9b Sympathetic Flashcards
Describe a catecholamine and give some natural and synthetic examples.
Benzene ring with 2 OH groups
Natural: epinephrine, norepinephrine, dopamine
Synthetic: Isoprenaline
What do catecholamines do
Increase adrenergic transmission - producing all the effects of sympathetic system.
Another name for the kinds of drugs that act like catecholamines
Sympathomimetics
What inhibits the transport of dopamine into the vesicle during synthesis of Norepinephrine?
Reserpine
Cathecolamine degradation: Describe the enzymes and where.
methylated by COMT (cathecol-o-methyltransferase) in liver and postsynaptic cleft (extraneural)
Oxidised by MAO-A and MAO-B in mitochondrial membranes of presynaptic bouton (intraneural) as well as liver.
Describe the synthesis of catecholamines
Neurons need a tyrosine transporter, tyrosine is converted into Dopa–> dopamine –>norepinephrine -> epinephrine
Describe Alpha 1 receptor: Where found and action.
Found in smooth muscles - causes vasoconstriction. - as such contracts blood vessels, eye, bladder, prostrate, uterus.
Liver: glycogenolysis
Salivary gland: secretion
GI - smooth muscle produces relaxation instead of constriction (remember its sympathetic!)
Describe the activation cascade of a Alpha 1 receptor
Gq protein coupled receptor coupled with activation of phospholipase C –> which cleaves phosphatidylinosotol into IP3 (inositol triphophosphate) and DAG (diacylglycerol), IP3 releases Ca++ from ER, DAG increases Ca++ entry into smooth muscle. Increased Calcium therefore CONTRACTION.
WHERE (specifically) are A2 receptors found? And in which organs? Main actions?
PRESYNAPTIC inhibitory receptors, inhibit release of neurotransmitters in :
- neurons - decrease NE/Ach release
- pancreas - decrease insulin release
- platelets - decrease platelet aggregation
- CNS - decrease sympathetic discharge
Describe the activation cascade of A2 receptors
G protein coupled receptors coupled with inactivation of adenylyl cyclase, resulting in decreased release in cAMP, thus lower intracellular Ca++ thus exocytosis inhibited. At adrenergic neutrons they play an important role in auto inhibitory feedback mechanisms of NE release
Where are B1 receptors found and what do they do
HEART - increase rate, force of contraction, automaticity, cardiac output increased. Thus beta blockers slow heart contraction and acts as antihypertensive.
Kidney - renin release at juxtaglomerular cells
Adipose - lipolysis
Effects of B1 (trophic) in the heart
Positive ionotrophic - increase force of contraction
Positive chronotrophic - increase rate of contraction
Where do you find Beta 2 receptors and what is their effect
Smooth muscle - causing relaxation of the bronchial tree = antiasthmatic effect
Main locations: relaxation of
Smooth muscle, vascular smooth muscle, uterine, bronchioles, glands, salivary glands (increase secretion), liver (glycogenolysis)
Mast cells - reduce histamine
Adrenergic neurons - increase NA release
What is the predominant receptor on vascular smooth muscle
BOTH A1 and B2 receptors are present but A1 are predominant. However vascular smooth muscle for muscle and liver have mainly B2 receptors = vasodilation.
At GIT smooth muscle BOTH receptors cause relaxation!
Where are B3 receptors found and what do they do
Adipose tissue - cause lipolysis.
Discuss the activity of catecholamines on the different receptors (alpha and beta) and discuss selectivity
Noradrenaline is a very small amino group - thus it has a very low BETA activity, so works mostly on Alpha.
Isoprenaline (synthetic) is very bulky (large alkyl group) so is beta selective.
Adrenaline is in the middle so it works on both alpha and beta.
When do you use adrenaline
Anaphalactic shock : - counteracts the massive histamine release. Bronchodilation of adrenaline is from stimulating the Beta 2 RECEPTORS.
Why don’t we use noradrenaline for anaphylactic shock?
It has a poor beta effect, works mostly on Alpha due to the fact that it is small, and so it will not reduce the bronchoconstriction of anaphylactic shock.
What is Phenylephrine and where is it used, how does it work?
Direct acting sympatimomimetic which is SELECTIVE - stimulates alpha 1 = vasoconstriction. Used in rhinitis (stop runny nose) and dentistry, keeps local anaesthetic local due to vasoconstrictive effect (also adrenaline sometimes used). Also, produces useful mydriasis for 10-30 minutes and well absorbed from the conjunctival sac. USUALLY CAUSES REFLEX BRADYCARDIA!
What is Chlonidine?
Direct acting sympatimomimetic, SELECTIVE for alpha 2; used as ANTIHYPERTENSIVE
, vasomotor centre has sympathetic neurons with alpha 2 receptors.
What is Dobutamine?
Direct acting sympatimomimetic, SELECTIVE for Beta 1: used in cardiac arrest (you could also use adrenaline as that is a very good beta 1 stimulant) also isoprenaline
Give an example of a direct acting selective cholinomimetic acting on B2 - what does it do
Beta-2 agonists: bronchodilators
Name an example of Indirect acting sympatimomimetic releasing agents
Amphetamine
tyramine (cheese and wine) release catecholamines
Name an example of an indirect acting sympatimomimetic MAO inhbitor
Selegiline: keeps up cathecolamine activity by inhibiting MAO because MAO normally degrades catecholamines
What is Entacapone?
Indirect acting sympatimomimetic acting as COMT inhibitor - antiparkinson.
Classify cocaine
It is a sympatimomimetic, indirect acting, uptake inhibitor. this gives you all the sympathetic effects - overstimulation of heart, hypertensive crisis, heart attack.
Can we use dopamine as a drug? Classify the drug and give examples
It would be an adrenergic agonist (sympatimomimetic) with mixed action : Kidney has D1 receptors, if you stimulate with dopamine you get vasodilation of kidney vessels –> fluid loss because you accelerate kidney function. By increasing the dose of the drug you can increase effect on other receptors, such as Beta 1 - can simulate heart contraction (useful for edema and weak heart - weak contractions). Can act on alpha and beta receptors as well. We use a dopamine analog fenoldapam in emergency treatment of hypertension.
Main indications of cathecolamines (in general)
Cardiac arrest (can also use isoprotenerol) Anaphalactic shock Adjunct to local anesthetics Bronchospasm (epinephrine for all)
What is fenoldapam
a dopamine analogue used in ER treatment of hypertension. Side effects are those associated with sympathetic stimulation: Palpitations, high BP, anxiety, tremor, arrythmias.
Why don’t we use norepinephrine for cardiac arrest?
It preferentially acts on alpha receptors (its small) with insignificant action on beta receptors.
Why don’t we use Isoproterenol for anaphylactic shock?
It works preferentially on beta receptors (its big) rather than alpha receptors. And we want alpha receptors as we want to cause constriction to counter act the vasodilation of shock.
Why do we use epinephrine as adjunct to local anesthetic?
It produces vasoconstriction increasing localisation of aesthetic.
What do we give for bronchospasm?
Epinephrine
What is an advantage of having a non cathecolamine adrenergic agonist?
not degraded by COMT or MAO and show a longer action than catecholamines, can be given orally, specific for adrenergic receptors with less possible side effects
Name 3 alpha 1 agonists.
Side effects?
Phenylephrine mostly selective for Alpha 1 - mostly used systemically syrup as nasal decongestant. Also mydriasis of the eye (well absorbed from conjunctiva) - 10-30mins
Oxymetazoline, Xylometazoline
both less selective but act mainly on alpha 1 still. Nasal spray solutions.
They increase vasoconstriction and increase bp. Systemically will lead to increased vagal activity and bradycardia. Mostly used though for local (nasal decongestant and to reduce eye redness). Sympathetic side effects: headache, nervousness, anxiety, palpitations, rebound congestion.
Name an alpha 2 agonist and its side effects, and where is it used
Clonidine: inhibits central sympathetic discharge by acting as an agonist on the alpha 2 receptors, because they are presynaptic inhibitory receptors. they act by reduction in production of camp, reducing Ca++ in presynaptic terminal and thus inhibiting neurotransmitter release. Side effects are related to its receptor action: so:
sedation, lethargy, constipation, xerostomia,
Mostly as antihypertensive, to reduce withdrawal of opioids, benzodiazepines, and other addictive drugs. But basically anything with excessive sympathetic stimulation.
Name a B1 agonist
and two advantages of this drug. What are the side effects and indications.
Dobutamine: specifically acts on cardiac muscle increasing force and rate of contraction. Increases cAMP levels, which stimulates protein kinases increasing intracellular calcium = increased force of contraction.
Advantages: selective for B1, doesn’t increase cardiac oxygen consumption (as opposed to epinephrine which does)
SE: cardiac stimulatory: palpitations, nervousness, tachycardia, high BP.
Indicated for congestive heart failure (fluid buildup around the heart) or cardiogenic shock.
Why is epinephrine not preferred in HEART FAILURE
It is not specific for B1 receptors, and it increases cardiac work and oxygen consumption which are deleterious effects in heart failure.
Name four B2 agonists and classify them based on their action, also name their action.
What is the cascade? Indicated for?
Relaxation of bronchioles: Short acting: 3-4 hours - terbutaline - salbutamol (albuterol now) Long acting: 12 h -salmeterol - formoterol They increase cAMP which causes the phosphorylation of myosin light chain kinases (MLCK) which are actually required for contraction. As MLCK is phosphorylated it cannot contract = relaxation of bronchial smooth muscle. Indications: Bronchodilators in asthma, COPD, exercise induced bronchospasm
Why is salmeterol B2 (bronchodilator) long acting?
The longer the length of the alkyl group, the longer the duration of action. It has a more lipophilic carbon chain.
What are the side effects of B2 agonists?
heart: increase HR
Muscles: increase twitch
Effects are less if given via inhalation rather than systemic - but some will get absorbed anyway.
Explain exactly how tyramine functions in the synapse? Are they direct or indirect?
Where is tyramine found? What is an important effect of tyramine?
How is it metabolised?
Indirect - they don’t act directly on receptors but increase NE levels in cleft by 2 ways:
- displacement of NE from storage vessicles
- inhibition of uptake
It is found in cheese, meat, soya sauce, chocolate and fish.
NB effect: increases BP
Explain the “Cheese reaction” in relation to tyramine and MAO
Tyramine is metabolised by MAO-A (presynaptic) and B (plasma and gut wall). B is in the gut wall and with MAO inhibitors, tyrosine present in the diet is not metabolised, leading to increased tyramine in the body - increasing NE transmission = severe hypertension, muscle rigidity and hyperthermia = can be fatal. Cheese reaction is shown mostly in non-selective MAO inhibitors that inhibit both A and B. Tyramine is not a drug but can be used as flavouring agent.
Talk about cocaine
Inhibition of uptake 1 (on presynaptic terminal of dopamine): side effects: alertness, insomnia, euphoria, tachycardia, hypertension, hyperthermia. Also blocks voltage gated sodium channels acting as anaesthesia. Also nasal decongestion. So currently only used limited to local anaesthetic effect.
How do tricyclic antidepressants work?
by inhibition of uptake 1 (presynaptic side) of serotonin uptake.
Tell me about Amphetamine:
what does it do, what are the actions and side effects:
Indication?
CNS stimulant that can be modified into drugs like:
methamphetamine / dextromethamphetamine (abuse drugs)
They displace NE from storage vessicles, they have a high affinity for uptake into the nerve via uptake 1 process. NE then leaks into cleft for one exchange of amphetamine.
Actions:
Increase in memory, alertness, hyperactivity, decreased fatigue, insomnia, loss of appetite, euphoria, increased blood pressure. SE: anxiety, hypertension, nausea, diarrhoea. Indications: ADHD (decreases hyperactivity), Narcolepsy (increase alertness), CNS stimulant.
Two drug interactions that are important with amphetamines:
Interaction with uptake inhibitors: cocaine and tricyclic antidepressants will inhibit their uptake the decreasing their action.
Interaction with MAO inhibitors: metabolism is prevented causing a increased leak of NE into cleft. With MAO-B blocked it can lead to increased levels of amphetamine and tyramine = severe hypertension.
Mixed acting adrenergic DRUGS - name 2 and describe their effect and action.
Ephedrine (natural alkaloid) and pseudoephedrine: act on both alpha and beta receptors producing direct and indirect actions. Can directly bind to receptors. Cannot be metabolised by COMT so long duration. Indirect action by entering into the presynaptic terminal by uptake 1, there displacing NE, allowing it to leak into synaptic cleft. Action is similar to epinephrine as it acts on both receptors: vasoconstriction –> increased BP, nasal decongestion, from beta receptors cause bronchodilation, increased renin release, increased food glucose.
Can cause euphoria in bloodstream so pseudo-epinephrine is limited to nasal decongestion in few cough syrups. Side effects: anxiety, palpitations, tremor, addiction.
Name 5 Alpha 1 blockers
and describe action
and cascade:
- prazosin
- doxazosin
- terazosin
- alfuzosin
- tamsulosin - Alpha1A blocker specific for prostate tissue.
Antihypertensive drugs causing vasodilation:
Inhibit alpha 1 mediated activation of phospholipase C, and subsequent release of IP3 and DAG, secondary messengers are not released, thus no calcium = relaxation.
They also decrease hypertrophy as result of chronic hypertension
Name 2 important effects to remember with alpha 1 blockers! and some 3 other effects for con lode
1.First dose effect:
vascular smooth muscle tone is important to maintain postural balance - since A1 blockers produce direct vasodilation, they inhibit necessary vasoconstriction to maintain posture -can cause sudden fall of BP when standing (dizziness), reduced blood to brain = increased fall risk. More observed in first few doses, thus should be taken at night and advised not to drive or work with machinery for a while.
2. Reflex tachycardia:
Headache, nasal congestion, sexual dysfunction.
What do we use Alpha 1 blockers for?
- Severe hypertension - only used in emergency due to the 2 side effects (first dose and reflex tachycardia) so prefer Beta blockers for long term.
- benign prostatic hypertrophy
- congestive heart failure - prazosin improves cardiac output by decreasing preload and after load - thus decreasing cardiac work and improving the congestion.
How do non selective beta blockers work?
Act on all the beta receptors preventing action of catecholamines. Inhibit AC, cAMP levels fall, cAMP mediated protein kinases are not activated thus inhibition of contraction. Decrease in rate and force of contraction. But since they also act on B2, they cause bronchoconstriction. they also reduce cAMP, MLCK is not inactivated (instead is ACTIVE) and so produces a contraction. This is important in patients with asthma and COPD.
Describe the action of selective beta 1 blockers:
Cardioselective, specifically acting on the heart, inhibiting cardiac stimulation with cathecolamines - decreasing rate and force of contraction. Produce less bronchospasm.
When would you use a non selective beta blocker? Give an example
Anxiety, tremor, we use a non selective beta blocker like propranolol.
what is the action of a beta blocker in the liver?
Will decrease gluconeogenesis and glycogenolysis –> decreasing blood glucose levels. Important in diabetic patients (if say on metformin)
What is the effect of a beta blocker on blood vessels?
Vessels express more alpha receptors than beta, however they have an indirect effect, decreasing blood pressure. Beta receptors are predominant though on vessels going to the liver and skeletal muscle so a blocker would decrease blood flow to skeletal muscle and liver = decreased blood flow = decreases twitch response = decrease tremor.
Effect of beta blockers on the kidney
liver and kidney are supplied by sympathetic system ONLY - WITHOUT any parasympathetic innervation. Beta blockers decrease renin release, thus decreasing BP
Effect of beta blockers on the eye - give example of one
Timolol - can decrease intraoccqular pressure
Categorise the 4 additional activities of beta blockers
- Partial agonist activity - stimulate beta receptors but at a lower level: Non selective include pindolol and penbutalol, selective is acebutolol
- Membrane stabilising activity - membranes can’t respond to cathecolamines (propranolol)
- vasodilatory activity:
Nebivolol - block beta receptors and at the same time release NO from endothelium = relaxation. - alpha blocker activity: Carvedilol - antagonist at both receptors (alpha block reduces cardiac stimulation, beta block inhibits stimulation by catecholamines hence used in hypertension)
What is an autoreceptor
Presynaptic receptor that bind the primary transmitter substance thereby regulating its release.
What is a heteroreceptor?
transmitter release that is modulated by another presynaptic receptor (eg histamine, prostaglandins etc).
Phentolamine
Binds Alpha receptors and prevents activation
What is isoproterenol
DIRECT SYMPATIMOMIMETIC.
Binds BOTH B receptors, activates adenylyl cyclase
What is propranalol
Non selective Beta receptor blocker - prevents activation of Beta. Used in Hyperthyroidism - reduces HR, reduces tremor, symptom control of thyroid storm.
What do you use to examine the retina of an old diabetic, if you don’t want cycloplegia
Phenylephrine - it is well absorbed from the conjunctival sac and produces useful mydriasis for 10-35 minutes.
What are antimuscarinic effects on the eye
Mydriasis and cycloplegia
What is pilocarpine
Direct cholinomimetic agonist, alkaloid activates muscarinic receptors - contracts ciliary muscle of the eye (open-angle glaucoma), resistant to AchE, can cross the BBB. “You cry, sweat and drool on your PILO.”
It is a potent stimulator of tears , sweat, saliva, glaucoma, and xerostomia (Sjogren syndrome)
What is a common side effect of highly selective B2 bronchodilator.
MUSCLE TREMOR (idiopathic, assumed to have something to do with hypokalaemia .
A marked increase in pulse pressure (SBP-DBP) indicates a strong increase in stroke volume, which is a _____ agonist effect. Name such a drug with THESE effects
B agonist.
Isoproterenol
ISO= BETA 1 AND 2 EQUALLY
when you see an increase of pulse pressure you should always think….
BETA AGONIST
A marked increase in both systolic and diastolic BP along with a moderate increase in Pulse Pressure indicates ….?
Strong alpha effect on vessels and Beta involvement.
