4.3 Sympatomimetic drugs Flashcards
CATECHOLAMINE BIOSYNTHESIS
____________ is converted into ___________ by ______________ (rate-limiting step):
- L-DOPA is then converted by the _________________ into dopamine (within the cytoplasm) → packaged into vesicles along with __________________ –> Dopamine is converted into noradrenaline by dopamine β-hydroxylase (end product in some regions of the sympathetic system)
- Noradrenaline is further metabolised into adrenaline by ____________ in other regions
L-tyrosine; L-DOPA; tyrosine hydroxylase;
DOPA decarboxylase enzyme;
dopamine β-hydroxylase;
phenylethanolamine N-methyltransferase
The organs and tissues which respond to either noradrenaline or adrenaline contain 4 main types of adrenoceptors (α1, α2, β1, β2):
- All the adrenoceptors are G-protein coupled receptors; α1 signals through ________________, while α2, β1, β2 signal through ________________
Noradrenaline and adrenaline are endogenous mediators which are non-selective (with slight differences in potency):
- Adrenaline is ______________, while noradrenaline is ________________
- Potencies are the same between the two α and two β receptors
PLC, IP3 and DAG;
cAMP (α2 reduces, β1, β2 increases);
less potent on the α receptors than β receptors;
more potent on the α receptors than β receptors
Adrenoceptors are differentially distributed throughout the body, which determines the effects of the endogenous mediators and sympathomimetics:
- Activation of the sympathetic nervous system allows the body to cope with stress (fright, fight or flight response)
- Blood vessels with α1 adrenoceptors tend to be ___________, while blood vessels with β2 adrenoceptors tend to be __________________
o Constricted blood vessels tend to supply areas of less importance → shunts blood to dilated blood vessels to skeletal muscles (important in stress)
- Main location of α2 adrenoceptors (presynaptic autoinhibitory receptors) are on __________________
constricted;
dilated in a sympathetic response;
presynaptic terminals of noradrenergic neurones → limits further NA release
Uptake 1
- Back into presynaptic terminal
- Metabolised by _____________ into inactive metabolites
monoamine oxidase (MAO)
Uptake 2
- Into postsynaptic cell
- Degraded by ______________ into inactive metabolites
catechol-O-methyltransferase (COMT)
what is the selectivity of adrenaline?
α1 = α2 = β1 = β2
what is the selectivity of phenylephrine?
α1 > α2 > β1 / β2
whit is the selectivity of clonidine?
α2 > α1 > β1 / β2
what is the selectivity of isoprenaline?
β1 / β2 > α1 / α2
What is the selectivity of dobutamine?
β1 > β2 > α1 / α2
what is the selectivity of salbutamol?
β2 > β1 > α1 / α2
Adrenaline is released naturally from the ___________________, and is also used as a drug in medical emergencies → non-selective agonist (activates all adrenoceptors):
- Administered______________ → poor oral absorption (charged molecule which has difficulty passing through membranes) - Rapidly metabolised in the gut, liver, and other tissues by _____________ –> Short-lived duration of action (within minutes)
adrenal medulla by chromaffin cells;
IV/IM/locally/topically;
MAO and COMT
ADRENALINE: Allergic reactions/ anaphylaxis (IgE reactions): Histamine from mast cells acts on blood vessels to cause ________________ → hypotensive crisis; bronchoconstriction → breathing difficulties
Adrenaline (given IM as autoinjector delivery) counteracts via:
- ______________ (α1) → increase BP
- _____________ (β1) → increase CO and BP
- ______________ (β2) → open the airways
- Blocks release of hypotensive and bronchoconstrictor mediators from mast cells and other WBCs
massive peripheral vasodilation ;
Peripheral vasoconstriction;
Increase HR and contractility;
Bronchodilation
ADRENALINE: Acute management of cardiogenic shock:
- Heart fails to pump enough O2 rich blood to the body (decreased CO) leading to severe MI and cardiac arrest
- Adrenaline counteracts via ______________
positive inotropic & chronotropic actions
ADRENALINE: Prolonged duration of LA
Adrenaline has ______________ → prolongs drug action and minimises dose of LA required
α1 vasoconstrictor properties
What are the side effects of adrenaline (secretions)?
Reduced and thickened secretions Mucous secretions (dry mouth)
What are the side effects of adrenaline (CNS)?
Minimal effects (does not readily cross blood-brain barrier)
What are the side effects of adrenaline (cardio vascular)
Tachycardia, palpitations, arrhythmias Cold extremities (vasoconstriction in hands and feet) Severe hypertension Overdose: cerebral haemorrhage, pulmonary oedema
what are the side effects of adrenaline (GI)?
Minimal effects
What are the side effects of adrenaline (skeletal muscle)
Tremor (muscle spindles have β adrenoceptors)
What are the uses of phenylephrine if given IV/ topical?
α1 vasoconstrictor properties → stops superficial bleed
What are the uses of phenylephrine if given as eyedrops ?
α1 constricts radial muscles → pupil dilation (allows for inspection of fundus of the eye)
What are the uses of phenylephrine if given as nasal drops/ pral ?
α1 vasoconstrictor properties → reduced fluid supply to nasal region (less fluid to become congested)
What are the side effects of phenylephrine?
- hypertension: Due to the vasoconstrictor effects
- Rhinitis medicamentosa: Rebound nasal congestion (mechanism not well understood)
Clonidine is a selective α2 adrenoceptor agonist (on presynaptic membranes) given via oral or IV administration. What is it used for?
Reduces sympathetic tone via:
• Central action in the brainstem (within baroreceptor pathway): reduces sympathetic outflow → reduced vasoconstrictor tone to peripheral blood vessels → reduced TPR
• α2 adrenoceptor-mediated presynaptic inhibition of NA release (becomes less effective with continual usage of the drug
what are the side effects of clonidine?
hypotension, bradycardia, congestive heart failure, weakness, oedema
Isoprenaline has similar potencies at both β1 and β2 receptors, and is less susceptible to uptake 1 protein and MAO compared to adrenaline:
• Possess a plasma half-life of 2 hours
What are its uses?
- Cardiogenic shock, acute heart failure, myocardial infarction (IV)
- Asthma → discontinued due to unwanted actions (reflex tachycardia and dysrhythmias)
What is the mechanism of having reflex tachycardia from isoprenaline?
Reflex tachycardia (from β1 and β2 effects):
• β1: increases heart rate and cardiac output
• β2: vascular smooth muscles in blood vessels supplying the skeletal muscles relax → vasodilation (sensed by baroreceptors)
o Marked fall in TPR signals to the sympathetic nervous system to increase outflow to the heart
o Further enhances the β1 adrenoceptor response
Dobutamine is a selective β1 agonist rapidly metabolised by _____________ and is poorly absorbed:
• Not selective for the β2 adrenoceptor → lacks the _____________ (can be safely administered)
Uses:
- Cardiogenic shock (Positive inotropic and chronotropic actions)
- Heart failure: Increases the ______________
COMT;
reflex tachycardia side effect seen in isoprenaline;
inotropic effect on the heart (augmenting left ventricular function)
What are the uses of salbutamol (ventolin)
- Asthma (inhalation/oral administration): relaxation of bronchial smooth muscle (inhibition of release of bronchoconstrictor substances from mast cells)
- Threatened uncomplicated premature labour (IV): triggers uterine smooth muscle relaxation
What are the side effects of salbutamol (ventolin)
- Reflex tachycardia (rare; salbutamol rarely reaches the systemic circulation in concentrations high enough to cause this) 2. Tremor (triggers receptors in muscle spindles)
What are the contraindications for salvutamol (ventolin)
- Cardiac patients (potential cross-reactivity with β1 receptors)
- Hyperthyroidism (hormones sensitise actions of β receptors)
- Diabetics (IV – increases glycolysis and gluconeogenesis)
what are examples of main indirectly acting sympathomimetics?
Cocaine and tyramine (cheese reaction)
Cocaine blocks the _______________ in monoamine terminals, which increases the amount of monoamines (e.g. NA, dopamine, other neurotransmitters) in the synapse:
uptake 1 protein
What are the CNS side effects of cocaine?
- Euphoria, excitement
- Increased motor activity
- Activation of vomiting centres
- CNS depression, respiratory failure, death
What are the CVS effects of cocaine?
- Tachycardia, vasoconstriction, increased BP
* Ventricular fibrillation, cardiac arrest
What are the skeletal muscle effects on cocaine?
• Tremors, convulsions
Tyramine is a dietary amino acid found in cheese, red wine, and soy sauce, which can potentially act as a _________________
• Normally not a problem as there are normal mechanisms for degradation of monoamines in the body
- intestines: ____________
- liver, endothelium:__________________
- adrenergic nerve terminals: _________
Interaction with MAO inhibitors (used for large amounts of dietary tyramine can
enter circulation to stimulate cardiovascular and SNS activity –> _______________
Tyramine has weak agonistic activity at adrenoceptors and competes with ________________:
• Displaces NA from intracellular storage vesicles into the cytosol once it is taken up into adrenergic terminals
• Cytoplasmic NA leaks through the neuronal membrane to act at postsynaptic adrenoceptors, causing excessive stimulation
false neurotransmitter (mimics activity in the SNS);
MAO-A (80%) and MAO-B (20%);
MAO-A (50%) and MAO-B (50%)
MAO-A;
hypertensive crisis;
catecholamines for uptake 1 protein
