Pharmacology 1 - Basic Pharmacology, Part 1 2023-2024 PDF

Pharmacology -1 Basic pharmacology) Part 1 By Prof. Dr. Ihab Talat College of Pharmacy, Damanhur University 2023- 2024  Autonomic Nervous System Sympathetic Nervous System...

Pharmacology -1 Basic pharmacology) Part 1 By Prof. Dr. Ihab Talat College of Pharmacy, Damanhur University 2023- 2024  Autonomic Nervous System Sympathetic Nervous System  Adrenergic Transmission SYNTHESIS AND STORAGE OF NOREPINEPHRINE (NORADRENALINE): Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the rate limiting step in the formation of noradrenaline. DOPA is decarboxylated to form dopamine. Dopamine is transported into synaptic vesicles by an amine transporter system that can be blocked by reserpine. Dopamine is converted to noradrenaline in the vesicle by dopamine-β-hydroxylase.  Adrenal gland NE PNMT EP Epinephrine\NE MAO, COMT 80\20% MAO NE COMT 7  Release of noradrenaline: Release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of noradrenaline. Noradrenaline released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to the presynaptic receptors on the nerve ending. Adrenaline (epinephrine) is formed in the adrenal medulla by the methylation of noradrenaline by enzyme phenylethanolamine N-methyltransferase (PNMT). Both adrenaline and noradrenaline, as well as dopamine, are known as the catecholamines. Termination of action of catecholamines: (Uptake & Enzymatic degradation) 1. Uptake Uptake-1 (neuronal uptake): This located on neuronal terminals, and it is the main mechanism for noradrenaline inactivation. It is blocked by cocaine, amphetamines and tricyclic antidepressants (e.g. imipramine), which therefore potentiate the actions of noradrenaline. Uptake-2 (extra-neuronal, tissue uptake): This located outside neurons (e.g. in smooth muscle, cardiac muscle and endothelium) and it is the main mechanism for the removal of circulating adrenaline from the blood stream (tissue uptake). It is blocked by corticosteroids. Uptake-3 (granular uptake): It is the intra-granular uptake of catecholamines into the vesicles; it is inhibited by reserpine leading to increase in NE in cytoplasm which is metabolized by MAO resulting in a depletion of granular NE and decrease sympathetic activity.  Adrenal gland NE PNMT EP Epinephrine MAO, COMT MAO NE COMT 2- Enzymatic degradation of endogenous and exogenous catecholamines Catecholamines are metabolized mainly by two enzymes, monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). MAO is found on the surface of mitochondria, principally within adrenergic nerve terminals but also in other cells, such as those of the liver and intestines. COMT is a widespread enzyme that occurs in both neuronal and non- neuronal tissues. COMT changes adrenaline and noradrenaline to metanephrine and normetanephrine, respectively. MAO oxidizes these products into vanil mandelic acid (VMA). The inactive metabolites that are excreted in urine are metanephrine, normetanephrine and VMA. Adrenergic receptors (adrenoceptors): These receptors respond to catecholamines (adrenaline and noradrenaline). Adrenergic receptors are subdivided as follows: 1. Alpha adrenergic receptors: The α-adrenergic receptors are subdivided into two groups, α1 and, α2, based on their different affinities for α agonists and blocking drugs. a. Alpha1 receptors: These receptors are located post synaptically. Their activation causes smooth muscle contraction (except the for the non-sphincter part of gastrointestinal tract, where activation causes relaxation), glycogenolysis in the liver. b. Alpha2 receptors: These receptors are located mainly presynaptically, but also postsynaptically on liver cells, platelets and the smooth muscle of blood vessels. The activation of presynaptic α2-receptors inhibits noradrenaline release and, therefore provides a means of end product negative feedback. Activation of postsynaptic α2- receptors causes blood vessel constriction and platelet aggregation. 2. Beta adrenergic receptors: The β-receptors are also subdivided into three major groups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists a. Beta1 receptors. These are mainly postsynaptic and located in the heart, platelets and non-sphincter part of the gastrointestinal tract. They can, however, be found presynaptically. Activation causes an increase in the rate and force of contraction of the heart, relaxation of the non-sphincter part of the gastrointestinal tract, aggregation of platelets, an increase in the release of noradrenaline, and amylase secretion from the salivary glands. Presynaptically, their activation causes an increase in noradrenaline release. b. Beta2 receptors. These are located postsynaptically. Their activation causes smooth muscle relaxation (e.g. Bronchi), glycogenolysis in the liver, inhibition of histamine release from the mast cells and tremor in skeletal muscle. c.Beta3 receptors. These are present on the postsynaptic membrane of the effectors cells, especially lipocytes. Receptor LOCATION RESPONSE Agonist-Antagonist Vascular Smooth muscle in skin, mucous membranes and Vasoconstriction viscera Ciliary body blood vessels (eye) Decrease IOP (VC) Agonists GIT (non-sphincter-part) relaxation Phenylephrine Genitourinary (Urinary Bladder sphincter) Contraction Methoxamine Pregnant uterus Contraction Seminal vesicle Ejaculation Antagonists α1 Liver Glycogenolysis, Gluconeogenesis Prazosin Eye (radial papillary muscle of the iris) Active mydriasis. Presynaptic nerve terminal Decrease release of NE Platelets Aggregation Pancreas Decreased insulin release Agonists Vascular smooth muscles Contraction Clonidine Juxtaglomerular cells (kidney) Decreased Renin release Antagonists α2 Adipose tissues Decreased Lipolysis(↓FFA) Yohimbine Heart Increased force and rate Agonists Juxtaglomerular cells (kidney) Increased Renin release (↑BP) Dobutamine β1 Adipose tissues Increased Lipolysis Antagonists Atenolol, Acebutalol, Esmolol, Metoprolol Vascular smooth muscles Vasodilatations Urinary bladder muscle, Uterus Relaxation Agonists GIT (non-sphincter-part) Relaxation Metaproterenol Terbutaline, Bronchi Bronchodilator Liver Glycogenolysis, Gluconeogenesis ritodrine and albuterol Β2 Skeletal muscles Increased contractility Antagonists Pancreas Increased insulin release Butoxamine Β3 Adipose tissue Increased Lipolysis  ADRENOCEPTOR AGONISTS The adrenergic drugs affect receptors that are stimulated by noradrenaline or adrenaline. Some adrenergic drugs act directly on the adrenergic receptor by activating it and are said to be sympathomimetics. Catechol nucleus lacking the catechol nucleus called catecholamines non-catecholamines adrenaline, noradrenaline, isoproterenol phenylephrine, ephedrine and amphetamine , dopamine Have only a brief period of action when Have longer half-lives given parenterally They are rapidly metabolized by MAO or They are not inactivated by MAO or COMT. COMT. -They ineffective orally -Orally effective because of inactivation by gastric juices -Catecholamines are polar and therefore -Have CNS effects not readily penetrate into CNS  ADRENOCEPTOR AGONISTS Classification of Sympathomimetic: 1- Directly acting adrenoceptor agonists: directly activate their receptors (e.g. noradrenaline and adrenaline) 2- Indirectly acting adrenoceptor agonists: may act indirectly to increase the release of stored catecholamines (e.g. amphetamine and tyramine). 3- Mixed (direct-indirect) agonists: Some agonists have the capacity both to directly stimulate adrenoceptors and to release noradrenaline from the adrenergic neuron (e.g. ephedrine and metaraminol). 1. Direct acting-adrenergic agonists: These agents act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone adrenaline from the adrenal medulla. These drugs are widely used clinically. 1. Adrenaline: Adrenaline is a hormone secreted by the adrenal medulla. It stimulates both α and β adrenergic receptors. At high doses, α-effects (vasoconstrictor) are strongest, whereas at low doses, β-effects (vasodilatation) on the vascular system predominate. Pharmacokinetics: Adrenaline is ineffective after oral administration because of its rapid destruction by digestive juices and metabolism by the liver.  Absorption is slow with subcutaneous administration because the drug causes local vasoconstriction. Absorption is more rapid after intramuscular administration due to vasodilatation. Nebulized and inhaled solutions are usually used for their actions on the respiratory tract. The drug can be given intravenously, but this route must be used with caution so that the heart does not fibrillate. It may also be given topically to the eye. Pharmacological actions: a. Cardiovascular system: Adrenaline strengthens the contractility of the myocardium (positive inotropic, β1 action), and increases its rate of contraction (positive chronotropic, β1 action). Cardiac output therefore increases. Adrenaline constricts arterioles in the skin, mucous membranes and viscera (α effects) and dilates vessels going to the liver and skeletal muscle (β2 effects). The systolic blood pressure increases due to the increase in cardiac output but the diastolic pressure may be unchanged but increased in large doses because it depends on peripheral resistance. b. Respiratory system: Adrenaline is a potent bronchodilator. It relaxes bronchial smooth muscle by activating β2-adrenergic receptors. It is a physiological antagonist to endogenous bronchoconstrictor (e.g. histamine and 5- hydroxyltryptamine).  c. Gastrointestinal tract: The gastrointestinal tract contains both α and β receptors. Stimulation of either α and β receptors leads to relaxation of the smooth muscle. d. Genitourinary tract: Adrenaline causes contraction of the trigone and the sphincter muscles of the urinary bladder (α1, action). Adrenaline relaxes the pregnant human uterus. e. Eye: The radial papillary muscle of the iris contains α1-receptors and contracts in response to the activation of sympathetic neurons causing mydriasis. Because adrenaline is a highly polar molecule, it does not readily penetrate the cornea when instilled into the conjunctival sac. If adrenaline is instilled, however, intraocular pressure is lowered, possibly because the agent reduces the formation of aqueous humor by vasoconstriction of the ciliary body blood vessels.. f. Metabolic actions: Adrenaline has a significant hyperglycemic effect because of increased glycogenolysis in liver (β2 effect), increased release of glucagons (β2 effect), and a decreased release of insulin (α2 effect). The drug initiates lipolysis through its agonist activity on the β receptors of adipose tissues. Therapeutic uses: a. Bronchial asthma. b. Insulin hypoglycemia. c. Hypersensitivity reaction such as anaphylactic shock. d. Acute cardiac arrest. e. Adrenaline is added to local anesthetics to prolong their action. It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the site before being absorbed into the circulation and metabolized. f. As decongestant in the nose and eye. g. Local haemostatic, to stop hemorrhage from the nasal mucosa. h. Eye drops in open angle glaucoma. Adverse effects: A- Adrenaline can produce adverse CNS effects that include anxiety, tension, tremors and headache. B- Cardiac arrhythmias C- Gangrene of fingers may follow the use of infiltration anesthetics containing adrenaline. D- Large doses of adrenaline may cause a sharp rise in blood pressure leading to cerebral hemorrhage.  Interactions: a. Hyperthyroidism: Adrenaline may have enhanced cardiovascular actions in patients with hyperthyroidism. The mechanism appears to involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual leading to a hypersensitive response. b. Cocaine: In the presence of cocaine, adrenaline produces exaggerated cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron, thus adrenaline remains at the receptor site for longer periods of time. Contraindications: a. Coronary heart disease b. Hypertension. c. Pulmonary embolism. d. Arrhythmia. Thank YOU