PHID1502 Integrated Sequence 2 Pharm Adrenergic agonists Winter 2024-2025 Lecture PDF

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Adrenoreceptor activating drugs (Agonists) Required reading: Foye’s, Sixth Edition – Chapter 13, pages 392 – 416; Foye’s, Fifth Edition Online – Chapter 10...

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024-2025 Adrenoreceptor activating drugs (Agonists) Required reading: Foye’s, Sixth Edition – Chapter 13, pages 392 – 416; Foye’s, Fifth Edition Online – Chapter 10 Recommended: Katzung, Eleventh Edition - Chapter 9, pages 127 – 148. Oliver Grundmann, Ph.D. Adjunct Assistant Professor (MWU) Clinical Professor (UF) Phone: 352-246-4994 [email protected] Winter quarter 2024-2025 [email protected] 2 Definitions Catecholaminergic: pertaining to norepinephrine, epinephrine or dopamine effects Decongestant: a drug that decreases nasal or oropharyngeal mucosal swelling, usually by constricting blood vessels in the submucosal tissue Direct agonist: directly binds to and activates the receptor to cause the agonist effect Indirect agonist: brings about receptor activation by binding to some other molecule, e.g., a reuptake carrier or enzyme, causing an increase in the synaptic concentration of the normal neurotransmitter Winter quarter 2024-2025 [email protected] 3 Definitions Mydriatic: a drug that causes dilation of the pupil; opposite of miotic “Selective” alpha or beta adrenergic agonist: drugs that have relatively greater effects on alpha or beta adrenergic receptors; none are absolutely selective for a specific receptor Sympathomimetic: a drug that mimics stimulation of the sympathetic autonomic nervous system (SNS) when applied Winter quarter 2024-2025 [email protected] 4 Definitions Reuptake Inhibitor: an indirectly acting drug that increases the activity of the neurotransmitter in the synapse by inhibiting the reuptake of the transmitter back into the presynaptic nerve terminal; may act on more than one transporter at a time (i.e. norepinephrine and serotonin); considered an indirect agonist Winter quarter 2024-2025 [email protected] 5 Sympathomimetic drugs/adrenergic agonists - spectrum of action D-amphetamine TCAs/SSRIs terbutaline dobutamine isoproterenol clonidine midodrine phenylephrine  Winter quarter 2024-2025 [email protected] 6 Direct, indirect, and mixed modes of action for sympathomimetic drugs Direct Bind and activate adrenergic receptors directly Indirect Displace stored catecholamines from adrenergic nerve endings (tyramine) Inhibition of reuptake (cocaine and TCAs) Mixed Drugs that possess both direct and indirect activities (amphetamine) Winter quarter 2024-2025 [email protected] 7 Organ system effect – receptor specificity Overall effect determined by: Receptor affinity Intrinsic activity Compensatory reflexes Winter quarter 2024-2025 [email protected] 8 Receptor specificity of direct sympathomimetics Winter quarter 2024-2025 [email protected] 9 Cardiovascular system effects Blood vessels – (smooth muscle tone is affected – response depends on which receptor is dominant in the tissue and the specificity of the drug)  increases arterial resistance (vasoconstriction) 2 causes smooth muscle relaxation D1 causes vasodilation Significant differences in receptor types found in vascular beds Skin vessels – mostly  Splanchnic – mostly  Skeletal muscle – both  and  Renal, splanchnic, coronary & cerebral – dopamine Winter quarter 2024-2025 [email protected] 10 Cardiovascular system effects Heart – mostly 1 Increase calcium influx Positive chronotropic – increase pacemaker rate Conduction velocity AV node increased Refractory period is decreased Positive inotropic effects Presence of normal reflexes – may get domination by reflex response to blood pressure changes Winter quarter 2024-2025 [email protected] 11 Cardiovascular system effects Blood pressure Pure alpha agonist – phenylephrine Increases peripheral arterial resistance Decreases venous capacitance Increase blood pressure (α1) but a reflex or compensatory decrease in heart rate (decreased β1) Cardiac output may not change - increase venous return may increase stroke volume Pure beta agonist - isoproterenol - Increases cardiac output (β1; heart rate & contractility). β2 effect vasodilates select vascular beds so net effect is based on balance of effect Winter quarter 2024-2025 [email protected] 12 Cardiovascular system effects Winter quarter 2024-2025 [email protected] 13 Visual system effects Eye 2 agonist – increases aqueous humor outflow  agonist – increases the production of aqueous humor 1 agonist – contracts pupillary dilatory muscle causing dilation of the pupils → mydriasis Winter quarter 2024-2025 [email protected] 14 Respiratory system effects Respiratory tract 2 → bronchodilation 1 → blood vessels of upper respiratory tract vasoconstrict - basis of decongestant action of adrenoceptor stimulants Winter quarter 2024-2025 [email protected] 15 Gastrointestinal & genitourinary effects Gastrointestinal 1/ 2 → relax GI smooth muscles Genitourinary Human uterus contains both  and 2 2 – mediates relaxation → useful in pregnancy Bladder base, urethral sphincter and prostate 1 promotes contraction → urinary continence or retention 2 mediates relaxation Ejaculation – proper  receptor activation Winter quarter 2024-2025 [email protected] 16 Metabolic effects Metabolic effects on intermediary metabolism 3 activation in fat cells → lipolysis 2 in lipocytes → inhibits lipolysis by decreasing intracellular cAMP Sympathomimetic drugs increase glycogenolysis in the liver → mostly  but  may play a role β2 promotes potassium (K+) uptake into cells → decrease extracellular fluid (ECF) K+ Winter quarter 2024-2025 [email protected] 17 Metabolic effects Winter quarter 2024-2025 [email protected] 18 Exocrine and endocrine glands Exocrine glands Clonidine → dry mouth Mechanism unknown Central effect Endocrine glands 2 receptor activation → stimulates insulin secretion in beta cells of the Langerhans Islet cells of the pancreas Inhibited by 2 Renin stimulation by 1, inhibited by 2 One mechanism by which -receptor antagonists are effective for the treatment of hypertension (lower renin secretion?) Winter quarter 2024-2025 [email protected] 19 Central Nervous System Effects vary significantly with ability to pass BBB Catecholamines do not pass based on charge (basic amine) Effects only seen at highest rate of infusions Nervousness → to impending doom Peripheral effects of  agonist – similar to somatic feelings of anxiety Tachycardia Tremor β-antagonists may provide benefits for treating migraines and tension headaches Noncatecholamines with indirect actions – amphetamine enhances dopamine effects in the CNS Mild alerting effects Improved attention to boring tasks Elevation of mood Insomnia Euphoria Anorexia Psychotic behavior  Winter quarter 2024-2025 [email protected] 25 CNS effects - amphetamine Amphetamine low concentrations Amphetamine high concentrations Winter quarter 2024-2025 [email protected] 26 Dominant effects of adrenergic drugs Blood vessels: α1 constricts smooth vasculature → increased blood pressure initially, but reflex slow heart rate Heart: β1 increase heart rate and force, increases blood pressure initially Bronchial Smooth Muscle: β2 relaxes smooth muscles & open airways Eye: α1 constricts muscle and dilates pupils (also constricts nasal mucosa) CNS: varied effects  Winter quarter 2024-2025 [email protected] 27 Catecholamines – receptor selectivity Catecholamines Epinephrine (Adrenalin): 1 = 2 ; 1= 2 Significant  &  agonist → vasoconstrictor, cardiac stimulant, and bronchodilation Norepinephrine (Noradrenalin): 1=2 ; 1 >> 2 Isoproterenol: 1= 2 >>>>  Dopamine: D1 = D2>>>>>others Winter quarter 2024-2025 [email protected] 28 Catecholamines – cardiovascular effects Increased potency Winter quarter 2024-2025 [email protected] 35 Dopamine & sympathomimetics Dopamine D1= D2 >> 1>> 1 D1 → vasodilation Especially important for renal blood flow and shock Activation of presynaptic D2 → suppresses norepinephrine release Activates 1 in heart Higher doses effect vascular  → vasoconstriction → at high concentration mimics the actions of epinephrine Fenoldopam (Corlopam) D1>> D2 Causes peripheral vasodilation → used in severe hypertension Dobutamine (Dobutrex) 1> 2 >>>>  1 selective but can also activate 1  Winter quarter 2024-2025 [email protected] 36 Adrenergic agonists – α receptors Phenylephrine: 1 > 2 >>>>> 1 Direct acting ”pure” α agonist Not a catechol – not inactivated by COMT → longer duration of action Effective mydriatic and decongestant Can be used to raise blood pressure Midodrine (ProAmatine): 1 selective agonist Prodrug - hydrolyzed to desgly- midodrine - peak effect 1 hr after administration Primary Use: chronic orthostatic hypotension Unlabeled use – urinary incontinence Methoxamine (Vasoxyl): 1 > 2 >>>>> 1 Similar to phenylephrine pharmacologically Limited use – only in hypotensive states Increased BP (vasoconstriction) & reflex bradycardia Midodrine Winter quarter 2024-2025 [email protected] 37 Adrenergic agonists – α receptors Other newer direct acting alpha agonists: Xylometazoline (Otrivin) and oxymetazoline (Afrin) Direct acting 1 agonists Topical decongestants → constrict nasal mucosa Continued use beyond 5 days may lead to rebound congestion → Rhinitis medicamentosa Large dose of oxymetazoline → hypotension similar to clonidine High 2a affinity as well Winter quarter 2024-2025 [email protected] 38 Adrenergic agonists – α receptors Alpha2 Receptor selective drugs 2 selective agonists: 2 > 1 >>>>>  Decrease blood pressure → central effect, decreasing sympathetic outflow Binds to non-adrenegic receptor → imidazoline receptor – may mediate antihypertensive effect Local application produces vasoconstriction Drugs in class Clonidine (Catapress) Methyldopa (Aldomet) – converted to active metabolite → methylnorepinephrine Guanfacine (Tenex) – may have less adverse effects than clonidine Guanabenz (Wytensin) Dexmedetomidine (Folalin) – indicated for sedation during initial intubation Winter quarter 2024-2025 [email protected] 39 α2 receptor agonists – mechanism of action Winter quarter 2024-2025 [email protected] 40 Adrenergic agonists – β receptors Isoproterenol: 1= 2 >>>>  very potent but unselective β agonist almost devoid of α receptor effects result: increased force of contraction, heart rate & also a potent bronchodilator Winter quarter 2024-2025 [email protected] 41 Adrenergic agonists – β receptors 1 selective agonists Dobutamine: 1> 2 >>>>  Two isomers & given as a racemic mixture (+)-isomer is a potent 1 agonist and 1 antagonist (less reflex tachycardia because less vasodilation through 2 ) (-)-isomer is an 1 agonist Significant vasoconstriction when given alone & reduces vasodilation contributes to inotropic action caused by isomer with predominate  activity Limitation – tolerance may develop with prolonged use  Winter quarter 2024-2025 [email protected] 42 Adrenergic agonists – β receptors 2 selective agonists used for asthma 2-selective agents – short acting Albuterol (Proventil; Ventolin) – inhalant, oral Bitolterol (Tornalate) – inhalant Metaproterenol (Alupent; Metaprel) – inhalant, oral Pirbuterol (Maxair) – inhalant Terbutaline (Brethine; Bricanyl) – inhalant, oral, parenteral Lavalbuterol (Xenopex) – inhalant 2-selective agents – long acting Salmeterol (Serevent) – inhalant Formoterol (Oxis, Foradil) 2 selective agonists used for uterine relaxation in premature labor Ritodrine (Yutopar) Terbutaline (Brethine) Winter quarter 2024-2025 [email protected] 43 Adrenergic agonists – mixed agonists Ephedrine - release of stored catecholamines with some direct action Plant constituent Non-catechol → long duration of action Nonselective, similar to epinephrine in actions Mild stimulant → enters CNS Use: Nasal decongestant Pressor agent Stress incontinence in women Pseudoephedrine – indirect only Nasal decongestant Stress incontinence in woman Winter quarter 2024-2025 [email protected] 44 Adrenergic agonists – indirect agonists – Mechanisms of Action Winter quarter 2024-2025 [email protected] 45 Adrenergic agonists – receptor selectivity for indirect agonists Winter quarter 2024-2025 [email protected] 46 Adrenergic agonists – indirect agonists Amphetamine (Dexedrine) – indirect only CNS stimulant Peripheral actions → release of catecholamines Mood, alertness, appetite suppressant Dexedrine® contains only dextroamphetamined Adderall® contains both dextro- and levamphetamine Methamphetamine (Desoxyn) Higher ratio central to peripheral effect Both regulated in DEA schedule II because of high potential for abuse and dependence Winter quarter 2024-2025 [email protected] 47 Adrenergic agonists – indirect agonists Phenmetrazine - indirect only Anorexiant and drug of abuse Methylphenidate (Ritalin) - indirect only With amphetamine – Treatment of ADHD Mephentermine (Wyamine) & Metaraminol (Aramine) - both direct and indirect actions Modafinil (Provigil) Effects on central 1B receptors and also has effects on GABA, glutamine, and serotonin neurotransmission Used for narcolepsy & sleep disorders Provigil® vs. Adderall® Winter quarter 2024-2025 [email protected] 48 Adrenergic agonists – indirect agonists Tyramine Naturally occurring in body High concentration in fermented food (cheese, wine, etc.) Metabolized by monoamine oxidase (MAO) in liver Oral use – high first pass metabolism If administered IV – indirect sympathomimetic actions that releases stored catecholamines Patients on a monoamine oxidase inhibitor (MAOI) who ingest foods high in tyramine → can lead to significant drug-food interactions Significant increase in blood pressure Therefore should avoid foods high in tyramine Winter quarter 2024-2025 [email protected] 49 Adrenergic agonists – other sympathomimetics Cocaine: Local anesthetic through blockade of sodium channels Peripheral sympathomimetic action via inhibiting reuptake of norepinephrine and dopamine CNS – produces a shorter-lasting and more intense effect than amphetamine Major action at dopaminergic pleasure center of brain – inhibit dopamine reuptake Ergot alkaloids (e.g. ergonovine (Ergotrate) & ergotamine (Ergomar))  agonists (but with many other interactions on serotonin, acetylcholine and additional receptors) Powerful vasoconstrictors Ergotism – CNS effects - hallucinations Winter quarter 2024-2025 [email protected] 50 Adrenergic agonists – “selective” reuptake inhibitors Atomoxetine – selective norepinephrine reuptake inhibitor Treatment of attention deficit disorders (ADHD) little cardiovascular effects (central vs peripheral effects) orthostatic tachycardia can occur Reboxetine – similar to Atomoxetine Sibutramine – selective serotonin & norepinephrine reuptake inhibitor the only appetite suppressant approved by the FDA for long term treatment of obesity Duloxetine – another serotonin & norepinephrine reuptake inhibitor Antidepressant and anti-anxiety as well as urinary stress incontinence Winter quarter 2024-2025 [email protected] 51 Catecholamines & Non-catecholamines Winter quarter 2024-2025 [email protected] 52 Adrenergic agonists – therapeutic applications Treatment of Acute Hypotension/Shock Chronic Orthostatic Hypotension Cardiac Applications Inducing Local Vasoconstriction Pulmonary Applications: Asthma Anaphylaxis Ophthalmic Applications: mydriatic & glaucoma Genitourinary Applications: premature labor & stress incontinence CNS Applications: narcolepsy, appetite suppressant, ADHD Winter quarter 2024-2025 [email protected] 53 Acute hypotension and chronic orthostatic hypotension Acute Hypotension Use only to preserve cerebral and coronary blood flow Severe hemorrhage Spinal cord injury Overdose of antihypertensive or CNS depressant Usually best to just place patient in recumbent position and give IV fluids Use of these drugs may increase morbidity when used in non- life threatening situations Direct acting  agonists – if vasoconstriction is desired (norepinephrine or phenylephrine, methoxamine) Chronic Orthostatic Hypotension Oral ephedrine – used traditionally Midodrine – α1 agonist, is now replacing ephedrine  Winter quarter 2024-2025 [email protected] 54 Shock Shock: typically due to hypovolemia, cardiac insufficiency, or altered vascular resistance Volume replacement & treatment of underlying disease best course of action Efficacy of drugs is unclear - vasoconstriction via compensatory sympathetic discharge may already be significant so may need to reduce peripheral vascular resistance to allow cerebral and/or renal perfusion Cardiogenic shock (due to massive myocardial infarction) - use of positive inotropic agents (dobutamine or dopamine) may be needed (increase cardiac output) Goal: Optimize tissue perfusion, not blood pressure Beneficial effects of vasoconstriction → improvement of coronary perfusion possible but Deleterious effects → increased cardiac oxygen demand & constriction of vessels in abdominal viscera Winter quarter 2024-2025 [email protected] 55 Cardiac applications Congestive heart failure Positive inotropic effects - dobutamine Tolerance and desensitization may limit usefulness Complete Heart Block or myocardial infarction Epinephrine or isoproterenol while awaiting pacemaker placement Hypertension 2 agonists at central level (clonidine) Anaphylaxis Since this involves immediate IgE-mediated reactions that affect both the respiratory and cardiovascular system - usually helped by IM epinephrine (0.3 - 0.5 mg of 1:1000 solution) Drug of choice since α, β1 and β2 receptor activation Secondary treatment – glucocorticoids & antihistamines Winter quarter 2024-2025 [email protected] 56 Glaucoma Epinephrine & Dipivefrin (prodrug of epinephrine) which lower intraocular pressure by: Increasing aqueous outflow Now Rarely Used because of systemic side effects! 2 selective agonists Apraclonidine (Iopidine) - second line Brimonidine (Alphagan) - first line Increase aqueous outflow β blocking agents now primarily used Decrease aqueous humor production Timolol, betaxolol, carteolol, levobunolol, metipranolol Winter quarter 2024-2025 [email protected] 57 Genitourinary applications Suppress premature labor 2 selective agents relax the uterus (tocolytic) Other options for tocolytic action are available (with less chance of maternal morbidity?) Ritodrine (Yutopar) Terbutaline (Bricanyl) Stress incontinence Oral use of ephedrine or pseudoephedrine Priapism Use 1 agonists (phenylephrine) via injection into the penis to cause detumescence Winter quarter 2024-2025 [email protected] 58 Central Nervous System applications Addiction Craving decreased with clonidine treatment (for narcotics, ethanol, nicotine) Narcolepsy Sudden brief sleep attacks – duration is up to 30 minutes Modafinil (Provigil®), a newer amphetamine substitute, is approved for narcolepsy (effects alpha1b, GABA, serotonin, and glutamate receptors) Appetite Suppression short term with amphetamine like drugs Winter quarter 2024-2025 [email protected] 59 Attention Deficit and Hyperactivity Disorder (ADHD) Amphetamine and amphetamine-like drugs have a mood- elevating (euphoric) effect & alerting, sleep-deferring action that helps to improve attention to repetitive tasks Treatment is to modulate dopamine and norepinephrine neurotransmission 3-5 % school-aged children diagnosed 10-50 % show symptoms into adulthood Stimulants effective in ~ 80 % Risk of dependence Many still need multimodal therapy (e.g. family therapy, classroom interventions) Clonidine & methylphenidate have shown some effectiveness Atomoxetine (Strattera®) – selective norepinephrine reuptake inhibitor Winter quarter 2024-2025 [email protected] 60 Bronchial asthma & COPD Clinical symptoms of asthma are recurrent episodes of bouts of coughing, shortness of breath, chest tightness, and wheezing Asthma is responsible for: 500,000 hospital admissions 5,000 deaths a year 1-3 % of all physician office visits Pathophysiology of asthma Asthma is primarily an inflammatory illness that causes: bronchial hyperactivity, bronchoconstriction, and bronchospasm. Increased number of inflammatory cells found in asthmatics. Since inflammation underlying problem bronchodilators use limited to symptomatic relief COPD (chronic obstructive pulmonary disease) is a structural disorder that is not associated with inflammation but a narrowing of the airways COPD is the 3rd leading cause of death in the US Increase in incidence in smokers and through occupational exposure Nonselective agents used – epinephrine & isoproterenol 2 selective drugs more effective & less toxic Winter quarter 2024-2025 [email protected] 61 Bronchial asthma & COPD – therapeutic approaches Short-term relievers Short acting -adrenoceptor agonists (albuterol, terbutaline) Cause Bronchodilation via direct relaxation of airway smooth muscle Treatment by inhalation alone – effective in > 90 % who can handle inhalers Systemic corticosteroids Long-term controllers Inhaled corticosteroids Inhibitors of mast cell degranulation Leukotriene antagonists Methylxanthines (theophylline) Long acting -adrenoceptor agonists (salmeterol, formeterol) Increase lung functions, decrease symptoms of asthma, decrease use of short acting agents, and decrease nocturnal asthma – but not associated with decrease in airway inflammation – need inhaled corticosteroids. Corticosteroids are not effective in long-term treatment of COPD but reduce or prevent acute exacerbations Winter quarter 2024-2025 [email protected] 62 Adrenergic agents - toxicity Extension of pharmacological response Cardiovascular system Marked elevation in blood pressure Cerebral hemorrhage Pulmonary edema Increased cardiac work load Angina Myocardial infarction Sinus tachycardia (β receptors) → ventricular arrhythmia Myocardial damage from long infusion Reversal of effect – use specific antagonist Central Nervous System Cocaine – convulsions, cerebral hemorrhage, arrhythmias, myocardial infarction