autonomic nervous system pharmacolgy
TRANSCRIPT
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AUTONOMIC NERVOUS SYSTEM
PHARMACOLGY
NERVOUS SYSTEM
PERIHERAL CENTRAL
AFFERENT EFFERENT
AUTONOMIC SOMATIC
(Involuntary control of (voluntary control of
visceral functions) skeletal muscle)
ANTOMICALLY PHYSIOLOGICALLY
* Sympathetic * Adrenergic
* Parasympathetic * Cholinergic
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The involuntary effector organs controlled by A.N.S. are:
a) Heart: Cardiac properties include: Automaticity, rhythmicity, Conductivity,
Excitability and Contractility.
b) Smooth muscle fibers (SMF):
1- Blood vessels
2- Eye: dilator pupillae muscle (DPM), constrictor pupillae muscle (CPM), and ciliary
muscle & ciliary body.
3- Bronchi
4- GIT & Urinary bladder: both the wall and sphincters.
5- Sex organs: The uterus - the male sex organs.
c) Exocrine glands:
Including salivary, lacrimal, bronchial, gastric (secreting HCl), intestinal, and sweat
glands.
❖ Differences between sympathetic and parasympathetic divisions of ANS
Sympathetic Parasympathetic
1- Neurotransmitter Major: noradrenaline (NA)
and adrenaline
Major: acetylcholine (Ach)
2- Function:
• CVS:
• SMF:
*Bl.vesseles
* ↑ HR, contractility, AVN
conduction
* V.C. of blood vessels
except skeletal & coronary
→ VD
* ↑ blood pressure
* HR, AVN conduction
No effect (most blood vessels
contain non-innervated
muscarinic receptors)
* blood pressure
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* eye
*Bronchi
*GIT & urinary
* Sex organs
• Exocrine gl.:
* salivary
* sweat
Mydriasis
Dilatation
Relax wall and contract
sphincters
Ejaculation in male
↑ secretion (scanty, viscid)
↑ sweat
Miosis, accommodation for
near vision, IOP
Constriction
Contract wall and relax
sphincters
Erection in male
↑secretion (profuse, watery)
No effect
CHOLINERGIC PHARMACOLOGY
• Acetylcholine (Ach) is a major neurohumoral transmitter at autonomic,
somatic as well as central sites
• Ach mediates its effects by activating muscarinic & nicotinic cholinergic
receptors present centrally & peripherally:
I. Muscarinic receptors: M1,2,3,4,5
M1 receptors M2 receptors M3 receptors
coupled to Gq → PLC
→ ↑ DAG & IP3 →↑Ca++
* coupled to Gi → adenylate
cyclase
coupled to Gq → PLC
→ ↑ DAG& IP3 →↑Ca+
• CNS:
a. a. Arousal, learning,
short-term memory and
control of movement
Gastric:
a. ↑ HCL
• Heart:
a. SAN & AVN → ↓ heart
rate & AVN conduction
• SMF:
- Vascular endothelium → NO
release → VD → ↓ BP.
- Bronchi → spasm
- Eye → - miosis
- accommodation for near
vision - ↓IOP
- GIT,Ur.→ wall & relax
sphincters &
Exocrine glands:↑All secretions
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II. Nicotinic receptors : ligand-gated Na+ ion channels:
• Neuronal (NN): in all autonomic ganglia & adrenal medulla
• Muscle (NM): at NMJ →skeletal muscle depolarization → contraction.
Actions of Ach:
I. Muscarinic actions:
1. CVS:
a. Heart: - ↓ HR→↓ COP & ↓AVN conduction
b. Blood vessels: VD
c. Blood pressure: hypotension
2. Eye:
a. Miosis b. IOP
c. Accommodation for NEAR vision d. ↑ lacrimation
3. Respiration:- Bronchospasm - ↑ bronchial secretions
4. GIT & Ur.Bladder: - Contract the wall - Relax the sphincters
5.Exocrine glands:↑ all secretions (watery secretions)
II. Nicotinic actions (Ach large dose):
1. Hypertension (Nn in autonomic ganglia & adrenal medulla)
2. Skeletal muscle twitches (Nm in neuromuscular junction)
Uses of Ach: Not used clinically
- Not absorbed orally -Rapidly hydrolysed→ very short duration
- Non specific → stimulates all (M) receptors
CLASSIFICATION OF CHOLINOMIMETICS
Carbachol
Bethanechol
II. Indirectly acting
(choline esterase
Inhibitors; ChEIs)
I. Directly acting
(cholinergic receptors
agonists)
Neostigmine
Physostigmine
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Directly acting (Carbachol & Bethanechol):
Uses:
1. Glucoma (eye drops)
2. Non-obstructiveUrine retention e.g. postoperative
3. Non-obstructiveParalytic ileus e.g. postoperative
4. Neurogenic bladder
5. Gastroesophageal reflux
Choline Esterase Inhibitors (ChEIs)
Anti-cholinestrases
Mechanism of Action
• ChEIs act indirectly by inhibiting choline esterase → accumulation of ACh.
Physostigmine (Eserine) Neostigmine(Prostigmine)
Nature: 3ry amine 4ry ammonium
Kinetics: - Well absorbed orally
- Pass BBB & conjunctiva
- Poor oral absorption
- NOT Pass BBB & conjunctiva
Dynamics: - Mainly muscarinic & weak
nicotinic effects
- CNS stimulation
- Muscarinic & Nicotinic effects
- Direct skeletal muscle stimulation
Uses: 1. Miotic
2. Atropine toxicity (correct central
& peripheral effects)
1. Non-obstructive paralytic ileus &
urine retention
2. Myasthenia gravis
3. Antidote to neuromuscular
blockers (Nicotinic + Direct)
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Adverse effects and contraindications:
Adverse effects contraindications
1-Bradycardia.
2-Slow AV conduction.
3-Hypotension.
4-Bronchospasm + ↑ secretions
5-↑ HCl secretion.
7. ↑ Secretions: lacrimat., saliva....
8. Urination
9. Nausea,Vomiting, Diarrhea, Colic
6- Drugs passing B.B.B. worsen
parkinsonism
1-Bradycardia.
2-AV block (heart block).
3-Hypotension.
4-Bronchial asthma.
5-Peptic ulcer.
6-Carbachol, bethanechol, physostigmine are
contraindicated in parkinsonism
ANTIMUSCARINIC AGENTS
Atropine
• It is a 3ry ammonium → well absorbed from GIT, conjunctiva & can cross BBB.
Mechanism of Action
• Atropine causes reversible competitive blockade of the actions of Ach at
muscarinic receptors
Pharmacological Actions
1. CNS
• Stimulates cardioinhibitory center (vagal nucleus) → initial bradycardia
• Respiratory center stimulation.
• Antiemetic (blocks M1 receptors in vestibular pathway).
• Antiparkinsonian (blocks M1 receptors in basal ganglia).
• Stimulation of vasomotor center
• High doses → cortical excitation followed by depression
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2. Eye
• Passive Mydriasis ( paralysis of constrictor pupillae).
• Cycloplegia (ciliary muscle paralysis
& loss of accommodation for near vision).
• ↓ Aquous out flow → ↑IOP → acute glaucoma
3. Secretions
• ↓ Salivation (→ dry mouth), ↓ lacrimation (→ dry sandy eyes).
• ↓ Sweating (→↑ body temperature) (???)
• ↓ bronchial secretions.
• ↓Gastric secretion
4. Smooth Muscle
• GIT& Urinary: relaxes wall & contracts sphincters → constipation, urine
retention & antispasmodic.
• Bronchi: Bronchodilation.
5. CVS
• Tachycardia (mainly) & ↑AVN conduction (blocks M2 receptors).
• Tachycardia+ VMC stimulation → ↑ BP
Clinical Uses Atropine
1. Preanesthetic medication → inhibits secretions - dilates bronchi - antiemetic -
inhibits bradycardia - stimulates respiration.
2. Heart block - bradycardia.
3. Antiemetic in motion sickness
4. Organophosphate poisoning.
Adverse effects of atropine
1.Confusion, restlessness → hallucinations, delirium & mania
2. Dry mouth and skin
3. Hyperthermia (complete skin dryness)
4. Vasodilation & flushing
5. Tachycardia.
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6. Blurred vision - photophobia
7. Acute glaucoma in patients with narrow anterior chamber
8. Urine retention in old patients with enlarged prostate
9. Constipation.
Contraindications:
1. Glaucoma
2. Enlarged prostate.
ADRENERGIC PHARMACOLOGY
Adrenergic Neurotransmitters (endogenous catecholamines)
1. Norepinephrine (NE) = Noradrenaline
2. Epinephrine = Adrenaline
3. Dopamine (DA)
Classification of Adrenergic Receptors:
I-ALPHA (α):
α1 α2
Coupled to Gq → PLC → ↑IP3&
DAG →↑Ca2+ & PKC
Coupled to Gi → adenylate cyclase
→↓ cAMP → PKA
1. Vasoconstriction
2. Relaxation of walls & Contraction of
sphincters of GIT & urinary tracts.
3. Contraction of prostate & vas deferens.
4. Active mydriasis.
5. ↑ Liver glycogenolysis & K+ release.
1. ↓ Central sympathetic outflow → ↓BP.
2. ↓ Lipolysis.
3. ↓ Insulin secretion (predominant).
4. ↓ Renin release.
5. ↑ Platelet aggregation.
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II- BETA (β):
β1 β2
Coupled to Gs protein→ adenylate cyclase →↑cAMP → PKA
1. Cardiac stimulation.
2. Lipolysis → ↑ plasma FFA
3. ↑Renin secretion.
1. Bronchodilation & mast cell stabilization.
2. Vasodilation of skeletal & coronary blood
vessels.
3. Uterine and intestinal relaxation.
4. ↑ Liver & muscle glycogenolysis and k+
uptake.
5. Skeletal muscle tremors
β3 ↑ Lipolysis → ↑ plasma FFA
III. DOPAMINE RECEPTORS
D1: Vasodilation of blood vessels. D2: in CNS
Sympathomimetic Drugs
Classification According to Mechanism of Action
Adrenergic Receptor Agonists
NE:
1 2 1
1. Endogenous
Neurotransmitters
Epinephrine:
1 2 1 2
2. Agonists 3. Agonists
Clonidine
Selective 2
Salbutamol
Selective 2
A. Direct Acting
B. Indirectly Acting
• Amphetamine
N.B.:
• Selective α2- agonists are sympatholytics as they ↓ NE release.
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A. Endogenous Catecholamines
1. Epinephrine
Pharmacological actions
I. Cardiovascular System
A. Heart (1)
• ↑Force of contraction (positive inotropic).
• ↑ Heart rate (positive chronotropic).
• ↑ Conduction velocity (positive dromotropic) in atria, A-V node, conductive
tissues & ventricles.
• ↑ Automaticity → Arrhythmias.
B. Blood vessels
• VC of arterioles of skin, mucosa, splanchnic & renal vessels (α1).
• VC of veins (α1).
• Vasodilatation of skeletal & coronary vessels (β2 effect).
C. Effects on Blood Pressure
Large dose: ↑ systolic & diastolic BP →↑mean BP through:
• Vasoconstriction of arterioles and veins (1).
• Positive chronotropic & inotropic actions (1)
II. Respiratory System:
• Bronchodilatation (β2 action).
• Decongestion of BV of mucous membrane of upper respiratory tract (α1).
III. Eye
• Contraction of dilator pupillae (α1) → Active mydriasis
• ↓ IOP by decreasing aqueous humor formation.
IV. Effect on other smooth muscles
• Relaxation of GIT wall (, , α 2).
• Contraction of sphincters of GIT & urinary tracts (1).
• Inhibition of uterine tone & contractions in last months of pregnancy (2).
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V. Metabolic actions
• Hepatic & skeletal muscle glycogenolysis → β2 (mainly) & α1.
• Insulin release → inhibited (α2)
• Lipolysis (β1 & β 3).
• ↑ Renin release (β1)
• ↓ serum K+ (by renin release; β1 & ↑ hepatic uptake; β2)
VI. CNS: mild stimulation → Anxiety.
VII. Skeletal muscle: tremors
Therapeutic Uses
1. Anaphylactic shock (reverses bronchospasm & hypotension → life saving).
2. Asthma (2 - agonists are preferred).
3. Cardiac Arrest.
4. Arrests bleeding (topical hemostatic →VC, e.g. in epistaxis).
5. Added to local Anesthetics to prolong their action.
6. Open Angle glaucoma (↓ IOP).
Adverse effects:
1. CNS: Anxiety, restlessness
2. CVS: Hypertension → cerebral hemorrhage
Arrhythmia & Angina
3. Eye: Blurred vision
4. Skeletal muscle tremors
5. Gangrene if injected around finger or toe
Contraindications:
1. Around finger, toe & circumcision
2. Hypertension, cerebral hemorrhage
3. Patients on beta-blocker therapy (unopposed alpha → sever HTN)
4. Ischemic heart disease
5. Arrhythmia, with Digitalis & General anesthesia
6. Thyrotoxicosis
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2. Norepinephrine (Noradrenaline) • Acts on α & β1 receptors (minimal effect on β2 receptors).
• α effect → marked vasoconstriction →↑↑ BP.
• β1 effect → positive inotropic & chronotropic effect.
• Marked ↑↑ BP → reflex bradycardia which overcomes its direct positive
chronotropic effect
• Used in shock:
Septic - cardiogenic
B. α2-Agonists (sympatholytic)
C. β- agonists
Selective β2 agonists
Therapeutic uses
1. Bronchial asthma (salbutamol - salmeterol).
2. Prevent premature labor & threatened abortion (terbutaline & ritodrine).
Adverse effects (less with inhalation therapy):
1. Anxiety, restlessness and headache.
2. Tremors of skeletal muscle.
3. Tachycardia (at high concentration they stimulate β1 receptors).
4. Tolerance on long term systemic use (β receptor downregulation).
5. Hypokalemia and muscle cramps. 6. Hyperglycemia
D. Indirectly Acting Sympathomimetics
Amphetamine
Mechanism of actions: ↑ release NE centrally & peripherally →
A. CNS:
- CNS stimulation - alertness - ↓ fatigue - marked mood elevation
- Appetite Suppression
B. CVS: ↑ arterial blood pressure → reflex bradycardia.
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Therapeutic uses (CNS):
1-Attention deficit hyperactivity disorder (ADHD) in children
2. Obesity
Adverse effects:
1. CNS:
- Psychological dependence - schizophrenia-like syndrome.
- Anorexia & weight loss
- Insomnia & tremors → depression & fatigue (depletion of CA store).
- Convulsion → coma & cerebral hemorrhage (severe toxicity)
2. CVS: palpitation, arrhythmia, anginal pain and hypertension
Sympatholytic Drugs A. α2-Agonists
Clonidine
Mechanism of Action
1. Activates central α2 receptors → ↓central sympathetic outflow → ↓ BP.
3. Stimulates peripheral α2 receptors → ↓ renin & aldosterone.
Uses
1. Preanesthetic medication (sedative & analgesic).
2. Morphine withdrawal
3. Menopausal hot flushes.
4. Migraine prophylaxis
5. Hypertensive urgencies.
Adverse effects
1.Sympatholytic: Sedation - Sexual dysfunction - Dry mouth - Diarrhea
Peptic ulcer aggravation – Bradycardia.
2. Salt and water retention → Tolerance & Weight gain.
3. Rebound hypertension: treated by α & β blockers e.g. labetalol.
Sympathetic discharge
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B- α-antagonists
Selective α1 blockers Prazosin- Doxazosin
I. Cardiovascular actions
1. Vasodilators:
a. ↓blood pressure.
b. postural hypotension.
2. Tachycardia
3. Fluid retention on prolonged use (compensatory ↑ in blood volume).
II. Other actions
• Block α receptor at base of bladder & prostate →↓ resistance to urine flow→
useful in benign prostatic hyperplasia (BPH).
• Relaxation of vas deferens→ inhibition of ejaculation.
• Miosis - Nasal congestion.
Therapeutic uses of α blockers
1. BPH.
2. Essential hypertension
3. Hypertensive emergencies
- In most hypertensive emergencies (labetalol)
5. Raynaud's disease
Adverse Effects of αblockers
1. 1st dose postural hypotension: ↓ by giving small dose (1 mg) at bed time.
2. Tachycardia.
3. Impaired ejaculation and sexual dysfunction.
4. Nasal congestion, flushing, headache.
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C. β-Blockers
• Bs antagonize the effects of catecholamines at -adrenoceptors.
• Different Bs are distinguished by:
1. Relative selectivity for 1 & 2 receptors
2. Differences in lipid solubility
3. Vasodilator effects.
Members of Different Generations of Bs
Lipophilic Hydrophilic
Non-selective Bs • Propranolol • Nadolol
Selective Bs =
cardioselective Bs
• Metoprolol • Atenolol
• Esmolol
Vasodilator Bs • Carvedilol
Pharmacokinetics of β-blockers
Lipophilic Hydrophilic
Absorption • Well absorbed • Irregularly absorbed
First pass effect • Extensive • Less
Bioavailability • Less • More
Distribution • More CNS penetration →
more CNS side effects
• Less CNS penetration → less
CNS side effects
Elimination • Mainly hepatic → suitable
in renal impairment.
• Mainly renal → suitable in
hepatic impairment.
t½ • Short t½ → frequent
administration.
• Long t½ (except esmolol) →
once/ day administration.
• Esmolol is hydrophilic, yet it has a very short duration of action (t1/2 8 min) due to
hydrolysis by plasma esterases.
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Pharmacological Actions of βBs
A. Cardiovascular Actions
1. Antianginal effect:
- ↓ HR
- ↓myocardial contractility.
- ↓ BP.
2. Antiarrhythmic effect
• ↓ SAN rate & AVN conduction.
• Phase 4 slope → slow automaticity of ectopic focus.
3. Antihypertensive effect
• renin release
• -ve inotropic & chronotropic effects.
• Resetting of baroreceptors.
• Some β-blockers are vasodilators.
4. Vasoconstriction (unopposed actions)
• In Eye: ↓ IOP.
• In GIT →↓ hepatic blood flow.
• In skeletal muscles → ↓ blood flow during exercise→ ↓work capacity.
B. Non-cardiovascular Actions
1. Respiratory: bronchoconstriction .
2. Metabolic
• Inhibit sympathetic-induced glycogenolysis→ delay recovery from hypoglycemia.
• Inhibit sympathetic-induced lipolysis.
• ↑ Plasma TGs (↑ VLDL) - ↓ HDL.
• ↓ Insulin release.
• ↑ Plasma K+ during exercise (inhibit uptake by liver). 3. CNS (lipophilic Bs): CNS depression - anxiolytics.
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Therapeutic Uses
1. Hypertension
2. Angina pectoris
3. Arrhythmias.
4. Heart failure (???)
5. Open-angle glaucoma
6. Prophylactic in oesophageal varices
7. Essential tremors.
8. Acute dissecting aortic aneurysm
9. Social anxiety disorder
Adverse effects, contraindications & precautions
1. Bradycardia
2. Heart Block.
3. Heart failure
4. Hypotension
5. Hypertriglyceridaemia.
6. Cold extremities, fatigue & Claudications
7. Bronchospasm
8. Prolongation of insulin-induced hypoglycemia.
9. Mask warning symptoms of hypoglycemic coma (tachycardia)
10. Hyperkalemia in susceptible patients (e.g. renal impairment & DM).
11. CNS effects: nightmares & depression.
12. Abrupt cessation → rebound angina & arrhythmias (due to up regulation of
ß receptors)
13. Sexual dysfunction (impotence may be due to VC and ↓ blood pressure in
erectile tissue of penis).
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AUTACOIDS & RELATED DRUGS
• Autacoids are biologically active substances of heterogenous chemical
structures, which may be involved in some pathological conditions, and
are known as "Locally- acting hormones".
Classification:
• Autacoids are classified chemically into:
a) Amino Acid derivatives:
1. Histamine (derived from histidine).
2. Serotonin = 5-Hydroxytryptamine (5-HT; derived from tryptophan).
b) Vasoactive Peptides:
1. Angiotensin.
2. Kinins
3. Substance P.
4. Endothelin.
5. Vasoactive Intestinal Peptide (VIP).
6. Atrial Natriuretic Peptide (ANP).
c) (Fatty acid derivatives):
1. Eicosanoids: Prostaglandins & Leukotrienes.
2. Platelet Activating Factor (PAF).
d) Others: Cytokines as interferons
HISTAMINE (HI)
Synthesis: by decraboxylation of the amino acid L-histidine with L-aromatic
amino acid decarboxylase enzyme.
Storage: in storage granules inside mast cells (with heparin), in basophils, and
other cells (in most tissues e.g. lung, skin & GIT).
Release:
Decarboxylase
L-histidine Histamine
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• Histamine liberation: HI liberators are basic drugs (e.g. morphine, atropine,
curare, hydralazine) that replace HI in storage granules without degranulation.
• Immunogenic release: interaction of antigenic drugs (e.g. penicillin) with IgE
on surface of sensitized mast cells →↑ intracellular calcium & release of the
whole histamine- containing granules (exocytosis).
Mechanism of action:
• Histamine stimulates specific G-protein coupled receptors:
Receptor Signal transduction Sites Actions
H1 Gq→ activation
PLC→ ↑DAG and
IP3→↑ Ca2+.
1. Smooth muscle fibers
as bronchi, GIT, uterus.
2. Endothelium of Bl.vessel
3. Skin & sensory nerve end.
4. CNS (post-synaptic).
5. Vestibular system
1. Spasmogenic effect.
2. Vasodilatation &
↑ capillary permeability.
3. Itching, urticaria, pain.
4. Alertness.
5. Vomiting
H2 Gs→ activation of
A.C.→ ↑c-AMP.
1. Gastric Parietal cells
2. Heart.
3. Blood vessels.
4. CNS (post-synaptic).
1. ↑ secretion of HCl and
pepsin.
2. ↑ cardiac properties (+ve
inotropic & chronotropic).
3. Vasodilatation.
4. Alertness.
H3
Gi → inhibition of
A.C.→↓ c-AMP
CNS (pre-synaptic) ↓ Release of
neurotransmitters
H4 Inflammatory cells as:
T-lymphocytes, Neutrophils,
Esinophils.
Modulation of cytokines.
Role of histamine
1. Allergy: immediate hypersensitivity reactions:
a. Local allergic response: localized H1 receptors stimulation on blood
vessels & nerve endings →
i. Redness.
ii. Edema.
iii. Pain & itching.
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b. Anaphylactic shock: generalized H1 receptors stimulation → marked
hypotension.
c. Bronchospasm.
2. Vomiting of vestibular origin (e.g. motion sickness) is H1-receptor mediated.
3. Peptic ulcer: H2 receptors mediate more than 70% of HCl secretion.
4. Heart: myocardial stimulation, ↑ heart rate
5. CNS: alertness
Drugs that antagonize the action of histamine
1. Pharmacological Antagonists:
a) H1-Antagonists = Antihistaminics = Antiallergic drugs.
b) H2-Antagonists: Cimetidine-Famotidine → treatment of peptic ulcer.
2. Physiological Antagonist:
Adrenaline is the physiological antagonist of histamine
3. Inhibitors of Histamine release:
a) Glucocorticoids: inhibit antibody formation and antigen-antibody reaction,
→ inhibit histamine release.
b) Mast Cell Stabilizers = Degranulation inhibitors: as cromolyn, nedocromil
4. Desensitization.
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H1-ANTAGONISTS (ANTIHISTAMINICS-
ANTIALLERGICS)
• All antihistaminics are competitive antagonists with histamine on H1-
receptors.
• All antihistaminics are "Antiallergic drugs" used in treatment of allergic
conditions such as: skin rash- urticaria- angioneurotic edema-anaphylactic
shock (Adrenaline is life-saving in anaphylactic shock).
Pharmacokinetics:
1. They can be given orally, parenterally, and topically as skin ointment, eye
drops, nasal drops and ear drops.
2. "First generation" antihistaminics can pass easily B.B.B. whereas "Second
generation" drugs poorly penetrate B.B.B.
3. Pass placental barrier and (may be teratogenic in experimental animals
"Cyclizine & Meclizine").
4. Metabolized by the liver and excreted in urine, and are partly excreted in
breast milk.
Classification:
1st Generation = Sedating Antihistaminics 2nd Generation= less sedating Antihist.
●Pass B.B.B. → sedation and drowsiness,
but toxic doses → hallucination, excitation and
convulsions.
●They block H1 and M receptors in the
medullary vomiting center → anti-emetic
● They block M receptors in basal ganglia →
anti-parkinsonian action
● Short duration (6 hours) due to rapid
metabolism by hepatic microsomal enzymes.
●Poor passage through B.B.B. → No CNS
actions, i.e. No sedation & No antiemetic.
● Long duration (24 hours) due to
slower metabolism by hepatic microsomal
enzymes.
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Actions:
1. Antihistaminic action: antagonize the actions
of histamine on H1-receptors in blood vessels,
bronchi, GIT, and skin.
2. Antimuscarinic (Atropine-like) action →
a) Antiemetic action including motion sickness.
b) Antiparkinsonian action.
c) Urine retention (contraindicated in BPH).
d) ↑IOP (contraindicated in glaucoma).
3. Some have Antiserotonin action → ↑appetite;
e.g. Cyproheptadine.
4. Some block Na+-channels (Membrane
stabilizing action) → Local anaesthetic and
Antiarrhythmic action (Quinidine-like action);
e.g: Antazoline.
5. α-blocking action.
Actions:
1. Antihistaminic action.
2. NO Atropine-like action →
a) NOT Antiemetic
b) NOT Antiparkinsonian action.
c) NOT contraindicated in BPH.
d) NOT contraindicated in glaucoma.
3. NO Antiserotonin action
4. NO block Na+-channels
5. NO α-blocking action
Examples:
• Diphenhydramine (antiemetics and
antiparkinsonian).
• Meclizine and Cyclizine (antiemetic but
contraindicated in pregnancy, may teratogenic).
• Chlorpheniramine (common cold medication)
• Antazoline (antiarrhythmic).
• Cyproheptadine (antiserotonin→ appetizer)
• Ketotifen (antiserotonin & mast cell stabilizer)
Examples:
• Cetrizine
• Loratadine.
• Fexofenadine
Therapeutic uses:
1. Treatment of allergic conditions (allergic
rhinitis, rash, urticaria, angioneurotic edeme, and
anaphylactic shock).
Therapeutic uses:
1. Treatment of allergic conditions (allergic
rhinitis, rash, urticaria, angioneurotic edeme,
and anaphylactic shock).
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2. Antiemetics in motion sickness, vertigo
and Meniere's disease.
3. Parkinsonism (Diphenhydramine).
4. Arrhythmias (Antazoline).
5. Anxiety and insomnia (situational).
Adverse effects:
1. Sedation and drowsiness.
2. Excitation is more common in children
3. Teratogenicity (Cyclizine and Meclizine).
4. Allergic reactions.
5. Atropine-like adverse effects as dry mouth,
constipation, urine retention,
tachycardia, and elevation of IOP.
2. Acute toxicity: excitement, hallucinations,
convulsions, and may be coma.
Contraindications:
1-Car drivers.
2-Pregnancy.
3-Glaucoma.
4-BPH
Adverse effects:
Cardiac arrhythmias especially in overdose
or if given with HME inhibitors as
erythromycin & ketoconazole.
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EICOSANOIDS
• They are endogenous 20-C (eicosanoid) fatty acid derivatives with
profound physiological effects.
• They include:
1. Prostaglandins (PGs) & Thromboxanes (TXs)
2. Leukotienes (LTs)
• They are not stored in the body but are synthesized and rapidly
metabolized, they have very short duration
1. Prostaglandins (PGS) and Thromboxanes (TXS)
• Synthesis: they are synthesized from arachidonic acid by cyclooxygenase
enzyme (COX)
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• Mechanism of action:
PGs and TXA2 act on specific G-protein coupled receptors:
1. IP (Gs) receptors for PGI2 (prostacyclin).
2. DP1 (Gs), DP2 (Gi) receptors for PGD.
3. FP (Gq) receptors for PGF2.
4. EP1(Gq), EP2 (Gs), EP3 (Gi) and EP4 (Gs) receptors for PGE.
5. TP receptors (Gq) for TXA2.
Physiological Role of PGs Uses of PG Analogs
1. Role in Inflammation
PGE, I2 & D2 released from mast cells in acute
inflammation potentiate effects of histamine &
bradykinin (BK)→
a. VD.
b. ↑ capillary permeability.
c. ↑ pain induced by BK
2. Role in Pain (algesic action):
a. PGs → ↑ pain transmission in the thalamus
b. sensitize pain receptors to serotonin & kinins
(pain mediators).
3. Role in Fever (pyretic action):
Pyrogens→ release of interleukin-1(IL-1) from
inflammatory cells → Stimulates COX enz.→
↑production of PGE2→ elevates the set point
of hypothalamic heat regulating centre (HRC)
4. Kidney (PGE)
a. VD →↑ renal blood flow.
b. Inhibits Na+ reabsorption.
c. ↑ renin secretion.
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5. GIT:
a. Stomach: cytoprotective effects
PGE →
- ↓ gastric HCl.
- ↑ mucus secretion.
- ↑ HCO3 secretion
- ↑blood flow →↑ healing of damaged mucosa
b. Intestine: ↑ motility → colic, diarrhea
• Misoprostol (PGE): is given with
NSAIDs or Steroids to ↓ their
ulcerogenic effect
• S/E: Misoprostol → colic , diarrhea
6. CVS:
a. PGI2 → ↓ platelet aggregation, VD
b. TXA2 → ↑ platelet aggregation, VC.
c. PGE2 and PGI2 → maintain Patency of
ductus arteriosus.
d. PGE2 recently, is assumed that it induces
angiogenesis which may be the cause of
cancer colon
• Epoprostenol (PGI2)
- Prevents platelet aggregation in
dialysis machine
- used in peripheral vascular disease &
pulmonary hypertension.
• Alprostadil (PGE1):
Maintains patency of ductus
arteriosus in congenital pulmonary
stenosis until surgery is performed.
7. Reproduction
• Male: PGE → VD → erection & sperm
motility
• Females: PGF2 & PGE → stimulate
uterine contractions (oxytocic action) →
induction of labor, abortion and control
postpartum hemorrhage.
• Alprostadil:
In erectile dysfunction (impotence).
• Dinoprostone (PGE2):
Induction of labor
• Dinoprost/ carboprost (PGF2):for
induction of labor & abortion
8. Bronchial Tone
a. PGI2 - PGE → bronchodilation.
b. PGF2 - PGD2 - TXA2 → bronchospasm.
• PGF2 induces bronchospasm thus
9. Eye: PGF2 → ↑ aquous humor outflow
→↓IOP • Latanoprost (PGF2) used locally
in open angle glaucoma
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Effects of PGs Inhibition:
1. NSAIDs: they inhibit COX enzymes→↓ PG synthesis →
Analgesic, Anti-inflammatory and Antipyretic effect
2. Corticosteroids: induce inhibitory protein (Lipocortin) →
inhibit phospholipase-A2 → ↓ PGs, LTs & PAF
synthesis → - Anti-inflammatory effects
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2. Leukotrienes (LTs)
• Synthesis: LTs are synthesized from arachidonic acid by 5-lipooxygenase
enzyme (LOX).
• LTs include:
1. LTB4: powerful chemotactic agent → local accumulation of WBCs.
2. LTC4, D4 & E4 (Cysteinyl LTs):
▪ Previously named as slowly reacting substances of anaphylaxis (SRSA)
▪ act on specific Gq-protein coupled receptors (LT receptors) →
- potent bronchospasm
- ↑ mucus Mediators of asthma
- ↑ inflammatory reactions in bronchi
▪ Present in sputum of patients with asthma, chronic bronchitis & allergic
rhinitis.
• Inhibitors of LTs include:
1. Lipooxygenase inhibitors: zileuton.
2. LT receptor antagonists: zafirlukast and montelukast.
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NON-NARCOTIC ANALGESICS
• Analgesics are drugs that relieve pain due to multiple causes.
Classification of Analgesics
• Non-steroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous
group having anti-inflammatory, analgesic & antipyretic effects.
Cyclooxygenase Enzymes
• COX-1: constitutive (present normally in tissues regulating its
physiologic functions), forming protective PGs involved in the essential
physiological functions such as platelet aggregation, cytoprotection in the
stomach and maintenance of normal kidney function.
• COX-2: inducible (only expressed by inflammatory mediators such as
endotoxin and cytokines,forming PGs which exacerbate pain and
inflammation)- [constitutive in endothelium & kidney].
• COX-3 (COX-Ib):present in the CNS??
Mechanism of Action of NSAIDs & Paracetamol:
They Inhibit cyclooxygenase enzymes inhibits conversion of arachidonic
acid to endoperoxides inhibits PGs & TXA2 production.
1. Non-selective COX inhibitors
1. Salicylic acid derivatives: Aspirin Irreversible inhibition of COX
enzymes
Analgesics narcotic-Non
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Paracetamol.
Used in mild to moderate pain
Analgesics Narcotic
• Morphine.
• Synthetic opioids.
Used in moderate to severe
pain
•
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Other NSAIDs cause reversibleinhibition of COX enzymes.
2- Pyrazolone derivatives: Phenylbutazone.
3- Acetic acid derivatives: Indomethacin & sulindac- Diclofenac
4- Fenamic acid derivatives: Mefenamic acid, flufenamic acid.
5-Propionic acid derivatives: Ibuprofen, ketoprofen, naproxene.
6- Oxicams: Piroxicarn, Meloxicam
2. Selective COX-2 inhibitors: Celecoxib, Rofecoxib
Paracetamol:(may act on COX-3). Inhibits PG synthesis in CNS
I. ACETYLSALICYLIC ACID (ASPIRIN)
Mechanism: Aspirin Irreversible inhibition of COX-1 & COX-2 enzymes
Pharmacological actions:
1- Analgesic action
2- Antipyretic action
3- Antiinflammatory action
4- GIT:
1. Gastric irritation, nausea and vomiting.
2. Hyperacidity, ulceration induced:
- locally
- systemically by ↓ PGs→↓ mucus secretion (No protection).
5- Blood:
1. Small dose (75-150mg/d) → Inhibit TXA2→ ↓ platelet aggregation.
2. Large dose (5 g/d) → Hypoprothrombinemia: ↓synthesis of vit.K
dependent factors (10,9,7,2)
• Inhibition of COX-1 is responsible for the adverse effects of NSAIDs.
• Inhibition of COX-2 is responsible for their therapeutic effects.
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6- Kidney:
1. Large dose (>5 g/day) → ↓ uric acid reabsorption by PCT→ treats gout
2. Nephropathy (large dose for prolonged time of combined NSAIDs)
Therapeutic uses:
1. Small (infantile)-Dose (75-150mg/d)
Prophylaxis for:
Transient ischemic attacks, unstable angina, acute myocardial infarction.
2. Intermediate dose (325 mg tab) 1-2 tab/4-6 hrs
• Antipyretic in fever.
• Analgesic:
o Mild to moderate pain e.g. arthritis, dental pain.
o Headache
o dysmenorrhea.
3. High-Dose (4-8 g/d)
Anti-inflammatory
1. Rheumatic fever.
2. Rheumatoid arthritis
3. Other inflammatory joint diseases.
Adverse Effects:
A. Effects Common to all NSAIDs
1. GIT (most common; direct mucosal irritation &↓protective PGs)
• Epigastric pain, Nausea, vomiting, gastritis
• Acute & chronic peptic ulcers with ↑ risk of bleeding.
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2. Nephrotoxicity (less frequent with aspirin)
* Analgesic nephropathy: irreversible chronic nephritis due to
prolonged use of high doses of combinations of NSAIDs.
3. Hypersensitivity reactions
- Skin rash, rhinitis
- Asthma in susceptible patients
4. Bleeding tendency
- Displacement of warfarin from plasma proteins potentiating
its effect.
B. Effects Specific to Aspirin
1. Bleeding tendency
1. Antiplatelet effect by small dose
2. Hypoprothrombinemia by large dose
2. Reye’s syndrome: encephalopathy and liver damage in children with
fever due to viral infection.
Contraindications:
1. GIT disorders: peptic ulcers, gastritis
2. Bleeding disorders: hemophilia, thrombocytopenia
3. Chronic renal impairment
4. Chronic liver diseases (bleeding tendency)
5. Hypersensitivity to aspirin
6. Children < 12 y
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II.OTHER NON-SELECTIVE NSAIDs
• Mechanism: Reversible inhibition of COX enzymes
• Action: All have analgesic, antipyretic & anti-inflammatory effects.
• Members: Ibuprofen - Piroxicam - Diclofenac
• Uses:
1. Inflammatory joint diseases (osteoarthritis, rheumatoid arthritis,
gout)
2. Dysmenorrhea 3. Renal colic 4. postoperative pain
Adverse effects: see before (common adverse effects of NSAIDs)
III. SELECTIVE COX-2 INHIBITORS
Celecoxib
• Selective COX-2 inhibitors were developed to avoid the adverse effects
resulting from inhibition of constitutive COX-1 in GIT and kidney.
Uses:
1. Anti-inflammatory: chronic inflammatory musculoskeletal disorders
(with less risk of gastric ulceration).
2. Progression of Alzheimer disease (anti-inflammatory effect).
3. Risk of colorectal cancer (COX-2 is responsible for tumor growth).
Adverse Effects of COX-2 Inhibitors
1. Nephrotoxicity (COX-2 is constitutive in kidney).
2. Stroke & infarction (COX-2 is responsible for endothelial PGI2 synthesis).
3. Skin rash with celecoxib (structurally related to sulfonamides).
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IV. PARACETAMOL (Acetaminophen)
• It is an analgesic antipyretic with NO anti-inflammatory action.
• It is preferred to aspirin in:
1. Patients Allergic to aspirin.
2. Bleeding disorders (does not affect platelet function).
3. Peptic ulcer (no GIT disturbances).
4. Children with viral infections (to avoid Reye’s syndrome with aspirin).
5. Gout (aspirin may cause hyperuricemia).
Dose: - Oral: 500 mg /4hrs or 6hrs/day
- Can be given IV or rectal
Kinetics
• Paracetamol is metabolized in liver by two pathways:
1. Major pathway: 95 % undergoes sulphation and glucuronic acid
conjugation → inactive metabolites
2. Minor pathway: Only 5% is converted by CYP450 to a hepatotoxic
metabolite N-acetyl-p-benzoquinone imine (NAPQI) deactivated
by conjugation with glutathione (GSH).
• In toxic doses saturation of sulphation and conjugating enzymes
↑ conversion of the drug to the toxic metabolite(NAPQI) >> the capacity
of liver to conjugate it with glutathione hepatotoxicity (centrilobular
necrosis).
Adverse Effects and Toxicity
• Minimal adverse effects - well tolerated.
• Nephrotoxicity: with high doses for long periods.
• Paracetamol hepatotoxicity in toxic doses [10 gm or 150 mg/kg]:
nausea and vomiting, followed in 24-48 h by liver damage
Treatment: - Precursors for glutathione synthesis to prevent liver damage
- should be given early within 7-14 hrs
* N-Acetylcysteine (orally or IV) or methionine (orally).