Transcript 2nd T. 7th L. Updated

Pharmacology-1 PHL 211
2nd Term
7th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Para-aminophenol Derivatives: Acetaminophen
(Paracetamol)
 Paracetamol is one of the most important drugs used for the treatment of
mild to moderate pain when an anti-inflammatory effect is not necessary
 It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and
possesses no significant anti-inflammatory effects. Paracetamol may
inhibit a third enzyme, COX-3, in the CNS
 Paracetamol is administered orally. Absorption is related to the rate of gastric emptying,
and peak blood concentrations are usually reached in 30-60 min. It is slightly bound to
plasma proteins and is partially metabolized by hepatic microsomal enzymes & converted
to acetaminophen sulfate and glucuronide, which are pharmacologically inactive
 Less than 5% of paracetamol is excreted unchanged. A minor but highly active metabolite
(N-acetyl-p-benzoquinone “NAPQI”) is important in large doses because it is toxic to both
liver and kidney. The t1/2 of acetaminophen is 2-3 hrs and is relatively unaffected by renal
function. With toxic doses or liver disease, the t1/2 may be increased twofold or more
 Paracetamol is useful in mild to moderate pain such as headache, myalgia, postpartum
pain, and other circumstances in which aspirin is an effective analgesic
 For mild analgesia, paracetamol is the preferred drug in patients allergic to aspirin or
when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemophilia
(it lacks platelet-inhibiting properties) or a history of peptic ulcer and in those in whom
bronchospasm is precipitated by aspirin
 Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents. It is
preferred to aspirin in children with viral infections
Para-aminophenol Derivatives: Acetaminophen
(Paracetamol)
 Adverse Effects
In therapeutic doses, a mild increase in hepatic enzymes may occasionally occur in the
absence of jaundice; this is reversible when the drug is withdrawn.
Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal
pain. Cases of renal damage without hepatic damage have occurred, even after usual
doses of paracetamol. N-acetylcysteine (NAC) can neutralize toxic paracetamol
metabolites
• NAC functions by detoxifying NAPQI. It both repletes GSH stores and may conjugate
directly with NAPQI by serving as a GSH substitute. NAC may protect against
extrahepatic injury by its antioxidant and antiinflammatory properties
With larger doses, dizziness, excitement, and disorientation are seen. Ingestion of 15
g of paracetamol may be fatal, death being caused by severe hepatotoxicity with
centrilobular necrosis, sometimes associated with acute renal tubular necrosis. Doses
greater than 4 g/d are not recommended
Caution is necessary in patients with any type of liver disease
Glucocorticoids, Overview
 The adrenal cortex synthesizes two classes of steroids: the corticosteroids
(glucocorticoids and mineralocorticoids), and the androgens
 The actions of corticosteroids are described as glucocorticoid (carbohydrate metabolismregulating) and mineralocorticoid (electrolyte balance-regulating), reflecting their
preferential activities
 In humans, cortisol (hydrocortisone) is the main glucocorticoid and aldosterone is the
main mineralocorticoid
 The mineralocorticoids regulate water and electrolyte balance ( Na+ retention, associated
with a passive reabsorption of water, as well as the active secretion of K +)
 The glucocorticoids have widespread actions on intermediate metabolism, affecting
carbohydrate and protein metabolism and innate and acquired immune responses
 Glucocorticoids are most commonly employed for their anti-inflammatory and
immunosuppressive properties. Under these circumstances, all their metabolic and other
actions are seen as unwanted side effects
 Adrenocorticotrophic hormone (corticotrophin, ACTH) is the anterior pituitary secretion that
controls the synthesis and release of the glucocorticoids at the adrenal cortex
 ACTH secretion is positively regulated by corticotrophin-releasing factor (CRF) released
from the hypothalamus and vasopressin from the posterior gland, and negatively by blood
glucocorticoids. The release of CRF is inhibited by the level of glucocorticoids in the blood.
This functional hypothalamic-pituitary-adrenal unit is referred to as the HPA axis
 Common glucocorticoids used include hydrocortisone, prednisolone and dexamethasone
Mechanism of Glucocorticoid Action
 The glucocorticoid effects are initiated by
interaction of the drugs with specific intracellular
glucocorticoid receptors belonging to the nuclear
receptor superfamily
 in the absence of the hormone, a heat-shock
protein, hsp90, binds to the glucocorticoid receptor
polypeptide and prevents folding into the active
conformation of the receptor
 Binding of the hormone causes dissociation of the
hsp90 stabilizer and permits conversion of
glucocorticoid receptor to the active configuration
 The active glucocorticoid receptor binds to +ve or
-ve glucocorticoid response elements present in
the promoters of target genes, thus bringing about
corresponding changes (induction or repression)
in transcription  actions (see next slide)
 The receptor is eventually recycled in an ATPdependent process and combined again with hsp90
in the cytoplasm to complete the cycle
Glucocorticoids, Actions
 Carbohydrate Metabolism: Glucocorticoids profoundly affect carbohydrate metabolism.
These glucocorticoids effects on intermediary metabolism can be viewed as protecting
glucose-dependent tissues (e.g., the brain and heart) from starvation
 They stimulate the liver to form glucose from amino acids and glycerol and to store glucose
as liver glycogen
 In the periphery, glucocorticoids diminish glucose utilization, increase protein breakdown
and the synthesis of glutamine, and activate lipolysis, thereby providing amino acids and
glycerol for gluconeogenesis. The net result is to increase blood glucose levels
 Because of their effects on glucose metabolism, glucocorticoids can worsen glycemic
control in patients with diabetes and can precipitate the onset of hyperglycemia in patients
who are otherwise predisposed
 Lipid Metabolism: Two effects of corticosteroids on lipid metabolism are firmly
established:
 The first is the dramatic redistribution of body fat. There is increased fat in the back of the
neck ("buffalo hump"), face ("moon face"), and supraclavicular area, coupled with a loss of
fat in the extremities (c.f. Cushing's syndrome)
 The other is the permissive facilitation of the lipolytic effect of other agents e.g., growth
hormone and b adrenergic receptor agonists, resulting in an increase in free fatty acids
Glucocorticoids, Actions
 Electrolyte and Water Balance:
 In non-physiological concentrations, the glucocorticoids have some mineralocorticoid
actions, causing Na+ retention and K+
 Glucocorticoids tend to produce a negative calcium balance by decreasing Ca2+ absorption
in the gastrointestinal tract and increasing its excretion by the kidney. This may result in
osteoporosis
 Antiinflammatory and Immunosuppressive Actions:
 Glucocorticoids can prevent or suppress inflammation in response to multiple stimuli,
including radiant, mechanical, chemical, infectious, and immunological stimuli
• They have suppressive effects on mediators of inflammation
• They cause vasoconstriction and decrease capillary permeability (by reducing the
amount of histamine released by basophils and mast cells)
 Glucocorticoids are of immense value in treating diseases that result from undesirable
immune reactions such as urticaria and transplantation rejection
Glucocorticoid increase the concentration of neutrophils in the circulation (due to
decreased migration from the blood vessels, leading to a reduction in the number of
cells at the site of inflammation) while decrease that of the lymphocytes, monocytes,
eosinophils and basophils (due to their movement from the vascular bed to lymphoid
tissue). They also inhibit the functions of tissue macrophages and other APCs
 The immunosuppressive and antiinflammatory actions of glucocorticoids are linked, perhaps
because they both involve inhibition of leukocyte functions
 Glucocorticoids also influence the inflammatory response by reducing expression of
proinflammatory enzymes, such as COX-2 and NOS2 and by reducing PGs & leukotriene
Glucocorticoids, Actions & Side Effects
 Catabolic and anti-anabolic effects:
 Although glucocorticoids stimulate RNA and protein synthesis in the liver, they have
catabolic and anti-anabolic effects in lymphoid and connective tissue, muscle,
peripheral fat, and skin
 Supraphysiologic amounts of glucocorticoids lead to a number of catabolic actions,
including decreased muscle mass and weakness, negative nitrogen balance and
thinning of the skin
 Catabolic and anti-anabolic effects on bone are the cause of osteoporosis in
Cushing's syndrome and impose a major limitation in the long-term therapeutic use of
glucocorticoids
 In children, glucocorticoids reduce growth
 Therapeutic uses:
 Physiological replacement: Any glucocorticoid can be given in a dose that provides
approximately the same glucocorticoid effects as normal cortisol production; this is
referred to as physiologic, replacement, or maintenance dosing in patients with
adrenal insufficiency (e.g., Addison’s disease)
 In higher doses, glucocorticoids are used to suppress various allergic, inflammatory
and autoimmune disorders (e.g., bronchial asthma, allergic rhinitis, drug
hypersensitivity reactions, osteoarthritis, ankylosing spondylitis, rheumatoid arthritis)
 They are also administered as post-transplantory immunosuppressants to prevent the
acute transplant rejection
Glucocorticoids, Actions & Side Effects
 Side effects:
 Suppression of the response to infection; an opportunistic infection can be potentially
very serious unless quickly treated with antimicrobial agents
 Wound healing may be impaired
 Peptic ulcer with possible perforation and hemorrhage
 When these drugs are used in anti-inflammatory and immunosuppressive therapy, the
metabolic actions and the effects on water and electrolyte balance and on organ
systems are considered unwanted side effects, and Cushing's syndrome may occur.
Osteoporosis, with the hazard of fractures, is probably one of the main limitations to
long-term glucocorticoid therapy
 Hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired
glucose tolerance ("steroid diabetes"); caution in those with diabetes mellitus
 Weight gain due to increased visceral and truncal fat deposition (central obesity) and
appetite stimulation
 Hypertension due to sodium and fluid retention
 Adrenal insufficiency (if used for long time and stopped suddenly without a taper)
 Muscle breakdown (proteolysis), weakness; reduced muscle mass and repair
 Suppression of growth in children and pubertal delay