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Sympathetic Drugs, so positive and negative isomers cancel each other out!…

- - - - non-Selective
        
        epinephrine
        
        binds to all adrenergic receptors (low levels = beta2, high levels alpha1)... must be administered via IV as we have MAO inhibitors in the GI tract
        
        effects
        
        pulmonary - will cause bronchodilation due to beta 2 effects
        
        metabolic - beta2 effects on hepatcyptes which will break down glycogen
        
        cardio - at low levels will increase systolic BP and decrease diastolic BP (because of the increased arterial pressure and the vasodilation)... @ high levels we have increased systolic and diastolic BP, increased HR, increased CO as we have increased alpha 1 activity
        
        used for
        
        cardiac arrest to promote ROSC
        
        serious hypersensitivity reactions to other drugs and allergies (will counteract huge release of histamine that results in broncho-constriction
        
        asthma - ok but we have better treatments
        
        admin with local anesthetics as alpha effects will result in vasoconstriction [remember that while epi activates both a1 and b2, you have alpha 1 dominated effects]... you lose anesthetic when it gets absorbed, so keep it there
        
        adverse effects
        
        increased HR and BP
        
        Stroke and MI
        
        arrythemias
        
        neurological disabilities
        
        will worsen angle-closure glaucoma symptoms
      - Selective
        
        alpha AND beta
        
        norepinerphine
        
        binds to alpha 1, alpha 2, and beta 1 (NOT beta 2)
        
        used for
        
        to treat shock as the CVS can't circulate enough blood and oxygen throughout body
        
        can also be used to tx tachycardia
        
        effects
        
        expect to see a elevated heart rate, but we do see a lower heart rate
        
        increased contractility, increased systolic BP
        
        dopamine
        
        only binds to the 1s (so alpha 1 and beta1)
        
        used for
        
        cardiac energetics and shock
        
        vasodilation of renal arteries (while not part of ANS) does help ensure healthy blood flow to renal
        
        dobutamine
        
        effects
        
        negative isomer is a a1 agonist and a weak b1 and b2 agnoist
        
        positive isomer is a B1 agonist - so vasodilation and increased cardiac energetics, weak beta 2 agonist, BUT alpha 1 antagonist
        
        uses
        
        you use this for a CHEMICAL cardiac stress test, increase heart rate and BP for patients who can't get on a treadmill..... note that you give this with a dilator bc you don't want an MI
        
        binds to alpha1, beta1, beta2 (NOT alpha2) - beta 1 selective
        
        alpha ONLY
        
        clonidine
        
        alpha 2 agonist
        
        effects
        
        activates alpha 2 receptors in lower brainstem (ONLY CNS) to DECREASE sympathetic drive
        
        so no peripheral effects
        
        used for
        
        mild to moderate HTN (second line drug - use only if first line doesn't work)
        
        opiate and alcohol withdrawal (we have in these cases increase in sympathetic drive output, so tremors, increase HR, etc) -- clonidine counteracts
        
        adverse effects
        
        sedation, dry mouth, and constipation
        
        abrupt withdrawal can produce rebound HTN, so we need to taper it off
        
        brimondine
        
        alpha 2 agonist
        
        reduces rate of formation of aqueous humor in eye and decreases interocular pressure - GLAUCOMA
        
        phenylephrine
        
        acts as a alpha 1 agonist
        
        used for
        
        hypotension --> treats really low BP via vasoconstriction of arteries, arterioles, veins, venuoles
        
        nasal congestion --> vapor form to inhale and activate alpha 1 nasal mucosa
        
        blood-shot eyes so you constrict and decrease blood flow to that area and decrease blood-shot look
        
        contraindications
        
        should not be used in hypertensive patients... vasoconstriction will make things worse for them
        
        beta ONLY
        
        albuterol
        
        effects
        
        bronchodilators
        
        adverse effects
        
        fine tremors - pre-junctional receptors at neuromuscular endplate will result in leakage of Ach
        
        increase in blood glucose - can activate hepatocyte B2 receptor in glycogen and glucose
        
        receptor down-regulation can occur as it acting to increase the activity a GPCR receptor (Gs), so if you use it too much, then you will down-regulate and decrease effectiveness
        
        terbutaline
        
        suppresses premature labor
    - - releasers
        
        amphetamine
        
        effects
        
        pre-junctional uptake transporter will work in reverse cauing more norepi to be displaced to the cleft
        
        storage vesicle is also in reverse, also displacing norepi back to the cleft
        
        elevated norepinephrine causes alpha 1 activation on effector cell, so increased systolic and diastolic pressure, dilated pupills
        
        adverse affects
        
        with very high doses, you can get so much norepi that you INCREASE your risk for cardiac arrythmias
        
        used for
        
        ADHD
        
        narcolepsy
        
        chronic fatigue syndrome
        
        methylphenidate
        
        acts like amphetamine (aka ritalin)
        
        tyramine
        
        not a drug
        
        chemical found at high levels of processed and smoked meats, many cheeses, and certain fruits and uts
        
        normally broken down in the gut, so not harmful... BUT, if you are on MAO inhibitors, you don't break this down and now have effects like amphetamine --> increase risk of MI and stroke
      - uptake inhibitors
        
        cocaine
        
        blocks uptake so accumulation of norepi at the effector cell of junctions
        
        adverse effects
        
        too much = cocaine induced sudden death syndrome, so much norepi results in ventricular arrhythmia and the heart stops
        
        effects
        
        amphetamine = cocaine, so increase HR, increased contractility, but greater abuse potential
        
        tricycyclic antidepressants
        
        same action as cocaine
      - inhibitors of metabolism
        
        MAO inhibitors
  - - - non-selective
        
        phentoalanine
        
        effects
        
        reduced diastolic and systolic pressure due to lack of binding of alpha 1 receptors, so vasodilation
        
        accelerates reversal of local anesthesia as it competes with alpha 1 agonist (vasoconstrictor - epi) and allows for vasodilation, letting the local anesthetic clear out
        
        some binds to alpha 2 receptor, so you cause the release of additional norepi, but alpha 1 isn't bound, so beta 1 will cause the uptake of norepi from effector cell and increase heart rate
        
        adverse effects
        
        orthostatic hypotension - thought to be becuse we are blocking all alpha 1 receptors
        
        tachycardia
      - selective
        
        prazosin
        
        binds to alpha 1 receptors in the same way as phentoalanine
        
        used for
        
        hypertension
        
        consider first dose effect, which may cuase serious orthostatic hypertension at first dose
        after this occurs, it either disappears or dramatically reduced. So they take first dose at night
        
        tamsulosin
        
        binds to alpha 1 a (A1a) receptors - on the smooth muscles of the prostate
        
        allows muscle to relax and the prostate to expand, decreasing pressure on the urethra and increasing urine flow
    - - non-selective - 1st gen
        
        propranolol (beta 1 and beta 2)
        
        effects
        
        binding to beta 1 receptors causes decreased heart rate, decreased contractility, and decreased BP
        
        however, at B2 at the heart, we would expect vasoconstriction (as it is blocking B2 which is designated for relaxation, but we see vaso-dilation and decreased BP and HR
        
        used for
        
        HTN
        
        angina
        
        arrythmias
        
        requires a large dose of this
        
        MI
        
        if given early one, can improve recovery and outcomes
        
        migraines
        
        hyperthyroidism
        
        adverse effects/contraindications
        
        asthmatics - the B2 receptor is used for bronchodilation, so blocking that, you may precipitate an asthma attack
        
        insulin-dependent diabetics - those with IDDM have glucose from liver and release glucagon. But since they don't enough, epi can do that and bind to beta 2 and breakdown glycogen.
        However, you are now blocking B2, so now they can't regulate glucose levels = HYPOGLYCEMIA
        
        timolol (b1 and b2)
        
        used for
        
        glaucoma
        
        decrease aqeuous humor production
      - selective - 2nd gen
        
        metoprolol
        
        effects
        
        same as above, but remove the beta 2 effects
        
        can NOW use with asthmatics and diabetics, if well controlled
      - third generation
        
        labetalol
        
        effects
        
        beta partial agonist - remember that these are competitive inhibitors of full agonists
        
        alpha 1 antagonist
        
        uses
        
        pregnancy to tx eclampsia (increased BP, seizures, and protein in urine) and pre-eclampsia (increased BP)... bad for mom and baby
    - - resperine
        
        blocks uptake of catecholamines in adrenergic storage vesicels
        
        takes 10 days to 2 weeks to take into effect... the catecholamines taken up are brown down as there is no usage
- - - - choline esters (derivatives of Act)
        
        carbachol
        
        topical application for the eye for glaucoma patients.. when applied at low levels there is no systemic effects
        
        there is no hydrolysis by cholinesterase so we can keep this
        
        good muscarinic activity, but a lot of ni
        
        bethanechol
        
        negligible hydrolysis AND negligible nicotinic activity... so this is the best type of drugs for precision and accuracy
        
        high muscarinic activity
        
        used for
        
        paralytic ileus - where peristalsis stops
        
        bladder atony - where detrusor muscle of the bladder stops, and you can't urinate.
        Increased risk from surgery, infection, peritoneal surgery, and new borns and eldery
        
        acetylcholine
        
        extremely likely to be hydrolyzed by cholinesteralses (very rapidly broken down everywhere in the body to keep Ach at bay and not allover)
        
        high muscarinic activity - as expected
        
        high nicotinic activity - we don't want this as there we don't it working with ganglia and the nicotinic receptors at the musculoskeletal junction... to much activity
        
        See what changes can be made to Ach?
      - alkaloids
        
        muscarine
        
        really high muscarinic activity and no nicotinic activity, no drug use
        
        nictotine
        
        used to help people quit smoking... really high nicotinic activity
        
        pilocarpine
        
        oral or injected
        
        high muscarinic activity
        
        used for glaucoma to contract longitudinal cillary muscle
        
        also used for xerostoma - dry mouth. Our saliva have anti-biotic properties, and prevent lesions and ulcers in the mouth
        
        also recently approved for presbyopia.
        
        Normally your lens can change it shape, so you can focus on close and far objects. When you grow older, your lens loses it's flexion, so you can't focus on close objects. Used to be corrected by reading glasses
      - Adverse effects
        
        SLUD - occupying muscarinic receptors @ other areas irrelevant to tx. Causes cholinergic crises, increases lacrimation, urination, defecation, salivation
        
        Bronchiolar smooth muscle contraction - decrease HR, vasodilation, decrease SBP and DBP
    - - non-covalent binding
        
        donepezil
        
        effects
        
        increases the levels of Ach in brain
        
        uses
        
        reduces Alzheimer's symptoms in early onset of disease. Cannot be used in late on set
        
        adverse effects
        
        expect salivation, decrease heart rate, increased urination, increased defection
      - carbamates - covalent binding
        
        physostigmine
        
        used only for glaucoma
        
        since it can cross BBB, cannot be given systematically.
        HOWEVER, it is used for therapy for atropine intoxication
        
        neostigimine
        
        can be given systematically as it won't cross BBB, IV or oral admin
        
        used with bethanechol as an alternative for paralytic ileum/bladder atony
        
        carbaryl
        
        pesticide (NOT drug)
        
        poisoning can cause cholinergic crisis (increased salivation, urination, delectation)
        
        will recover enzyme activity in minutes to hours.
        instant decetylation, but decarbarylation takes minutes to hours
      - organophosphates
        
        chloropyrifos
        
        it's a pesticide
        
        highly toxic, but you have time to tx as it takes time for Ach-ase to age
        
        soman
        
        nerve gas - chemical warfare agents
        
        praliidoxime
        
        antidote of some of the organophosphates, but you got to use it before the enzyme is aged.
        However, don't use it carbamate because it will make that reaction worse
        
        2-PAM is better then H2O
        
        worse then carbamates because of the potential for irreversible binding and inactivation of the achase. This occurs when one of the ethyl or methyl groups break off and now the binding is irreversible (process called aging)
      - keeping Ach in the presynaptic cleft
  - - - Natural Alkaloids
        
        Atropine
        
        most commonly used antagaonist
        
        comes from nightshade
        
        effects
        
        heart - block parasympathetic drive, up HR, up CO, used in cardiac emergencies to decrease parasympathetic drive
        
        eyes - dilate pupils by blocking Hillary muscle... DO NOT GIVE WITH GLAUCOMA
        
        salivary glands decrase
        
        bronchodilator of the respirator system and decrease mucous production (potential asthma tx)
        
        antispasmodic drug - occurs when certain conditions lead to very serious and strong painful contractions
        
        urinary urgency and incontience - block muscle receptors on deutrosor muscle
        
        antidote for cholinergic crisis
        
        Scopolamine
        
        similar to atropine
        
        decrease nausea, motion sickness
        
        lipid soluble and transdermal
      - synthetic
        
        ipratropium
        
        used to treat asthma
        
        darifenacin
        
        used to treat overactive bladder (urinary urge incontinence) secondary to the detrusor muscle
        
        benztropine
        
        decrease the effects of Parkinson's (muscarinic receptor that can deal with CNS) and lower movement disorder sxs