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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).