:
1. Prostaglandins & thromboxane's → cycloogygensae
enzymes (Cox-1 ‘constitutive’ & Cox-2 ‘inducible’).
2. Leukotrienes → lipoxygenase enzymes ‘Lox’
• Prostaglandins: either physiological “mediate protective
mechanism” or pathological “mediate pain sensitivity,
inflammation and swelling”.
• Thromboxanes: involved in blood clotting, constriction of
arteries.
• Leukotrienes: attract white cells, involved inflammatory
diseases (asthma, arthritis, etc.).
 Eicosanoids
Biosynthesis of eicosanoids
• Examples of eicosanoids:
• Prostaglandins, prostacyclins
• Thromboxanes, Leukotrienes
• Epoxyeicosatrienoic acids
• They have roles in:
• Inflammation & fever
• Regulation of blood pressure &blood clotting
• Immune system modulation
• Control of reproductive processes and tissue growth
• Regulation of sleep/wake cycle.
Pharmacological Actions & effects of prostaglandins
Prostaglandin receptors
The Cyclooxygenases Pathways
“Prostanoids”
Pharmacological actions
• Smooth muscle:
• Most stimulate myometrium and are known to be important in the
initiation and maintenance of labour. Prostaglandin E, has bronchodilator
action.
• GIT: they increase intestinal motility
• PG E inhibits gastric acid secretion.
• Both PG E and F produce contraction of the longitudinal muscle of the
gut.
• They also stimulate intestinal fluid secretion, resulting in diarrhea.
• CVS:
• PGE has a peripheral vasodilator and powerful natriuretic.
• PGF constricts arterioles and veins.
• Natural prostaglandins have no therapeutic application because
of short duration of action, but their derivatives such as:
• Cloprosterol, Fluprosterol and Misoprostol find for clinical
application.
Therapeutic uses of prostaglandins
Adverse effects
• Side Effects of prostaglandins are;
• Upper respiratory tract infection
• Bronchitis (inflammation of the airways)
• Anemia (low number of red blood cells)
• Hypoglycemia (low blood glucose level)
• Edema (swelling).
 Leukotriene antagonist
• Leukotriene antagonist, is an agent that blocks the effects of
leukotrienes-inflammatory chemicals involved in asthma and allergy
symptoms like airway constriction and inflammation.
• Examples include montelukast and zafirlukast, which are taken as tablets
to prevent symptoms of asthma, allergic rhinitis, and exercise-induced
bronchoconstriction, rather than to treat an acute attack.
• Lipoxygenase inhibitor blocks lipoxygenase (LOX) enzymes,
which are involved in producing lipid peroxides and leukotrienes.
• This inhibitor is developed to treat inflammatory diseases like asthma and
osteoarthritis by preventing the formation of harmful molecules.
• Zileuton is a well-known 5-LOX inhibitor.
Leukotriene antagonist
Leukotriene receptor antagonists
(LTRAs)
• These are generally well tolerated, but they may
cause side effects.
• Common adverse effects include headache,
abdominal pain, cough, and flu-like symptoms.
• Less frequent but more serious effects involve
neuropsychiatric disturbances, such as
aggression, anxiety, depression, insomnia, and
nightmares, particularly in children and young
adults.
• Rare but serious reactions can include severe
hypersensitivity and Churg–Strauss
syndrome, a systemic eosinophilic vasculitis.
Adverse Effects of 5-Lipoxygenase (5-LOX)
Inhibitors
• Gastrointestinal: indigestion, abdominal
pain, diarrhea
• Neuromuscular/Systemic: headache, muscle
pain, weakness
• Hematologic: leukopenia (low white blood
cell count)
• Hepatic: elevated liver enzymes, hepatitis,
jaundice, rarely liver failure
• Neuropsychiatric: behavioral changes,
suicidal ideation (reported with some agents)
 Angiotensin
• It is a peptide hormone that causes
vasoconstriction and an increase in blood
pressure.
• It is part of the renin–angiotensin–aldosterone
system, which regulates blood pressure.
• Angiotensin stimulates the release of
aldosterone from the adrenal cortex to
promote sodium retention by the kidneys.
• Angiotensin I Angiotensin II Angiotensin
III Angiotensin IV
• The enzyme responsible for conversion is;
angiotensin converting enzyme.
 Clinical application of RAAS inhibitors
• The renin–angiotensin–aldosterone system (RAAS) is an important
therapeutic target for managing conditions such as hypertension, heart
failure, and diabetic nephropathy.
• Over activation of RAAS contributes to the progression of these diseases,
and RAAS inhibitors are used to counteract its harmful effects.
• Recent studies also highlight broader applications of RAAS modulation.
• In septic shock, RAAS activation can serve as a vasopressor mechanism,
while in cancer treatment, RAAS inhibitors are being investigated for their
potential to reduce cardiovascular toxicities associated with certain
therapies.
 Renin inhibitors
• These are antihypertensive agents,
with Aliskiren being the first
approved oral agent, that block the
initial step of the renin-angiotensin-
aldosterone system (RAAS) by
directly inhibiting renin, an enzyme
that breaks down angiotensinogen
into angiotensin I.
• This action reduces the production of
angiotensin II, a potent
vasoconstrictor, thereby lowering
blood pressure (↓BP).
• Renin inhibitors are primarily used to treat essential
hypertension and, in some cases, can be combined
with other RAAS inhibitors for enhanced
antihypertensive effects or for proteinuria reduction
in conditions like diabetic kidney disease
• Adverse effects of Aliskiren:
• Gastrointestinal: stomach pain, nausea, vomiting
• Respiratory: difficulty with breathing
• Cardiovascular: irregular heartbeat
• Neurological: confusion, nervousness
• Neuromuscular: numbness or tingling in the
hands, feet, or lips; weakness or heaviness of the
legs
Angiotensin-Converting Enzyme (ACE)
inhibitors
• These are a class of agents that lower
blood pressure and treat cardiovascular
conditions by blocking the production of
angiotensin II, a hormone that constricts
blood vessels.
• They are commonly used for hypertension,
heart failure, diabetes, and certain kidney
diseases.
• Examples of ACE inhibitors include:
• Captopril, Enalapril, Fosinopril
Lisinopril, & Ramipril.
• Side effects
• Dry cough.
• Too much potassium in the blood.
• Extreme tiredness or dizziness from
blood pressure going too low.
• Headaches.
• Loss of taste.
• Rarely, short-term worsening of
kidney function.
Angiotensin receptor blockers (ARBs)
• These are agents that treat high blood pressure,
heart failure, and chronic kidney disease by
blocking the effects of the hormone angiotensin II,
which causes blood vessels to constrict and raises
blood pressure.
• These agents act by preventing angiotensin II from
binding to its receptor, leading to vasodilation
(widening of blood vessels), reduced sodium and
water retention, and lower blood pressure.
• Common ARBs include Candesartan, eprosartan
irbesartan, losartan, valsartan, and they are
characterized by names ending in "-sartan".
Angiotensin receptor blockers
(ARBs)
• ARBs are generally well tolerated, but they
can cause certain adverse effects.
• Common side effects include dizziness,
hyperkalemia (elevated potassium levels),
and worsening renal function.
• Less common but serious reactions include
angioedema, a potentially life-threatening
swelling of the face, tongue, or throat.
• ARBs are contraindicated in pregnancy due
to fetal risks and should be used with caution
in patients with severe hypotension or pre-
existing kidney disease.