Noradrenergic Pharmacology Transmission and Drugs 1 Submit PDF

CHEMICAL MEDIATORS – NON-ADRENERGIC TRANSMISSION Objectives Distinguish between various noradrenergic transmitters List major sites that contain significant number of – Beta1 and Beta2 receptors – Alpha 1 alpha 2 receptors – Dopamine receptors Describe the major organ system ef...

CHEMICAL MEDIATORS – NON-ADRENERGIC TRANSMISSION Objectives Distinguish between various noradrenergic transmitters List major sites that contain significant number of – Beta1 and Beta2 receptors – Alpha 1 alpha 2 receptors – Dopamine receptors Describe the major organ system effects of pure alpha agonists, pure Beta agonists and mixed alpha and Beta agonists List various classes of drugs that affect noradrenergic neurons and receptors Describe class mechanisms of action, class effects and class ADR and list key drug examples  Noradrenergic Transmission: Major catecholamine transmitters Major Catecholamines Noradrenaline - transmitter released by nor- adrenergic/sympathetic nerve terminals Adrenaline – hormone released by adrenal medulla Dopamine – metabolic precursor of nor adrenaline and adrenaline. Major neurotransmitter in CNS Isoprenaline – synthetic derivative of nor-adrenaline and an important pharmacological agent  CLASSIFICATION OF ADRENERGIC AGONISTS Classification of adrenoceptor agonists can be in 2 ways being – According to mode of action Direct acting Indirect acting – Spectrum of activity – Direct acting further divided according Alpha or Beta and – Further sub-receptor types – Further selective vs non selective  CLASSIFICATION OF ADRENERGIC AGONISTS Second messengers: – α1 receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers. – α2 receptors inhibit adenylyl cyclase, and also modulate Ca2+ and K+ channels.– – All types of β receptor stimulate adenylyl cyclase.  CLASSIFICATION OF ADRENERGIC AGONISTS Adrenergic agonists Indirect Direct acting acting Beta – coupled to Gs. Alpha Stimulate AC and others Releasers Alpha 1- coupled Alpha 2 coupled Reuptake to Gi/Go Beta1 Beta2 Beta3 to Gq→PLC inhibitors →↓cAMP, ↓Ca2+,↑K+ Smooth Smooth Heart, Fat muscles, muscles, salivary adipocytes liver liver, mast Presynaptic glands cells CLASSIFICATION OF ADRENOCEPTORS Distribution and actions of adrenoceptors Summarised in Table 15.1 Characteristics of adrenoceptors G-protein coupling – Table 15.2 Second messengers and effectors – table 15.2 Agonist potency order – table 15.2  Main actions/effects of receptor Alpha 1 receptors activation - Exercise – Effect on peripheral blood vessels – vascular smooth muscles? – Pupillary dilator muscles – Hepatic glycogenolysis ? Alpha 2 receptors – Effect on neurotransmitter release (Nor-adrenaline)? – Platelets Beta 1 receptors – Effect on Heart Rate (HR)? – Effect on cardiac force of contraction? Beta 2 receptors – Effect bronchiole smooth? – Effect on vascular smooth muscle? – Effect on visceral smooth muscles (e.g. uterus)? – Effect on hepatic glycogenolysis? – Effect on skeletal muscles? Beta 3 receptors – Lypolysis – Bladder detrosor muscle relaxation – Thermogenesis  Main actions/effects of receptor activation Alpha 1 receptors – Most vascular smooth muscles: Vasoconstriction – Pupillary dilator muscles: Contracts – Genito-urinary: Bladder and sphincter – contraction of sphincter Alpha 2 receptors – Adrenergic and cholinergic nerve terminals: Inhibition of neurotransmitter release (NA and Ach) – Pancrease: Inhibition of insulin secretion – Platelets: Stimulates platelet aggregation Beta 1 receptors – Heart: Increased HR, Increased cardiac force of contraction – Juxtaglomerular cells: Beta 2 receptors – Respiratory, Uterine and Vascular smooth muscles: Relaxes – Liver: Stimulates glycogenolysis – Skeletal muscle: tremor Beta 3 receptors – Fat cells: Lypolysis  Main actions/effects of receptor activation Issue of feedback mechanisms and net cardiovascular effects e.g: – Explain why a slow infusion of norepinephrine causes increased Blood Pressure and Bradycardia Norepinephrine with Beta1, Beta, Alpha1 and Alpha 2 activity may cause increase in vagal outflow coz increase BP and evoke baroreceptor response  PHYSIOLOGY OF NORADRENERGIC TRANSMISSION NEURON and POST SYNAPTIC Physiology noradrenergic Transmission – Processes and activities (Synthesis, Storage and Relaese, Degradation and Termination) as possible sites for pharmacological intervetion Noradrenaline Synthesis NA packaging into vesicles and storage Noradrenaline Release Noradrenaline interaction with post synaptic receptors Reuptake of NA into neurons Metabolic degradation of NA - MAO Uptake of NA into extraneuronal cells Interaction of NA with presynaptic receptors Adrenergic Transmission: Drug Potential  NA Transmission: Norepinephrine Synthesis Pathway Tyrosine Hydroxylase – Only found in catecholamine containing cells – Does not accept other substrates e.g. 5HT – Inhibited by NA itself – synthesis regulation Dopacarboxylase – Not confined to catecholamine synthesising cells – Not rate limiting DopamineBhydroxylase – Confined to catecholamine synthesizing cells though relatively non-specific PNMT – Mainly in adrenal medulla Noradrenaline Storage and Release – CV Pharmacy  Termination of Released Catecholamines Termination of released noradrenaline – Reuptake into adrenergic nerve termina (neuroral) – uptake into post synaptic cells (extraneuronal) – Metabolic degradation – Sequestration by other cells - Minor – Enzymatic degradation of circulating NA/A - Minor  POTENCY: DRUGS AFFECTING THE ADRENERGIC NS Factors that Influence Overall Potency and Receptor Selectivity for Adrenergic agents: – Affinity for adrenoceptors – Efficacy on adrenoceptors – Interactions with neuronal uptake systems – Interactions with MAO and COMT NB this is regardless of whether they are agonists or antagonists Noradrenergic receptors defined in terms of potency for adrenergic receptors – see agonist potency order for Table 15.2 – Alpha – Beta  POTENCY: DRUGS AFFECTING THE ADRENERGIC NS - EXERCISE Noradrenergic receptors defined in terms of potency for adrenergic receptors – see agonist potency order for Table 15.2 Compare potency of NA , A , ISO with respective to their activities at Alpha 1 receptors Alpha 2 receptors Beta 1 receptors Beta 2 receptors Beta 3 receptors Agonists vs. Antagonists Direct acting and Indirect acting DRUGS AFFECTING THE ADRENERGIC NS Agonists Drugs acting directly on adrenoceptors Categorised by receptor type and receptor subtype Drugs that affect adreneric neurons (Indirect and Mixed Acting) Drugs that affect nor-adrenaline release Evoking nor-adrenaline release in absence of nerve terminal depolarization Interaction with pre-syptic receptors to indirectly inhibit/enhance depolarisation evoked release Inhibitors of nor-adrenaline uptake e  Physiological Effects Direct Acting Agonists – Actions Smooth muscles Smooth Muscles – Blood vessels:ᾳ1 mediated e.g. systemic administration of ᾳ1agonist →↑TPVR, Exercise explain the underlying mechanism by which systemic adrenergic agonist action on smooth muscles causes the following: – Increased peripheral vascular resistance (TPVR), – Resultant reflex bradycardia – Blood vessels: Beta 2 mediated. Beta2 mediated vasodilation in humans thought to be endothelial related and due to NO – Bronchial Relaxed by activation of B2 receptors and are important in treatment of asthma – Uterus Relaxation of uterine smooth muscles by activation on and can be used to delay premature labour. Note the issue of possible hyperglycemia if high doses of the B2 agonists. ?Mechanism for hyperglycemia?  Physiological Effects Direct Acting Agonists – Actions Smooth muscles Note the issue of possible hyperglycemia if high doses of the B2 agonists. ?Mechanism for hyperglycemia?  Physiological Effects Direct Acting Agonists - Actions Nerve Terminals – Presynaptic: Alpha2 mediated activity – Mainly inhibitory Heart – B1 receptors – ↑Inotropic, Chronotropic and O2 consumption Metabolism – General stimulation of metabolic activity – ↑Lypolysis, Hyperglycemia – Alpha 2 activity on inhibition of insulin Other Actions/Effects – Skeletal Muscles and – Performance enhancement – Please read the article below from US Pharmacist on use of B2 agonists for performance enhancement https://www.uspharmacist.com/article/approved-beta2-agonists-might-enhance-sports- performance-in-nonasthmatics – Impact on Histamin release in response to anaphylactic challenge ADRENERGIC AGONISTS– Adapted from Goodman and Gillmans ADRENERGIC RECEPTORS: CLASSIFICATION, RESPONSES and SELECTIVITY Note the significance if receptor subtypes to pharmacology i.e – some drugs may be selective whilst others are note – Some may be selective at certain doses and non selective with increasing dose. – Importance of knowing the receptor type and response as an essential step in learning autonomic pharmacology  Pharmacological agents on adrenoceptors - Exercise Examples selective agonists – Table 15.2 Examples selective antagonists – Table 15.2 Relevance of selectivity???  Direct Adrenergic Agonists Receptor Selectivity Adrenergic Agonist Receptor Selectivity Exercise : Application Drug α1 α2 β1 β2 DA1 DA2 Using your table – in text as well as Phenylephrine +++ + 0 0 0 0 opposite Predict Agonist effect for Methyldopa + + 0 0 0 0 the following agents on Organs as Clonidine + ++ 0 0 0 0 listed in the table below. Dexmedetomidin CO = HR × SV e + +++ 0 0 0 0 Scale 0, ↑, ↑↑, ↑↑↑ Epinephrine1 ++ ++ +++ ++ 0 0 Ephedrine2 ++ ? ++ + 0 0 Fenoldopam 0 0 0 0+++ 0 Mean Peripheral Bronch Heart Arterial Cardiac Vascular odilatio Norepinephrine1 ++ ++ ++ 0 0 0 Drug Rate Pressure Output Resistance n Dopamine1 ++ ++ ++ + +++ +++ Phenylephrine ↓ ↑↑↑ ↓ ↑↑↑ 0 Dobutamine 0/+ 0+++ + 0 0 Epinephrine ↑↑ ↑ ↑↑ ↑/↓ ↑↑ Terbutaline 0 0+ +++ 0 0 Note body as an interconnected 1The α1-effects of epinephrine, norepinephrine, and dopamine become more prominent at high doses. system with feedback loops and not 2The primary mode of action of ephedrine is indirect individual disjointed processes stimulation.  Clinical Use of Direct Adrenergic Agonists - Comprehensive Table 13.3 Summary of Drugs that affect Nor-adrenergic transmission  Clinical Use of Direct Adrenergic Agonists - Respiratory: – Asthma e.g. salbutamol and note evolution from older products like isoprenaline What is the underlying receptor mechanism involved and related effects contributing to use of salbutamol in asthma What are the likely side effects of oral salbutamol compared to inhaled /aerosol salbutamol? What attributes of isoprenaline contributed to its becoming obsolete for management of asthma? Why wouldnt Norepinephrine be used in treatment of asthma?  Clinical Use of Direct Adrenergic Agonists - Respiratory cont – Nasal Decongestion: Pseudophedrine alpha and beta activity. decongestant effect due to alpha1 activity is available in the pharmacy without a prescription in various formulations including oral. Why advise caution in hypertension underlying mechanism for this drug disease interaction etc?? Other decongestants e.g. oxymetazoline nasal drops. Why caution against use for extended periods of time? Please see link below for Journal read https://www.pharmacytimes.com/publications/issu e/2017/November2017/pseudoephedrine-uses- indications-and-adverse-effects  Clinical Use of Direct Adrenergic Agonists - Respiratory cont – Nasal Decongestion: Pseudophedrine alpha and beta activity. decongestant effect due to alpha1 activity is available in the pharmacy without a prescription in various formulations including oral. Why advise caution in hypertension underlying mechanism for this drug disease interaction etc?? Other decongestants e.g. oxymetazoline nasal drops. Why caution against use for extended periods of time? – Haemostatic in epistaxis: Adrenaline/Ephedrine. Note oxymetazoline nasal can be used in management of epistaxis as well.  Clinical Use of Direct Adrenergic Agonists - Comprehensive Table 11.3/13.3Summary of Drugs that affect Nor-adrenergic transmission Cardiovascular – Shock - Underlying mechanism? Alpa1 and alpha 2 because it increases vascular resistance and, therefore, increases blood pressure. However, dopamine is favored, because it does not reduce blood flow to the kidney, as does norepinephrine. – Malignant hypertension – Clonidine. Why is clonidine, an adrenergic agonist, being given for hypertension when another, below, is also given for hypotension – Hypotension (alpha 1 agonist) – Phenylephrine – Heart Block – B agonist – Isoprenaline rarely used – Hypertension – Alpha2 agonists e. g. clonidine, methyldopa  Clinical Use of Direct Adrenergic Agonists - Miscellaneous: – Mydriatic: Ephedrine – Glaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV. – With local anesthetics: Adrenaline & NA. used in dentistry because of their vasoconstrictive actions on blood vessels. Added to local anesthetics because they prolong the action of the local anesthetic, reduce the risk for systemic toxicity, and help to create a dry field. – Anaphylactic shock  Clinical Use of Direct Adrenergic Agonists - Exercise Miscellaneous: – Anaphylactic shock – epinephrine What symptoms of anaphylactic shoch does epinephrine reverse and explain the underlying mechanism  Clinical Use of Direct Adrenergic Agonists Miscellaneous – Premature labor contractions: e.g. Salmeterol and Salbutamol respectively. Why is Norepinephrine NOT used in treatment of asthma? Why is it important to measure blood sugar levels when high dose salbutamol is used in diabetics? Exercise Drugs accumulated by transporter (NET) and displace noradrenaline from vesicles in neuron allowing it to escape to act on post synaptic receptors E.g amphetamines, tyramine and ephedrine, methylphenidate Methylphenidate for ADHD, narcolepsy Effects enhanced by MAOI and may lead to severe hypertension Class prone to abuse Drugs that inhibit NET e.g. cocaine, Tricyclic antidepressants (TCA) Coccaine anesthesia TCA antidepressants, peripheral neuropathy etcEffective in hypertension but cause severe side effects (postural hypotension, diarrhea) therefore not used as much DRUGS AFFECTING THE ADRENERGIC NS – Antagonists – Next lesson Drugs Acting Directly on Adrenoceptors Catergorised by receptor Drugs that affect Adrenoceptor Neurons (Indirect Acting) Drugs that affect nor-adrenaline synthesis Drugs that affect nor-adrenaline storage Drugs that affect nor-adrenaline release