Dr. Laila M. Matalqah Ph.D. Pharmacology PHARMACOLOGY OF ANS part 2 General Pharmacology M212

DOPA is decarboxylated to form dopamine Dopamine is hydroxylated to form norepinephrine

α1α1 α2α2 LocationPostsynaptic membrane of the e ff ector organs ‐ Presynaptic neuron membrane: sympathatic and parasympathatic ‐ Pancreas β cells ‐ At certain vascular smooth muscle cells Binding to agonist Adrenergic e ff ect Feedback inhibition: - ‐ ↓ sympathatic output - ‐ ↓ cholinergic output (minimal( E ff ect Classic adrenergic e ff ect (e.g. Contraction of the smooth muscles( ‐ Control adrenergic neuromediator ‐ Control insulin output α-Adrenergic Receptors

β-Adrenergic Receptors β receptors: β 1, β 2 and β 3 Different locations, hence, functions β 1 : more predominant at Heart β2: more predominant smooth muscle (blood vessel and bronchi) Β 3 and little β1 are located in adipose tissue ! lipolysis Drugs differ in affinity to β receptors β1 receptors have approximately equal affinities for epinephrine and norepinephrine, β2 receptors have a higher affinity for epinephrine than for norepinephrine

Adrenergic Agonists (Sympathomimetic) They are classified according to their structure: A. Catecholamines such as epinephrine, norepinephrine, isoproterenol, and dopamine show highest potency in activating α or β receptors. Rapid inactivation: metabolized by COMT and MAO Short t1/2 Poor penetration into the CNS: polar Only parenterally (not effective orally)

Adrenergic Agonists Sympathomimetic They are classified according to their structure: B. Noncatecholamines include phenylephrine, ephedrine, and amphetamine Low potency have longer half-lives, because they are not inactivated by COMT. Greater access to the CNS. Oral and parenterally

CatecholaminesNoncatecholamines DrugsEpinephrine, Norepinephrine, Isoproterenol, Dopamine Phenylephrine, Ephedrine, Amphetamine Potency in activating adrenergic receptors HighLess Inactivation (metabolism) rate Rapid (shorter T 1/2 )Slower (longer T 1/2 ) Inactivation enzymes COMT No e ff ect of COMT MAO Poor e ff ect of MAO Oral Ine ff ectivee ff ective CNS penetration Poor, but have e ff ect (e.g. anxiety, headache and tremor( High

EpinephrineNorepinephrine ReleaseAdrenal medullaMajor: postganglionic sympathatic neurons Minor: adrenal medulla Adrenergic receptorLow dose: β effect (vasodilation( High dose: α effect (vasoconstriction( Mainly α effect (vasoconstriction) Cardiovascular and kidney Effect 1) +ive inotropic (contractility) and chronotropic (heart rate) action 2)Increase renin release ! vasoconstriction 3)Vasoconstriction and vasodilation of certain vessels 4)Decrease in renal blood flow 5)↑ Systolic & ↓ diastolic BP 1)Vasoconstriction for all blood vessels and vasodilation of certain vessels 2)Initially: +ive inotropic ----??reflex bradycardia 3)↑ Systolic & ↑ diastolic BP Duration of actionShortVery short Therapeutic useCardiac arrestCardiac shock

I. Direct-acting adrenergic agonist 1. Epinephrine: Action CVS effect:  strengthens the contractility of the myocardium (positive inotropic) and increases its rate of contraction (positive chronotropic).  Activates β 1 receptors on the kidney to cause renin release ---- angiotensin II --- a potent vasoconstrictor.  constricts arterioles in the skin, mucous membranes, and viscera ( α effects).  Therefore, the cumulative effect is an increase in systolic blood pressure, with a slight decrease in diastolic pressure

I. Direct-acting adrenergic agonist 1. Epinephrine: Action Respiratory: causes powerful bronchodilation by acting directly on bronchial smooth muscle ( β 2 action). Hyperglycemia: increased glycogenolysis in the liver ( β 2 effect), increased release of glucagon ( β 2 effect), decreased release of insulin ( α 2 effect).

Therapeutic uses 1. Treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice 2. Anaphylactic shock 3. Cardiac arrest 4. Anesthetics Side effect: 1. Anxiety, fear, tension and tremors 2. Cerebral haemorrhage 3. Cardiac arrhythmias 4. Pulmonary oedema I. Direct-acting adrenergic agonist 1. Epinephrine:

I. Direct-acting adrenergic agonist 2. Norepinephrine Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction ( α 1 effect) of most vascular beds (including kidney) Both systolic and diastolic blood pressures increase Norepinephrine is used to treat cardiogenic shock

I. Direct-acting adrenergic agonist 3. Dopamine Dopamine stimulates: α 1 & β 1 adrenergic, D1 & D2 activate dopaminergic receptors, thereby increasing blood flow to the kidneys (vasodilation) Dopamine actions: Cardiovascular: +ive inotropic and chronotropic effect ( β 1 effect) vasoconstriction (high dose at α 1) Renal and visceral: vasodilation (dopaminergic receptor effect) Uses: Dopamine is the drug of choice for cardiogenic shock ?? Why??

4. Dobutamine β 1-receptor agonist ! ↑ heart rate without affecting blood vessels Therapeutic use: in congestive heart failure S.E: atrial fibrillation 5. Clonidine α 2-receptor agonist. Acts centrally by decreasing sympathatic outflow ! lower BP I. Direct-acting adrenergic agonist

Short acting: Albuterol, terbutaline, Long acting: Salmeterol and formoterol β 2 agonists used primarily as bronchodilators administered by inhaler for asthma Fast onset of action

I. Direct-acting adrenergic agonist Phenylephrine and Oxymetazoline: α 1-receptor agonist Used locally to induce vasoconstriction: Nasal spray: decongestant (may cause burning of the mucosa and sneezing)

II. Indirect-acting adrenergic agonists 1. Amphetamine stimulants of the CNS MOA: Blockade of norepinephrine uptake and enhances its release ! indirect stimulate α 1 and β 1 receptor agonist Centrally: stimulatory action ! drug abuse increase blood pressure significantly by α 1-agonist β -stimulatory effects on the heart. Therapeutic uses: attention deficit hyperactivity disorder (ADHD, and appetite control

2. Cocaine MOA: Blockade of norepinephrine uptake ! sympathatic activity by working indirectly on α 1 and β receptor agonist Centrally: stimulatory action ! drug abuse So: prolongs the CNS and cause intense euphoria II. Indirect-acting adrenergic agonists

III. MIXED-ACTION ADRENERGIC AGONISTS Ephedrine and pseudoephedrine MOA: release stored norepinephrine from nerve endings directly stimulate both α and β receptors. α 1-agonist that constricts the nasal mucosa, thereby decreasing airway resistance. Used as a nasal decongestant

THE END of ANS