Adrenergics and Antiadrenergics - Pharmacology - Spring 2022

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T/F: Drugs are entirely specific for only one receptor subtype
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T/F: Drugs are entirely specific for only one receptor subtype
False
Drug A works one way for one person and the same drug works a completely different way for another person. Why is this?
Drugs can affect a person completely different depending on:
-cytochrome p450 enzyme
-body weight
-age
-renal function
-albumin levels, etc.
T/F: If a drug has a greater affinity for beta-1 receptors, if given at high enough concentrations, will affect beta-2 receptors.
True
What do vasopressors do?
They increase vasoconstriction -> increase in systemic vascular resistance (SVR) -> increase mean arterial pressure (MAP) -> increase perfusion to organs

essentially just raises BP to have more perfusion to organs
What do inotropes do?
They increase cardiac contractility -> improves cardiac output, aiding in maintaining MAP and perfusion to the body
What drugs are used to treat shock?
Vasopressors and Inotropes
Patient comes into the ER via ambulance for a serious infection in the blood. Blood pressure is 70/30, fever of 102.4, 38 heart rate and the ER doc says "we need to treat this patient for septic shock". What medications are necessary to help save this patients life?
Vasopressors and Inotropes
What are the 4 main types of shock?
1. Hypovolemic
2. Obstructive
3. Septic/ Distributive
4. Cardiogenic
What is an overall summary of shock?
Decreased perfusion to vital organs, leading to multi organ failure, which eventually leads to death
Release norepinephrine as the primary neurotransmitter
Adrenergic neurons
Stimulated by norepinephrine or epinephrineAdrenergic receptorsBlock the activation of adrenergic receptorsSympatholytic DrugsWhen dehydration or hemorrhage reduces the volume of blood in the body, this leads to what kind of shock?Hypovolemic ShockWhen the heart cannot pump blood effectively, (heart attack or an obstruction like a pericardial effusion), this leads to what kind of shock?Cardiogenic ShockWhen someone has an allergic reaction, this leads to what kind of shock?Distributive/Septic ShockDamage to the nervous system, blood vessels vasodilate, become leaky which reduces the resistance and lowers the blood pressure, this leads to what kind of shock?Neurogenic ShockWhere does the synthesis of norepinephrine occur?Pre-synapticWhere does the storage of norepinephrine occur?Pre-SynapticWhere does the release of norepinephrine occur?Synaptic cleftWhere does the binding to receptors of norepinephrine occur?Post-synapticWhere does the reuptake of norepinephrine occur?Pre-synapticAdrenergic drugs, also known as ___________, activate adrenergic receptors (or adrenoceptors)SympathomimeticDifference between Sympathomimetic and Sympatholytic drugs?Sympathomimetic: Activate or Bind to adrenergic receptors Sympatholytic: Block the receptorsWhat is considered "Direct-acting agonists"?When a drug directly activates the receptor on the post-synaptic effector organWhat is considered "Indirect-acting"?When a drug blocks the re-uptake of norepinephrine on the pre-synaptic side, on the neuron.What are the 4 things that can happen if a drug binds to an alpha 1 adrenergic receptor?- vasoconstriction (increase Peripheral Vascular resistance and BP) -Mydriasis (dilation of pupils) -Urinary retention (tighten the closure of bladder sphincter) -Trigger ejaculation (can cause impediment) *Alpha 1, think you're the alpha male/female running towards danger to save the day, so sympathetic nervous system is kicking in* (located in blood vessels, eyes, bladder)What happens when a drug binds to the alpha 2 adrenergic receptor?Inhibits norepinephrine, ACh release (negative feedback control of alpha 1)What are the 3 things that can happen when a drug binds to a Beta 1 adrenergic receptor?-Tachycardia (increase contractions) -Increase lipolysis (Break down of fat and other lipids) -Increase renin release, so increase BP (Located in heart, juxtaglomerular cells in the kidneys and stimulate lipoprotein lipase found on the surface of capillaries which break down triglycerides to FFA and cholesterol)What are the 5 things that can happen when a drug binds to a Beta 2 adrenergic receptor?-Vasodilation (decrease PVR and BP) -Relax uterine smooth muscles (birth) -Increase glucagon release -Bronchodilation -Increase aqueous humor flow (glaucoma) (Located in smooth muscle cells, lungs, live, bladder)What are the 2 categories of adrenergic agonists?Catecholamines or Non-catecholamines-High potency (neurotransmitters made by adrenals) -short half-lives, rapid inactivation -poor penetration into CNS -dopamine, epinephrine, norepinephrineCatecholamines-Low potency -longer half-lives -> prolonged duration of action -increase lipid solubility -> can cross BBB -phenylephrine, ephedrine, amphetamineNon-catecholamineProlonged exposure to, which kind of adrenergic agonist, reduces the responsiveness of alpha receptors, a phenomenon known as desensitization of receptors (tachyplaxis)CatecholamineBind to adrenergic receptors on the effector organ without interacting with the presynaptic neuronDirect-Acting Adrenergic AgonistEpinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine, Phenylephrine, Fenoldopam are examples of what kind of drugs?Direct-Acting Agents-Stimulates alpha 1, Beta 1 and Beta 2 -Increase BP (B1 action, (+) inotrope/chronotrope) (alpha action - potent vasoconstrictor) -Bronchodilation (Beta 2 action, acts directly on bronchial smooth muscle, decreases allergic mediators (release of histamines from mast cells) -Hyperglycemic effect (adverse effect), increase glycogenolysis (Beta effect) and decrease release of insulin (alpha 2) -Lipolysis (Beta 1 action on adipose tissue, increases cAMP stimulate a hormone-sensitive lipase)EpinephrineMechanism of action, stimulates alpha 1, beta 1, beta 2 adrenergic receptors. At lower doses - increase Beta effects (vasodilate bronchioles). At higher doses - increases alpha effects (vasoconstriction)EpinephrineThis drug is used for anaphylaxis, anaphylactic shock -Common use because it acts quickly -Improves breathing -stimulates the heart (increase a dropping BP) -reverse hives, reduce swelling -increases after loadEpinephrineThis drug is used for Bronchospasms -emergency tx for asthma attack -quick onset, short duration of actionEpinephrineThis drug is used for Cardiogenic Shock -restores cardiac rhythm (hypotension) -(+) inotropic effect and vasoconstriction (increase TPR)EpinephrineThis drug is used as a 2nd line agent for septic shockEpinephrineWhat is the first line agent for septic shock?NorepinephrineThis drug is used in conjunction with a local anesthetic, it delays absorption of lidocaineEpinephrineCauses vasoconstriction of blood vessels and acts as a homeostatic agentEpinephrineWhat are some adverse effects that present with epinephrine?-CNS effects (anxiety, feat, tension, agitation) -Acute pulmonary edema (causes excess load on left ventricle, causing accumulation of fluids in air sacs of lungs) -Tachycardia (Beta 1 adrenergic receptor stimulation)What is the drug? Action -Simulates alpha adrenergic receptors causes INTENSE VASOCONSTRICTION - increases peripheral resistance -> increase BP Therapeutic Use -Shock IV, Severe Septic Shock, severely hypotensive Adverse Effects -similar to epinephrine -Potent vasoconstrictor -should not be given peripherally due to tissue necrosis (caustic agent) Given for SEVERE SEPTIC SHOCK, ONLY REASON TO GIVE THIS DRUGNorepinephrine1st choice for septic shock?NorepinephrineWhat is the treatment for extravasation?-Stop the injection, remove IV -administer phentolamine (alpha adrenergic antagonist) -Antidote = hyaluronidase (degrades acid) -application of hot or cold packs and/or sterile occlusive dressings, and elevation and rest of the affected limb.Actions (inotropic and chronotropic agent) -B1 effect: intense stimulation of heart (increases HR, CO, contractility) -B2 effect: vasodilation and decrease MAP (decrease peripheral resistance (dilates the arterioles of SKM) and also is a potent bronchodilator) Therapeutic Use -Hypotension due to bradycardia due to: (AV bloc, during tilt table test syncope)IsoproterenolActions (dose dependent) -alpha 1 vasculature effects: vasoconstriction, higher doses stimulates receptors -beta 1 cardiac affects (+) inotropic and chronotropic, lower doses stimulates receptors -Renal effect: Increase renal blood flow and urine production Therapeutic Use -Cardiogenic shock: severe heart failure, oliguria -Septic ShockDopamineImmediate precursor of norepinephrine, occurs naturally in CNS and adrenal medullaDopaminePharmacokinetics Rapid acting (1/2 life is <2 minutes (so given as a continuous infusion), rapidly metabolized by MAO or COMT, enzymes)) Adverse Effects -overdose produces same effects as sympathetic stimulation -nausea, HTN, arrhythmiasDopamineActions -Beta 1 receptor agonist ((+) inotropic effect with little increase in HR, increase in CO so increase blood flow to kidneys and gut, causes less tachycardia) Therapeutic Use -Cardiogenic Shock (increase CO), acute HF, after cardiac surgery to increase inotropic support, acute myocardial infarction Cardiac effects -improves the balance between myocardial oxygen demand and supply by increasing coronary blood flowDobutaminePharmacokinetics -Short term -1/2 life about 2 minutes used as an IV drip -Tolerance develops Adverse Effects -CAUSES AFIB -Tolerance may develop with prolonged useDobutaminePeripheral dopamine D1 receptor agonistFenoldopamTherapeutic Use -Severe HTN, IV (rapid acting vasodilator -> coronary arteries, kidney arterioles, and mesenteric arteries Adverse Effects -headache, flushing, dizziness, n/v, tachycardia Pharmacokinetics -1st pass metabolism, 10-minute elimination half-life after IV infusionFenoldopamAction -alpha 1 receptor agonist direct acting -vasoconstrictor that raises both SBP and DBP -no effect on heart itself, rather it induces reflex bradycardia when given parenterally Therapeutic Use -Shock, Hypotension (given when norepinephrine is contraindicated due to arrhythmia, failed other therapies, CO is high and BP is low) -Nasal congestion- intranasal "Ultra Drug"PhenylephrineVasoconstrictor, directly stimulates alpha receptors on blood vessels supplying the nasal mucosa, conjunctiva, vasoconstriction and decreasing congestion -eye drops= decrease redness. -can cause rebound congestion and dependence occurs with long-term useOxymetazolineActions Centrally acting on alpha 2 receptors, blocks sympathetic activity by binding to and activating alpha 2: -decrease sympathetic outflow to heart, thereby decreasing CO, HR and contractility -decreases sympathetic output to vasculature, thereby decreasing sympathetic vascular tone -> vasodilation and decrease arterial blood pressure Used for HTNClonidineTherapeutic Use -HTN -Minimize symptoms of withdrawsClonidineSelective alpha 1 agonist, acts in peripherally -increases arterial and venous tone -orthostatic hypotensionMidodrine-An increase release of this will inhibit reuptake, or inhibit degradation of epinephrine or norepinephrine -They can increase the amount of epinephrine or norepinephrine in the pre-synaptic cleft but do not directly affect postsynaptic receptors Some examples are: Amphetamines and Cocaine as well as TyramineIndirect-acting adrenergic agonist