ADRENERGIC SYSTEM PHARMACOLOGY DR. ISHOLA I.O. DEPT OF PHARMACOLOGY, THERAPEUTICS AND TOXICOLOGY CMUL

ADRENERGIC TRANSMISSION Adrenergic transmission is restricted to the sympathetic nervous system Norepinephrine is the transmitter at post-ganglionic sympathetic nerves – except sweat glands Epinephrine (Epi)– major hormone of the adrenal medulla Dopamine- the predominant transmitter of the mammalian extrapyramidal, mesocortical and mesolimbic neuronal pathways

ADRENERGIC TRANSMISSION Naturally occurring catecholamines - Epinephrine, Norepinephrine, Dopamine. Synthesis of Epi from tyrosine was proposed by Blaschko in 1939 Some of the enzymes for synthesis are not specific except tyrosine hydroxylase (TH)(Rate limiting) Stimulation of adrenergic nerves activate TH TH is a substrate for cAMP-dependent, Ca-calmodulin sensitive protein and PKC

Cont’d TH is subject to feedback inhibition by catechol compounds The storage vesicles contain NA (approx. 21%), Aa, ATP, chromogrannins, DBH, NPY, & enkephalins 2 types of storage vesicles: Large dense core (chromafin granules) Small dense core (NA, ATP, DBH)

SUMMARY OF SYNTHESIS 3-Hydroxylation of Tyrosine to DOPA Decarboxylation of dopa to DA AT of DA to vesicle or else deaminated to DOPAC or O-methylated to HVA β-hydroxylation of DA to NA NA diffuse into cytoplasm N-methylated to Epi Epi enters chromaffin cells until release Glucocorticoid controls the release of Epi

Cont’d Hydroxylation of tyrosine by tyrosine hydroxylase in the presence of THB, O2, ferric ion (rate limiting step in biosynthesis of catecholamines)

ADRENERGIC TRANSMISSION STORAGE : The granules take up dopamine from the cytoplasm and synthesis of NE occurs within the granules. NE is stored in the granules within the adrenergic terminal . Released by exocytosis Storage decreases intraneuronal metabolism of NT Vesicular monoamine transporter (VMAT-2) is driven by pH and potential gradients

Cont’d For every molecule of amine taken up, 2 hydrogen ions are extruded Reserpine inhibits monoamine transport into storage vesicles There are two neuronal membrane transporters for catecholamines; NET and DAT NET is sodium ion dependent (blocked by cocaine, TCA (imipramine) Indirectly acting sympathomimetic (ephedrine, tyramine

ADRENERGIC TRANSMISSION RELEASE : Nerve impulse effects the release of NE Entrance of calcium ion into cells results in the extrusion by exocytosis of granular contents (ADR, ATP, NPY, Chromogranins and DBH) The release of CA takes by exocytosis . Indirectly acting amines (tyramine and amphetamine) induce the release of NE by displacing it from the nerve endings. They make carrier available at the inner surface of the membrane for the outward transport of NE (facilitated diffusion) Reserpine inhibit uptake -1 Uptake-2 not sodium ion dependent

CONT’D Influx of Ca2+ plays an important role in coupling nerve impulses, membrane depolarization, and opening of voltage gated Ca2+ channels with the release of NE Blockade of N-type Ca2+ channels lead to hypotension

ADRENERGIC TRANSMISSION UPTAKE 2 (extra neuronal uptake) : CA are taken into other tissues. ADRENERGIC TRANSMISSION UPTAKE OF CA : It is an efficient mechanism after the release of NE – Axonal uptake (Uptake 1 ) : Transports NE at a higher rate than E. It is the most important mechanism for the termination of the NE. Cocaine, Imipramine inhibits this uptake 1.

Termination of the action of CAT Reuptake into nerve terminals by NET Dilution by diffusion out of the junctional cleft and uptake at extraneuronal sites by ENT, Metaboilic transformation (MAO, COMT and sulphotransferases) – little effect Termination of action of ACh by AChE is absent

Metabolism does not play a significant role in the termination of the action of the NE .

ADRENERGIC TRANSMISSION COMT plays a major role in the metabolism of catecholamines particularly in liver. ADRENERGIC TRANSMISSION METABOLISM : by two enzyme systems – MAO and COMT. NE after uptake -1 into the axoplasm is acted upon by MAO. NE which diffuses into the circulation is acted upon by COMT, mainly in the liver The major metabolites excreted in urine is VMA (Vanillyl mandelic acid)

ADRENERGIC TRANSMISSION Adrenergic receptors are G protein coupled receptors which acts by increasing or decreasing the production of c AMP ADRENERGIC RECEPTORS ALPHA – 1 -- A , B , D ALPHA – 2 -- A , B , C

ADRENERGIC TRANSMISSION ALPHA 1 : Acts by activating Phospholipase C – production of inositol triphosphate (IP3) and DAG IP3 promotes the release of calcium from the intracellular stores ---increase cytoplasm calcium

Adrenergic System ALPHA 1 receptors EYE – radial fibers – contraction –mydriasis Arterioles and veins – contraction – can increase peripheral resistance. Bladder trigone and sphincter – contraction – urinary retention Liver – Glycogenolysis. Vas deferens – ejaculation.

Adrenergic System ALPHA 2 : acts by inhibiting adenylyl cyclase – cAMP Platelets - aggregation Prejunctional receptors – decrease release of transmitter (NE) Pancreas -- decrease insulin release (predominant)

Adrenergic System BETA : beta receptors stimulate adenylyl cyclase – increasing the cAMP Beta 1 Heart JG cells in kidney (increase renin release).

Adrenergic System Blood vessels to skeletal muscle – Vasodilation Beta 2 receptors : cAMP Blood vessels to skeletal muscle – Vasodilation Uterus – Relaxation Bronchioles – Dilatation Skeletal muscles – tremors Liver - Glycogenolysis

Adrenergic System Dopamine 1 receptors : Acts by stimulation of adenylyl cyclase and increased cAMP Renal and mesenteric vasculature – vasodilation and increase blood flow and Na excretion. Dopamine 2 receptors : Acts by inhibition of adenylyl cyclase, decrease cAMP, open potassium channels, Brain

Adrenergic System Adrenergic Drugs: Directly acting : Epinephrine, Norepinephrine, Phenylephrine, Albuterol Indirectly acting : acts by release of NE : Tyramine, Amphetamine Mixed : Ephedrine

Adrenergic System Epinephrine acts on alpha 1, 2 beta 1, 2 Norepinephrine acts on alpha 1, 2 beta 1 Isoprenaline acts on beta 1 , 2 Dopamine 1 receptors agonist : Dobutamine, Fenoldopam

Adrenergic System AGENTS ACTING AT DIFFERENT SITES INTERFERE WITH THE SYNTHESIS : Metyrosine BLOCKADE OF UPTAKE 1 AT NERVE TERMINAL : Cocaine, Imipramine BLOCKADE OF STORAGE IN GRANULE OR GRANULAR UPTAKE : Reserpine PROMOTION OF RELEASE : Amphetamine PREVENTION OF RELEASE : Bretylium, Guanethidine

Metabolism does not play a significant role in the termination of the action of the NE .

Adrenergic System MAO MAO –A present in the nerves /intestine/ liver or Anywhere Metabolizes NE, 5-HT and tyramine Inhibitors are Phenelzine, Tranylcypromine MAO – B Present mainly in the Brain Metabolizes preferentially dopamine Inhibitors are Selegiline

Adrenergic System COMT INHIBITORS : Tolcapone -- Long acting Entacapone -- Short acting

Adrenergic System Agonist acting on Alpha 1 receptors Phenylephrine, Methoxamine Given systemically they increase the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP). The increase in BP can elicits reflex bradycardia.

Adrenergic System Alpha 2 receptors : Clonidine, Alpha Methyldopa Agonist acting specifically on Alpha 2 receptors : Clonidine, Alpha Methyldopa Beta 1 and beta 2 : Isoproterenol Beta 1 : Dobutamine Beta 2 : Terbutaline, Albuterol, Ritodrine, Metaproterenol

Adrenergic System Beta agonists : Beta 1 and Beta 2 Isoproterenol Beta 1 agonists increase the HR, stroke volume and cardiac output. Beta 2 agonists decrease the total peripheral resistance. Adrenergic System Beta agonists : Beta 1 and Beta 2 Isoproterenol It cause a decrease in peripheral resistance, a decrease in mean BP due to beta 2 receptor action and a reflex increase in heart rate. Systolic blood pressure does not fall significantly as diastolic, due to beta 1 receptor action, so the pulse pressure increases .

Adrenergic System Norepinephrine : It has little effect on beta 2 receptors. It increases TPR and both diastolic and systolic blood pressure. Positive inotropic action results in increase of pulse pressure. Compensatory vagal reflexes tend to overcome the direct chronotropic action of NE -- reflex bradycardia may occur.

Adrenergic System Epinephrine : Acts on alpha 1, 2 and beta 1 and 2. Epinephrine increase the HR, systolic BP and PP. Its effects on diastolic blood pressure depends on dose.

Adrenergic System Epinephrine : At low dose, beta 2 activation predominates resulting in decrease of diastolic pressure and TPR, although mean BP may not decrease significantly. At medium dose, increase in heart rate, increase in mean blood pressure and increase in pulse pressure due to both beta 1 and 2 receptor action.

Adrenergic System Non-selective Phenoxybenzamine, Phentolamine Tamsulosin ( Flomax) Adrenergic System ALPHA BLOCKERS: Non-selective Phenoxybenzamine, Phentolamine Alpha -1 selective Prazosin, Terazosin, Tamsulosin Alpha-2 selective Yohimbine

Adrenergic System Non selective : Propranolol, Nadolol, Timolol BETA BLOCKERS: Non selective : Propranolol, Nadolol, Timolol With Partial agonist : Pindolol Beta 1 selective : Atenolol, Metoprolol Beta and alpha 1 blocker : Labetolol, Carvedilol

Clinical pharmacology of a-adrenergic receptor antagonists Route of Drug Receptor admin. Clinical uses Phenoxybenzamine a , a Oral Pheochromocytoma, hypertensive crisis 1 2 Phentolamine a , a Parenteral Pheochromocytoma, hypertensive crisis, 1 2 male impotence Prazosin a Oral Hypertension, benign prostatic 1 hypertrophy Terazosin a Oral Hypertension, benign prostatic 1 hypertrophy Doxazosin a Oral Hypertension, benign prostatic 1 hypertrophy Side effects of a1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

Non-selective adrenergic receptor antagonists b-Haloalkylamines R= aromatic, alkyl X= Cl-, Br-, etc.

Non-selective adrenergic receptor antagonists b-Haloalkylamines Non-selective a receptor antagonist Also blocks acetylcholine, histamine, and serotonin receptors Irreversible antagonist resulting from covalent modification of receptor Phenoxybenzamine (Dibenzyline)

Non-selective adrenergic receptor antagonists Imidazolines Non-selective a receptor antagonist Competitive (reversible) blocker Potent vasodilator, but induces pronouced reflex tachycardia Block of presynaptic a2 receptors may promote release of NE Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist Phentolamine (Regitine)

a1-adrenergic receptor antagonists “Quinazolines” Vary in half-life: Prazosin 3 hrs Terazosin 12 hrs Doxazosin 20 hrs Undergo extensive metabolism, excreted mainly in the bile Vasodilators Relaxation of smooth muscle in enlarged prostate and in bladder base “First-dose” effect

Other a adrenergic receptor antagonists Ergot alkaloids Derivatives of Lysergic Acid Product of the grain fungus Claviceps purpura 5 Major alkaloids based on R and R’; Ergotamine the most common Used in the treatment of migraine Ergots possess strong oxytocic action

a2-adrenergic receptor antagonists Indole alkaloid Found in Rubaceae and related trees. Also in Rauwolfia Serpentina. Blockade of a2 receptors increases sympathetic discharge Folklore suggests use in the treatment of male impotence Yohimbine (Yocon)

b-adrenergic receptor antagonists Non-selective Lipophilic Local anesthetic properties Blockade is activity- dependent P r o p r a n o l o l ( I n d e r a l )

b-adrenergic receptor antagonists Pharmacological effects Decreased cardiac output and heart rate Reduced renin release Increase VLDL, Decrease HDL Inhibit lipolysis Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia Increase bronchial airway resistance P r o p r a n o l o l ( I n d e r a l ) Therapeutic uses for b-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

Non-selective b-adrenergic receptor antagonists Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine Nadolol (Corgard) Thiadiazole nucleus with morpholine ring Administered: Oral, Ophthalmic Uses: Hypertension, angina, migraine, glaucoma Timolol (Timoptic, Blocadren) How will -blockers affect pupil size?

Non-selective b-adrenergic receptor antagonists Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral Uses: Hypertension, angina, migraine Pindolol (Visken) What would a pindolol dose-response curve look like?

Selective b1-adrenergic receptor antagonists “Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic, congestive heart failure

Selective b1-adrenergic receptor antagonists “Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina Atenolol (Tenormin)

Selective b1-adrenergic receptor antagonists Very short acting Half-life: 9 minutes Rapid hydrolysis by esterases found in red blood cells Administered: Parenteral Note: incompatible with sodium bicarbonate Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension Esmolol (Brevibloc)

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Contraindications: Asthma, COPD, congestive heart failure (Type IV)

Mixed adrenergic receptor antagonists Non-selective b receptor antagonist a1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses b-blocking activity (1S, 1’R)-isomer possesses greatest a1 receptor blocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis Labetalol (Normodyne, Trandate)

Catecholamine depleters Reserpine (Serpasil) Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension May precipitate depression

Drugs that reduce storage or release of NE Possess guanidino moiety (pKa > 12) Resonance stabilization of cation “spreads” positive charge over the entire four atom system Almost completely protonated at physiological pH “Pharmacologic sympathectomy” Effects can be blocked by transport blockers Uses: Hypertension Guanethidine (Ismelin)