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M2 Pharmocology > 4.3 Sympatomimetic drugs > Flashcards

4.3 Sympatomimetic drugs Flashcards

1
Q

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

A

L-tyrosine; L-DOPA; tyrosine hydroxylase;

DOPA decarboxylase enzyme;

dopamine β-hydroxylase;

phenylethanolamine N-methyltransferase

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2
Q

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
A

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

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3
Q

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 __________________
A

constricted;

dilated in a sympathetic response;

presynaptic terminals of noradrenergic neurones → limits further NA release

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4
Q

Uptake 1

  • Back into presynaptic terminal
  • Metabolised by _____________ into inactive metabolites
A

monoamine oxidase (MAO)

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5
Q

Uptake 2

  • Into postsynaptic cell
  • Degraded by ______________ into inactive metabolites
A

catechol-O-methyltransferase (COMT)

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6
Q

what is the selectivity of adrenaline?

A

α1 = α2 = β1 = β2

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7
Q

what is the selectivity of phenylephrine?

A

α1 > α2 > β1 / β2

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8
Q

whit is the selectivity of clonidine?

A

α2 > α1 > β1 / β2

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9
Q

what is the selectivity of isoprenaline?

A

β1 / β2 > α1 / α2

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10
Q

What is the selectivity of dobutamine?

A

β1 > β2 > α1 / α2

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11
Q

what is the selectivity of salbutamol?

A

β2 > β1 > α1 / α2

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12
Q

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)

A

adrenal medulla by chromaffin cells;

IV/IM/locally/topically;

MAO and COMT

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13
Q

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
A

massive peripheral vasodilation ;

Peripheral vasoconstriction;

Increase HR and contractility;

Bronchodilation

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14
Q

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 ______________
A

positive inotropic & chronotropic actions

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15
Q

ADRENALINE: Prolonged duration of LA

Adrenaline has ______________ → prolongs drug action and minimises dose of LA required

A

α1 vasoconstrictor properties

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16
Q

What are the side effects of adrenaline (secretions)?

A

 Reduced and thickened secretions  Mucous secretions (dry mouth)

17
Q

What are the side effects of adrenaline (CNS)?

A

 Minimal effects (does not readily cross blood-brain barrier)

18
Q

What are the side effects of adrenaline (cardio vascular)

A

 Tachycardia, palpitations, arrhythmias  Cold extremities (vasoconstriction in hands and feet)  Severe hypertension  Overdose: cerebral haemorrhage, pulmonary oedema

19
Q

what are the side effects of adrenaline (GI)?

A

 Minimal effects

20
Q

What are the side effects of adrenaline (skeletal muscle)

A

 Tremor (muscle spindles have β adrenoceptors)

21
Q

What are the uses of phenylephrine if given IV/ topical?

A

α1 vasoconstrictor properties → stops superficial bleed

22
Q

What are the uses of phenylephrine if given as eyedrops ?

A

α1 constricts radial muscles → pupil dilation (allows for inspection of fundus of the eye)

23
Q

What are the uses of phenylephrine if given as nasal drops/ pral ?

A

α1 vasoconstrictor properties → reduced fluid supply to nasal region (less fluid to become congested)

24
Q

What are the side effects of phenylephrine?

A
  • hypertension: Due to the vasoconstrictor effects

- Rhinitis medicamentosa: Rebound nasal congestion (mechanism not well understood)

25
Q

Clonidine is a selective α2 adrenoceptor agonist (on presynaptic membranes) given via oral or IV administration. What is it used for?

A

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

26
Q

what are the side effects of clonidine?

A

hypotension, bradycardia, congestive heart failure, weakness, oedema

27
Q

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?

A
  1. Cardiogenic shock, acute heart failure, myocardial infarction (IV)
  2. Asthma → discontinued due to unwanted actions (reflex tachycardia and dysrhythmias)
28
Q

What is the mechanism of having reflex tachycardia from isoprenaline?

A

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

29
Q

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 ______________
A

COMT;

reflex tachycardia side effect seen in isoprenaline;

inotropic effect on the heart (augmenting left ventricular function)

30
Q

What are the uses of salbutamol (ventolin)

A
  1. Asthma (inhalation/oral administration): relaxation of bronchial smooth muscle (inhibition of release of bronchoconstrictor substances from mast cells)
  2. Threatened uncomplicated premature labour (IV): triggers uterine smooth muscle relaxation
31
Q

What are the side effects of salbutamol (ventolin)

A
  1. Reflex tachycardia (rare; salbutamol rarely reaches the systemic circulation in concentrations high enough to cause this) 2. Tremor (triggers receptors in muscle spindles)
32
Q

What are the contraindications for salvutamol (ventolin)

A
  1. Cardiac patients (potential cross-reactivity with β1 receptors)
  2. Hyperthyroidism (hormones sensitise actions of β receptors)
  3. Diabetics (IV – increases glycolysis and gluconeogenesis)
33
Q

what are examples of main indirectly acting sympathomimetics?

A

Cocaine and tyramine (cheese reaction)

34
Q

Cocaine blocks the _______________ in monoamine terminals, which increases the amount of monoamines (e.g. NA, dopamine, other neurotransmitters) in the synapse:

A

uptake 1 protein

35
Q

What are the CNS side effects of cocaine?

A
  • Euphoria, excitement
  • Increased motor activity
  • Activation of vomiting centres
  • CNS depression, respiratory failure, death
36
Q

What are the CVS effects of cocaine?

A
  • Tachycardia, vasoconstriction, increased BP

* Ventricular fibrillation, cardiac arrest

37
Q

What are the skeletal muscle effects on cocaine?

A

• Tremors, convulsions

38
Q

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

A

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

M2 Pharmocology (20 decks)

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