أسئلة الثامنة والتاسعة فارما PPPM (قبل التعديل)

• Pharmacology: Sympathetic (1&2)

Introduction to Sympathetic Pharmacology

Norepinephrine And Epinephrine Synthesis And Release

• Tyrosine converts to DOPA, then into Dopamine, which enters the presynaptic vesicle.
• Norepinephrine waits for an action potential to trigger its release.
• Some norepinephrine is converted into epinephrine, but this is not the primary source.
• Epinephrine's main source is the adrenal medulla, producing 80% adrenaline and 20% norepinephrine.
• Dopamine, norepinephrine, and epinephrine are catecholamines, characterized by a catechol group attached to an amine group.
• Soluble in water due to the presence of a catechol group.
• Can't pass lipid barriers, making them lipid insoluble.
• Cannot cross the blood-brain barrier (BBB).
• Rapidly broken down by MAO and COMT.
• Short duration of action.

Adrenergic Receptors (Sympathetic Receptors)

• The following are four types adrenergic receptors: α₁, α₂, β₁, and β₂.

α₁ Receptors

• Type of Receptor: G query (Gq)
• Effect of Stimulation: Increases inositol triphosphate (IP3) and diacylglycerol (DAG), and increases intracellular Ca.
• Response: Contraction
• Distribution: Blood vessels, sphincters of the body (UB, stomach, GIT), and dilator pupillae muscle of the eye
• Stimulation: Smooth muscle contraction

α₂ Receptors

• Type of Receptor: G inhibitory (Gi)
• Effect of Stimulation: Decreases cAMP.
• Response: Decreases the release of certain hormone's or neurotransmitters.
• Distribution: Presynaptic nerve terminal.
• Stimulation: Decreases norepinephrine release.

β₁ Receptors (Cardiogenic β₁)

• Type of Receptor: G stimulatory (Gs)
• Response: Contraction in cardiac muscle
• Distribution: Heart and kidney.

β₂ Receptors

• Type of Receptor: G stimulatory (Gs)
• Effect of Stimulation: Increases in cAMP
• Response: Relaxation in smooth muscles anywhere.
• Distribution: Pre-synaptic nerve endings (increases NA release)
• Central: Increases central sympathetic outflow
• VD (Vasodilation) of skeletal muscle BV (Blood vessels) and coronary artery

β₃ Receptors

• Distribution: Wall of the bladder and adipose tissue.
• Facilitation of neurotransmission (skeletal muscle tremors) observed.
• Wall of the bladder: Relaxation
• Increase plasma K⁺
• Increases liver glycogenolysis.
• Bronchodilation occurs.
• Relaxation of GIT and urinary bladder walls.
• Adipose tissue : lipolysis.
• Relaxation of the uterus.

Fate of Norepinephrine

• 80% is Reuptake into presynaptic vesicles to be recycled.
• 20% Destruction by:
  • Monoamine oxidase (MAO) enzyme.
  • Catechol-o-methyl transferase (COMT) enzyme.
• All adrenergic receptors are G-protein coupled receptors.

Adrenergic Agonists (Sympatho-Mimetics)

• Drugs produce pharmacological effects similar to sympathetic stimulation, are defined as adrenergic agonists (sympathomimetics).

Classification

• Directly Acting on Receptors:
  • Non-selective: Adrenaline
  • Selective: Phenylephrine (α₁)
• Indirectly Acting on the Receptors:
  • Releaser of NE: Amphetamines.
  • Reuptake inhibitor: Cocaine.
• Mixed Direct and Indirect:
  • Ephedrine.
  • Pseudoephedrine.
• Catecholamine drugs (Adrenaline, Noradrenaline, Dopamine, Dobutamine).
• The rest of sympathomimetics are non-catecholamines.

1. Adrenaline (Epinephrine)

• Chemistry: Natural alkaloid synthesized by Adrenal medulla.
• Pharmacokinetics:
  • Ineffective orally.
  • It's given by Injection (SC & IM), Inhalation and Topically
  • Not cross BBB (highly polar)
  • Rapidly destroyed (by MAO & COMT) → very short action.
• Pharmacodynamics:
  • Directly stimulate α₁,₂ and β₁,₂,₃ adrenoceptors (β more sensitive: stimulated by low concentration of adrenaline).
  • Intracellular pathways:
    • Al-Adrenoceptors Activation: Leads to increase intracellular IP3 & DAG (Gq).
    • B-Adrenoceptors Activation Leads to increase intracellular CAMP (Gs).
    • a2-Adrenoceptors Activation Leads to decrease intracellular CAMP (Gi).

Pharmacological Effects

• Heart: (β₁) ↑ all properties
  • Increases the rate and force of contraction.
  • Increases cardiac output and conduction.
• Blood Vessels:
  • Constriction of blood vessels (VC) in skin and MM (α₁).
  • Dilatation of skeletal muscle vessels (VD) (β₂).
• Blood pressure:
  • At therapeutic doses→ increases blood pressure.
• Respiration:
  • Relaxation of bronchi (Bronchodilatation) (β₂).
  • Bronchial decongestion due to VC of bronchial BV (α₁).
• GIT and urinary system:
  • Wall: relaxation (β₂).
  • Sphincters: contraction (α₁).
• Eye (α₁):
  • Mydriasis Reduction of intraocular pressure (IOP) (α₁).
• Uterus: relaxation (β₂).
• Sweat glands:
  • Sympathetic sweating (forehead and palms) (α₁).
• Liver: ↑ glycogenolysis (β₂).
• Fat cells: ↑ lipolysis (β₃).
• Kidney
  • ↑ renin secretion (β₁).
• Skeletal Muscle
  • Facilitation of neuromuscular transmission (β₂).
  • Vasodilatation of skeletal blood vessels (β₂).

Therapeutic Uses

• Systemic:
  • Anaphylactic shock.
  • Acute bronchial asthma.
  • Cardiac arrest.
• Local:
  • With local anesthesia: To prolong the duration of action.
  • Local hemostatic: To stop nasal bleeding.

Side Effects

• ↑↑↑ blood pressure → cerebral hemorrhage.
• Anxiety, restlessness, headache, and tremor.
• Palpitations, Cardiac arrhythmias (if given IV).
• Injection with local anesthesia in end arterial supply (fingers, toes, pinna, nose) may cause tissue damage.

2. Norepinephrine (Noradrenaline)

• Given by IV infusion slowly.
• Not Given SC or IM because of its strong VC effect producing necrosis and sloughing.
• Non-selective sympathomimetic predominantly α₁ (alpha 1, alpha 2, beta1).
• Reflex bradycardia.
• Used as a hypertensive agent in acute hypotensive states.

3. Dopamine

• Given by IV infusion because of its very short t¹/2.
• D1 > β1 > α1
• Shock state with impaired tissue perfusion.

4. Dobutamine

• Synthetic catecholamine, related to dopamine.
• I.V. infusion because of its short duration (2 min).
• It activates mainly a cardiac β₁-receptor.
• Heart (β₁):
  • ↑↑ force of contraction→↑COP (inotropic).
  • ↑ impulse conduction ↑ HR → ↑ COP (Cardiac output).
• Short-term use in patients with decreased contractility is used as a result for acute decompensated heart failure, cardiogenic shock or cardiac procedure resulting in cardiac decompensation.
• Side Effects:
  • Tachycardia & Tachyarrhythmia.
  • Hypertension.
  • Angina in predisposed patient (↑ cardiac work).

5. Selective α Agonists

α₁ Agonists

• Example: Phenylephrine.
• MOA: Direct acting selective α₁ agonists.
• Effects: Blood vessels (VC).
• Uses: Local decongestant (vasoconstriction) (oxymetazoline) and systemic to increase BP.
• Side Effects: Elevation of BP, atrophic rhinitis, and Rebound nasal congestion.

α₂ Agonists

• Example: Clonidine.
• MOA: Centrally-acting pre-synaptic α₂ agonist.
• Effects: ↓ NE release from presynaptic neuron & ↓ BP.
• Uses:
  • Antihypertensive drug.
  • Treatment of opioid withdrawal symptoms.
  • Treatment of ADHD (attention deficiency hyperactive disease).
• Side Effects: Dry mouth, sedation, and hypotension.

Selective β₂ Agonists

• Examples: Salbutamol, formoterol, and ritodrine.
• Pharmacodynamics: Direct acting selective β₂ agonists (Gs ↑ CAMP).
• Effects:
  • Bronchial smooth muscles → bronchodilation.
  • Uterine smooth muscles → uterine relaxation.
  • Blood vessels of skeletal MS → vasodilation.
• Uses:
  • Bronchial asthma (aerosol) (salbutamol, formoterol).
  • Delay premature labor (ritodrine).
• Side Effects:
  • Tachycardia & arrhythmias (due to loss of selectivity in high doses).
  • Tremors.
  • Tolerance.
  • Hypokalemia.

4. Selective β₃ Agonists

• Examples: Mirabegron.
• MOA: Selective potent beta-3 agonist → relax detrusor smooth muscle→↑ bladder storage capacity decreasing the feeling of urgency and frequency.
• Uses:
  • Treatment of overactive bladder syndrome with symptoms of urge urinary incontinence.
• Side Effects:
  • Hypertension.
  • Tachycardia.
  • Urinary tract infection.

Adrenergic Receptor Agonists (Activators)

• α₁ Agonists: Phenylephrine, Oxymetazoline.
• α₂ Agonists: Clonidine.
• β₁ Agonists: Dobutamine, Formoterol.
• β₂ Agonists: Salbutamol, Ritodrine.
• β₃ Agonists: Mirabegron.
• Non-Selective: Epinephrine (α₁, α₂, β₁, β₂), Norepinephrine (α₁, α₂, β₁), and Dopamine (D₁, β₁, α₁).
• Indirect Acting: Amphetamine, and Cocaine.
• Mixed: Ephedrine, and Pseudoephedrine.