Module 2 part 2 Flashcards
You are stimulating the sympathetic control center in a mouse.
What do you see?
Eye: Mydriasis
Lung: bronchodilation
GI-tract: Constipation
Heart: tachycardia
Blood vessels:
– Skin and viscera: vasoconstriction
– Skeletal muscle: vasodilation
– Adrenal gland: activation, NA and A release
Catecholamines:
Tyrosine-derived neurotransmitters
Tyrosine
DOPA
dopamine
Noradrenaline (Norepinephrine)
Adrenaline (Epinephrine)
Transmitters and Receptors in the
Sympathetic NS
Noradrenaline / Adrenaline
>
Adrenergic receptors GPCR
>
(α1, α2) (β1, β2)
*(β3 -adipose tissue, only)
α1
Gq
IP3/DAG ^
Smooth muscle contraction
Vasoconstriction in viscera,
M. dilator pupillae
GI sphincters
β1
Gs
cAMP
Heart:
Frequency, contractile force, conduction at A-V node
β2
Gs
cAMP
Smooth muscle relaxation:
Vasodilation in skeletal muscle GI motility
Bronchi: Dilation
andrenergic receptors
α1
Eyes: M. dil.pupillaecontraction (pupil dilation)
Arteries and veins: vasoconstriction in viscera and skin ; vasodilation in
skeletal muscle
β1
Heart: increased heart rate & force of beating (positive chronotropy and inotropy)
Arteries and veins: vasoconstriction in viscera and skin ; vasodilation in
skeletal muscle
β2
Lungs: relaxation of trachea & bronchi to facilitate respiration
Liver: increased glycogenolysis
Adrenals: NA and A release
Stomach & GI: decreased motility sphincter constriction
β3
Adipose tissue: increased lipolysis
Blood pressure
Blood pressure (BP) is regulated by the ANS through regulation of:
1) Resistance in arteries (vessel diameter)
+
2) Heart rate (cardiac output)
Baroreceptor reflex
mechanism that helps regulate blood pressure in the human body. It operates as a negative feedback system, meaning it works to maintain blood pressure within a relatively narrow range.
- Stretch receptors -Baroreflex in carotid sinus
- Stimulated by stretch or high BP
–> activation of parasympathetic nervous system to lower BP. - When BP low at baroreceptors, such as after moving from a prone to standing position
–> activation of sympathetic nervous system
-> heart rate and contractility increase and vasoconstriction (skin)
-> BP rises
This is the orthostatic reflex.
Heart:
β1 - increased heart rate & force of beating (positive chronotropy and inotropy)
What happens to peripheral resistance and heart rate
when you give NA vs. Adrenaline ?
NA mainly acts on α receptors (no relaxation of smooth muscle)
A acts on all adrenergic receptors.
NA: (no vasodilation) -> peripheral resistance up, heart rate down (because baroreceptors sense increased BP leading to activation of vagus/ cranial nerve X)
NA: little effect on heart rate and lung.
Therefore NA is not used as a drug for shock
OVERVIEW OF DRUG CLASSES
Sympathomimetic drugs
Sympatholytic drugs
Indirect sympathomimetic drugs
Sympathomimetic drugs
Agonists at α1, β1, β2 adrenoceptors
Adrenaline and noradrenaline: little receptor selectivity
Sympatholytic drugs:
- Antagonists at α1, β1, β2 adrenoceptors
- α2 agonists
- reserpine
Indirect sympathomimetic drugs:
- NA uptake inhibitors
- MAO-inhibitors
- Amphetamine, ephedrine
Adrenaline as a drug (1)
Epipen or Anapen
Used for treatment of anaphylactic shock:
Release of histamines causes system
vasodilation -> 1) drop in BP and 2) lung edema (breathing problems)
Adrenalin injected i.m. will lead to
vasoconstriction in skin (alpha 1 rec), rise in BP and bronchodilatation
Anaphylactic shock
treat with adrenaline
Alpha 1
+ vasoconstriction
+ blood pressure
- mucosal edema
beta 1
+ cardiac contraction force
+heart rate
beta 2
+bronchodilation
-mediator release
Adrenaline as a drug (2)
Adrenaline is added to local anaesthetics (used s.c.), because it limits the diffusion of the local anaesthetic by vasoconstriction in the skin (alpha 1 rec).
Be careful with patients with uncontrolled hypertension.
Alpha1-receptors:
Agonist:
e.g. Phenylephrine
- nasal decongestant
- Side effects: BP?
Hypertension
Antagonist:
- e.g. Prazosine
- treatment of hypertension
- Side effects ???
Postural hypotension
Another decongestant:
Pseudoephedrine –
indirect sympathomimetic
amine (see ephedrine)
Both alpha (and beta) agonist properties, and acts as an
indirectly acting agonist (tyramine like effect).
β1- adrenoceptors
Agonist:
Dobutamine
- increases cardiac contractility, thus used for (congestive) heart failure
- problem: dysarrhythmia (tachycardia)
β2-agonists
Salbutamol
Terbutaline
Salmeterol
Formeterol
used for asthma
β-blockers
Clinically very important!
Often non-β1/2 selective: propranolol
Or also β1-blocker: Atenolol
- Treatment of hypertension, angina pectoris
- Side effects:
bradycardia, few severe side effects
β2-antagonists: contraindicated in
asthma patients.
Feedback inhibition
- α2 agonists -sympatholytic drugs:
e.g. clonidine - MOA: blocks NA release by
reducing cAMP and inhibition of
Ca channels - Used for hypertensive crisis
-Lowers arterial pressure by effect on heart and vasculature -Side effects: bradycardia, orthostatic hypotension, sedation, depression
Alpha2 antagonist:
Yohimbine – no clinical importance
Other drugs affecting noradrenergic transmission
Monoamine
Oxidase
Noradrenaline
Transporter
Vesicular monoamine transporter
Simplified actions of
neurotransmitters in the CNS
NA: alertness, anti-depressant
DA: pleasure, movement control
5-HT: feeling happy, relaxed, calm,
motivated, anti-depressant
Block of vesicular monoamine
transporter
Reserpine
-> VMAT block
reduced amount of NA
in vesicles
reduced NA release
(treatment of hypertension,
now obsolete; causes depression)
Mono Amine Oxidase – inhibitors
Old antidepressants Selegiline (PD)
-> less NA degradation
-> increased NA levels
(problem: hypertension)
Note: dopamine is also degraded by MAO.
NAT – inhibitors
Specific NA reuptake inhibitors
(SNRIs): e.g. reboxetine
anti-depressant, blocks anxiety,
stimulates CNS, motivation
Also:
Tricyclic anti-depressants:
(inhibit both NA and 5-HT uptake)
- imipramine, amytriptyline
MOA:
-> increased NA (and 5-HT)
levels in synaptic cleft due to
uptake inhibition
Indirect sympathomimetics
Amphetamines, ephedrine
(NA displacers): uptake via NAT and VMAT
-> displacement of NA in vesicles
-> NA (DA, 5HT) leaks out
Central effects:
- CNS stimulation
- used for weight loss, narcolepsy,
ADHD (ritaline), decongestion
Amphetamines
Drugs of abuse! “Crystal-Meth, Chalk, Ice, Glass, Crank, Speed.“
Short term: exhilaration, hyperactivity, loss of appetite, insomnia, increase in energy level and talkativeness
Long term: nervousness, irritability,
hallucinations, paranoia -> depression
Addicts (speed freaks ) do not eat, sleep, or care for themselves
malnutrition, weight loss,
low resistance to disease, mental illness
-> eventually “Speed kills”
