Exam 4 - Lecture 37-38, Pharmacology of Sympathomimetics Flashcards
Primary endogenous neurotransmitters in the SNS
NE, E, DA
Primary drug targets in the SNS
a and b adrenergic receptors
Dopamine receptors
Monoamine transporters biosynthetic pathways
What does SNS do
Releases E and NE
Increases Heart and Lung action
Constricts bodily blood vessels, but increase blood flow to muscle
Increase BP, HR, BS, and fats
Releases Glucagon (increase glucose)
Inhibit digestion, relax bladder and inhibit erection
Promote clotting
Neuronal Membrane Transporters
NET, DAT, SERT
transport monoamines, rely on Na gradient to passively transport monoamines
Vesicular monoamine transporter
responsible for pacing monoamines into vesicles preventing MAO degradation.
relies on trans-vesicular proton gradient for driving force
Vesicles contain ATP and chromogranin A
Extraneuronal monoamine transporter
Passive transport, no ATP
Bind 1 molecule or ion, changes conformation and releases cargo opposite side of membrane
Transports HA, 5HT, NE, DA, MPP+
Found on SM, Cardiac Muscle, Endothelium
inhibited by drugs of abuse; cocaine, MDMA, amphetamines
Selectivity
Describes the property of a ligand having greater affinity for one receptor over another
Can be “overcome” with high concentrations of ligand, when other receptors experience binding and activation
Receptor Activation
Depends on drug structure, dose, receptor number, receptor status, physiology, disease state, polymorphisms, species
Also mood, atmosphere, place, diet, will, spirituality
Histamine greatest affinity for…
Vmat2 over Vmat 1
EMT vs Neuronal MT
EMT as quick transport and has higher saturation than Neuronal MT
Alpha 1a,1b,1d distribution
Bronchi GI tract GI sphincters Uterus Bladder sphincter Seminal tract Iris (radial muscle) Liver (hepatocytes) Salivary gland
Alpha 2a,2b,2c
GI tract
Directly on Pancreatic islet (beta cells) + Platelets
Brain stem
Nerve terminals
Predominantly presynaptic nerve terminals on brainstem causing presyanptic inhibitory effect
B1
HEART and salivary gland
B2
BRONCHI and uterus, heart, mast cells, liver
B3
Bladder detrusor
Skeletal muscle
Fat
Skeletal muscle contraction
Calcium binds troponin allowing for troponin to interact with actin/myosin allowing for muscle contraction
Fast and direct mechanism, little pharamcological activity
Cardiac muscle contraction
Still fast but has a plateau period (~100ms) after initial rapid depolarization. Cardiac specific RyR Ca channels release Ca2+ from sarcoplasmic reticulum.
contractile machinery of Troponin/Ca troponin resembles SKM
Ca2+ release from RyR Ca channels may cause arrhythmia. Of interest in adrenergic blockers
Smooth muscle contraction
Large organ variance in contraction.
** Not entirely dependent on depolarization as GPCR ligands by IP3 trigger Ca2+ release from the ER.
cAMP regulates myosin Lc kinase and myosin phosphatase to balance contraction/relaxation
several ways to have smooth muscle contraction
Alpha 1 receptor Signaling
Epinephrine> Norepinephrine affinity (but effect same)
a1 stimulates Gq coupled to PLC; PLC gets phosphorylated (activated)
PLC then hydrolyzes phosphoinositides, produces IP3 and DAG
DAG activates PKC and leads to cellular response
IP3 releases stored intracellular Ca and activates Ca channels
increased cytoplasmic Ca activates Ca dependent kinases leading to cellular response
Predominantly found in SM, all types of SM (except GI tract) contract in response to stimulation of a1-adrenoceptors
a1 effect on Bronchi
Contraction (narrowing)
a1 effect on GI tract + GI sphincter
relaxation(decrease motility) + contraction (decrease motility)
a1 effect on uterus
contraction (child birth/miscarriage)
a1 effect on Bladder sphincter
contraction (narrowing)
a1 effect on Seminal tract
contraction (ejaculation)
a1 effect Iris
contraction (small pupils)
a1 effect Liver
Glycogenolysis (increase glucose synthesis)
a1 effect salivary gland
K+ release (profuse saliva)
Alpha 2 receptor signaling
receptor found in blood vessels, presynaptic GI NMJ, pancreatic Bcells, platelets, brain stem and nerve terminals
Common effects due to negative feedback on presynaptic nerves to inhibit further release of NE from presynaptic nerve terminal
Gai, inhibit Adenylate Cyclase, decrease cAMP + PKA
a2 effect on Blood vessels
constriction (a2b) or dilation (a2A)
a2 effect on GI tract
Presynaptic relaxation (decrease motility)
a2 effect on Pancreatic B cells
Decreased insulin release
a2 effect on platelets
Aggregation
a2 effect on brain stem
inhibit sympathetic flow
a2 effect on Nerve terminals
Adrenergic: Decrease NE release
Cholingeric: Decrease ACH release
Locus ceruleus: Sedative
Dorsal horn: Analgesic effects
Beta receptor Signaling
receptor all signal by increase cAMP/PKA
B1 Primarily in heart (also salivary glands)
B2 receptors in SM, Heart, SKm, mast cells, nerve terminal
B3 small pharmacopeia, found in bladder SKm and fat
B1 activation
Increase HR, Force of contraction
Increase amylase secretion salivary gland
B2 activation
Increase HR, force of contraction
Bronchi Dilation
Relax Gi tract, uterus, bladder, seminal tract, ciliary muscle
Mast cell: inhibit histamine release (stop allergic reaction)
SKm: tremor, increase mass, speed of contraction and glycogenolysis
Adrenergic nerve terminal: increase Ne release
B3 activation
** Bladder detrusor: relax (increase flow) **
SKm: thermogenesis (“burn rate”)
Fat: increase lipolysis and thermogenesis
Dopamine Receptor signaling
D5R and D1R = Gs ( up cAMP)
D4R, D3R, D2R = Gi (down cAMP
D1 receptor activation
Increase HR and cardiac output
Improved renal perfusion and urine output in kidney
Can cause arterial vasodilation
Dopamine
Equal affinity for D1 and D2 receptor
Used for heart failure, shock and unstable bradycardia
Fendolpam
Hypertensive crisis/hypertension
methyldopa
increase inhibitory effect of a2
Epinephrine (Adrenaline)
released from adrenal medulla during excitement/stress
Potent alpha and beta agonist, highest affinity at a2, medium b1, b2 lowest…potent bronchodilator
Releases sugar stored in liver
increase strength of HR muscle contractions, increase HR and BP due to constrictions of blood vessels at higher doses
Lower eye pressure
Effect of epinephrine on vascular smooth muscle
number of a1> b2 receptors
At low doses, epinephrine selectively stimulates B2 leading to vasodilation (muscle relaxation and decrease in peripheral resistance)
At higher doses, epinephrine can activate a1 leading to vasoconstriction
as conc increase, predominate effect will vasoconstriction
Norepinephrine
released presynaptically
used to increase BP in hypotensive states
Good to use with anesthetics
Can be given IV,IM or SC but orally ineffective due to GI MAO
Dopamine usage
activates Dopamine receptors and B1 receptors, at high doses also a1 receptors
positive iontropic and chrontropic effects
At low doses, dilates renal (kidney) and mesenteric (intestinal) arteries via D1 receptors
Vasodilation - vascular D1 receptors respond at low concentration
Direct Acting drugs
at postsynaptic receptors
Mimic E, NE, DA
Indirect Acting drugs
blocking the breakdown or reuptake of neurotransmitters, or stimulating production and release of catecholamines
Increase levels of E,NE, DA
Fenoldopam (Dopamine receptor analog)
D1 partial agonist, no B receptor activity
May have a1 and a2 antagonist activity
Side effect:
Tachycardia, arrhythmias
headache and flushing
Contraindications: patients with asthma may have adverse effect to metabolites; avoid use in glaucoma and in patients on beta-blockers
Indications:
Antihypertensive, decreases cardiac after load
FDA pregnancy/lactation:
Class B
Dopamine as drug
B1 receptor agonist used in sever congestive heart failure
in low doses, vasodilation, increase sodium secretion
Direct-acting a-receptor agonist
Phenylephrine Oxymetazoline Methoxamine Midodrine Clonidine Brimonidine Guanfacine
Direct-acting b-receptor agonist
Dobutamine Terbutaline Albuterol/levalbuterol Brimonidine Salbutamol Salmeterol Clenbuterol Mirabegron
Phenylephrine (OTC)
Highly selective a1 agonist
Pregnancy class X 1st trimester, C 2nd trimester
Oral decongestant
Can be used in some hemorrhoid treatments
Oxymetazoline (OTC)
Selective a1 agonist
Intranasal admin, nasal decongestant by vasoconstriction
t1/2 ~ 8hr
Pregnancy class C, potentially B due to low systemic absorption
Midodrine
Prodrug, forms desglymidodrine (a1 receptor agonist)
** Only FDA approved to treat orthostatic hypotension **
Side effects:
Headache, flushing face (vasodilation), confusion/abnormal thoughts
Pregnancy class X: risk of fetal resorption, decrease fetal weight and increase risk of miscarriage
Methoxamine
Alpha 1 receptor agonist
Used for BP maintenance during surgery (no b activity)
Contraindicated: patients with hypertension
side effects: Acute nausea/vomiting, headache, anxiety
Droxidopa
Alpha 1 receptor agonist
Prodrug, converted into NE…it is orally viably available
Orphan drug designation: treat neurogenic orthostatic hypotension (DbH deficiency)
Blackbox warning: monitor supine BP before and during treatment, keep head elevated to prevent risk of hypertension
Clonidine
** For exam, specific a2 receptor agonist **
Prototypic and classical a2 receptor agonist
FDA approval: Hypertension
Off label use: ADHD, Migraine, Nicotine dependence + withdrawal
Side effects: Drowsiness, orthostatic hypotension, edema and weight gain, rebound hypertension
Abrupt discontinuation can result in withdrawal agitation, headache, tremor, rapid HR
Pregnancy class C
Tizanidine
a2 receptor agonist
muscle relaxant
Contraindications: benzo, alcohol, buprenorphine
Metabolized via CYP1A2, avoid fluoroquinolone (not cipro), antiarrhythmics, cimetidine, famotidine, acyclovir, oral birth control
Pregnancy class C
** Clinically significant differences may occur when switching between tablets or capsules; once a formulation has been selected, do not alter regimen **
Brimonidine
A2 agonist
Used for ocular hypertension, open angle glaucoma, red eye
Remove contacts before admin
Side effects: hypertension, contact dermatitis, dry out (xerostomia), allergic conjunctivitis, fainting (syncope)
Alphagan P has a purite preservative, may be better tolerated by those with allergic reactions to other preservatives
Apraclonidine
Alpha 2 agonist
Prophylatcis postoperative ocular hypertension for cataract and laser eye surgery, adjunct to intraocular pressure
No concomitant use of MAOIs
Side effects: allergic conjunctivitis, blurred vision, edema of eye lid, reduced visual acuity*
Dobutamine
B1 selective, prototype B1 agonist
Chronotropic (HR) and inotropic (CO) actions without vasodilation
Used to treat hear failure and cardiogenic shock (ventricles stop working)
Off label: toxic shock syndrome, septic shock, pulmonary embolism shock
only given IV
Side effects: cardiac dysrhythmia, coronary arteriosclerosis, syncope, dyspnea
Albuterol (salbutamol) ProAir/Ventolin
Prototypic B2 agonist
Fast-acting bronchodilator
Used for asthma, exercise asthma, COPD, premature infant respiratory distress syndrome
Pregnancy class: assume C
Caution in patients with Cardiovascular disorders, arrhythmias, hypertension, lactose intolerance
Salmeterol
B2 agonist
Used in Asthma, COPD, Nocturnal asthma
Contraindicated for use in patients with cardiac disorders
Causes prolonged QT interval, can cause headache and musculoskeletal pain
FDA black box warning: long acting B agonist increase risk of asthma related death when used as monotherapy; pediatric population is at increased risk for hospitalization
Terbutaline
IV B2 agonist, used to delay preterm labor in serious situations, PO should not be used to delay preterm labor
Contraindicated for use in patients with cardiac disorders and pulmonary edema
Clenbuterol
b2 agonist
Used in sports due to “anabolic” attempt to increase muscle strength, those with asthma shouldn’t use this med
Mirabegron
B3 agonist, prototypic
Used for Bladder muscle dysfunction, overactive
contraindicated patients with hypertension
side effects: nasopharyngitis, urinary tract infection, headache, constipation, diarrhea, and tachycardia
Inhibits CYP2D6, avoid drugs metabolized by this pathway
Drugs that release NE
Tyramine
Amphetamine
Methylphenidate
Drugs that inhibit release NE
Reserpine
Guanethidine
Drugs affecting NE uptake
Duloxetine (NET blocker)
Lisdexamfetamine (NET blocker)
Imipramine (NET blocker)
Cocaine (DAT/NET Blocker)
Amphetamine
Prototype
NE release, MAO inhibitor, NET inhibitor, CNS stimulant
Usage: narcolepsy, paradoxical benefits in children with ADHD
Abused as appetite suppression, drug of abuse
Side effects: tachycardia, hypertension, insomnia, acute psychosis with OD, can cause dependence
Well absorbed GI and cross BBB
Pregnancy Class: C
Methylphenidate
Amphetamine variants
Used as ADHD med with similar mechanism as amphetamine
Tyramine
product of tyrosine metabolism
cannot cross BBB
releases catecholamines
Found in cheese, cured meats, beer, fermented foods, critical interaction with MAOI
Duloxetine
SSNRI
Clinical uses: Major depression disorder, fibromyalgia, neuropathic pain, generalized anxiety disorder (off label: appetite suppressant**)
Side effects: Nausea, dry mouth, constipation, fatigue, decreased appetite
Imipramine
Pro drug, into desmethylimipramine
Blocks neuronal NET, also classified as TCA
Clinical use: Depression, IBS
Side effects: Atropine like effects (anti-slud), cardiac dysrhythmias in OD
Lisdexamfetamine
Prodrug of dextroamphetamine
Mechanism and side effects: similar to amphetamine
Clinical uses: ADHD
Inhibition of CYP2D6, CYP1A2, CYP3A4, considerations for drug interactions
Cocaine
inhibits NET by acting as substrate
Rarely used local anesthetic, maybe during ophthalmic procedures
Commonly abused
Methyldopa
Treatment of hypertension during pregnancy (a2 action), orphan drug in Type 1 diabetes (off label pediatric use); hot sweats during menopause
Do not use with MAOI or populations with liver disorders
Common side effects: 20% patients ED, disordered ejaculations, dizziness
Serious side effects: colitis, Congestive Heart Failure, jaundice or Parkinsonism
Reserpine
At v low conc blocks NE transport and VMAT, causing accumulation and degradation by MAO
Used to be used as antihypertensive, currently used only experimentally..still used in combo with hydrochlorothiazide
DO NOT prescribe to patients with active peptic ulcers, history of depression
Side effects: GI, Neurolgoic, psychiatric and congestion
Serious side effects: atrial fibrillation, cardiac dysrhythmia, GI hemorrhage
Guanethidine
inhibit release of NE from nerve terminals, and accumulates in VMAT displacing adrenaline and preventing release
Abolish response of nerves to sympathetic nerve activation
Previously used as hypertensive
Severe Side effects: lost of sympathetic nerve reflexes, postural hypotension, diarrhea, nasal congestion and inhibition of ejaculation
Ephedrine
Mixed sympathomimetics
used as decongestant, appetite suppressant, and treat hypotension associated wit anesthesia (hypothermia due to anesthetic with caesarean and spinal injury)
side effects: hypertension, palpitations, tachycardia, nausea, vomiting, dizziness and reslessness
Monitor renal function in at risk populations (elderly, renal impairment)
Commonly abused athletics
Pseudoephedrine
1/4 potent as ephedrine
counsel patients purchasing to monitor blood pressure
commonly used as decongestion
No concurrent admin with MAOI
side effect: anxiety, restlessness, atrial fibrillation, myocardial infarction, insomnia
