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Pharmacology for Anaesthetists > Other Antihypertensives > Flashcards

Other Antihypertensives Flashcards

1
Q

Classify Antihypertensive drugs

A

RAAS ANTAGONISTS

  1. Renin Antagonists (Aliskiren)
  2. ACE I
  3. ARB

VASODILATORS

  1. Calcium Channel Blockers
    - Dihydropyridine
    - Non-dihydropyridine
    2 .Nitrates
    - GTN
    - Nitroprusside
  2. Potassium channel activators
    - Hydralazine
  3. Phosphodiesterase Inhibitors
    - Papaverine

SYMPATHOLYTIC DRUGS

  1. Beta blockers
    - Selective (Atenolol, Esmolol, Metoprolol)
    - Non - selective (Carvedilol, Labetalol)
  2. Alpha blockers
    - Reversible (Prazosin)
    - Non-reversible (Phenoxybenzaprine, Phentolamine)
  3. Alpha 2 agonists
    - Clonidine
    - Dexmedetomidine
    - Alpha-methyldopa
  4. Monoamine Transport Inhibitors
    - Reserpine
  5. Catecholamine Synthesis Inhibitors
    - Alpha-methyltyrosine
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2
Q

What is hypotensive anaesthesia

A

Deliberately induced intra-operative hypotension to minimise blood loss and minimise blood in surgical field (Middle Ear ENT and neurosurgery).

Head up tilt
Increase volatile
Remifentanil / alfentanil

IF the above fail:

  • -> Esmolol (Beta blocker)
  • -> Labetalol (Alpha and beta blocker)
  • -> Nitrates: Glyceryl trinitrate, Sodium Nitroprusside

Target

  • Depends on starting BP
  • SBP 80 in previously normotensive patients
  • C/I patient’s with risk vascular insufficiency
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3
Q

What are the uses of beta blockers

A 
Angina
HPT
CCF
Arrhythmias
Hypethyroidism
Glaucoma (topically)
Anxiety disorders

Migraine prophylaxis
Secondary prevention following myocardial infarction

Anaesthesia:

  1. Attenuate SNS response to laryngoscopy and endotracheal intubation
  2. Perioperative HPT (phaeochromocytoma)
  3. Perioperative arrhythmias
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4
Q

On which receptors to ARB work

A

AT 1 receptor

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5
Q

Classify the beta blockers according to selsectivity

A

Non-Selective
- Propanolol

B1 Selective

  • Atenolol
  • Metoprolol
  • Esmolol
  • Bisoprolol
  • Nebivolol
  • Sotolol

Combined alpha and beta blocker

  • Carvedilol
  • Labetalol
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6
Q

Name 2 alpha 2 receptor agonists used in the treatment of hypertension

A

alpha-methyldopa

clonidine

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7
Q

How do alpha-methyldopa and clonidine bring about their antihypertensive affect?

A

Decreases central sympathetic outflow by presynaptic down regulation of noradrenalin release.

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8
Q

Compare the duration of action of methyldopa to clonidine

A

methyldopa - 10 hours

Clonidine - 6 hours

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9
Q

What are the clinical effects of methyldopa vs clonidine

A

Methyldopa

  1. Bradycardia and decreased BP
  2. Depression
  3. Sedation
  4. hemolytic anemia
  5. Drug induced lupus

Clonidine

  1. Bradycardia and decreased BP
  2. Sensitisation of opioid receptors
  3. Sedation
  4. Analgaesia
  5. Rebound hypertension after interruption of chronic use
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10
Q

Why is methyldopa still used in pregnancy

A

“Established long term safety” in terms of teratogenicity.

Nifedipine and labetalol also safe in pregnancy

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11
Q

Are the alpha agonisits suitable for long term BP control

A

No. Depression

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12
Q

Name the potassium channel activators

A
  1. Hydralazine
  2. Minoxidil
  3. Nicorandil
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13
Q

How are Hydralazine and minoxidil administered

A

IV or Oral (topical also for minoxidil)

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14
Q

What is the mechanism of action of hydralazine and minoxidil

A

ATP sensitive potassium channel activation –> inhibits opening of CA channels indirectly by hyperpolarising the membrane

Precapillary arteriolar vasodilation
No venodilation

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15
Q

Why is hydralazine used in ICU rather than in community management of hypertension

A

It does not have venodilator properties and so can be used to preserve preload whilst decreasing afterload.

It is not desirable as a long term agent as it is not effective when administered alone. It requires a co-administration with a beta blocker and a diuretic to counteract the reflex tachycardia and fluid retention that it causes.

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16
Q

Why is Nicorandil preferred for long term use than hydralazine and minoxidil

A

Angina preventor
Nitrate-like venodilator properties are present
Free from adverse effects (e.g. minoxidil and hypertrichosis)

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17
Q

Name the renin antagonists

A

Aliskiren

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18
Q

How is Aliskiren it administered

A

Oral only

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19
Q

What is the mechanism of action fo aliskiren

A

Inhibits the activity of renin thus inhibiting RAAS

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20
Q

Why are renin antagonsits seldom used

A

Very poor bioavailability ± 2.5%

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21
Q

What is papaverine used for and what is its mechanism of action

A

Used as an intra-arterial injection for the treatment of cerebral vasospasm / Rx thiopentone intrarterial injection.

Mechanism of action: Phosphodiesterase inhibitor with maximum selectivity for PDE10 –> increased cAMP in vascular smooth muscle –> Reduced IC calcium

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22
Q

How does increased cAMP in vascular smooth muscle cause relaxation versus increased cAMP in cardiac muscle which causes increased contractility?

A

Overall: cAMP influences different kinase enzymes in these different tissues

VASCULAR SMOOTH MUSCLE - relaxation

cAMP causes inhibition of MLCK (Myosin Light Chain Kinase in smooth muscle)
–> MLCK is the enzyme that causes smooth muscle contraction

CARDIAC MYOCYTES - contraction

cAMP activate PKA (Phosphokinase A) which phosphorylates L type Ca channels + the RyR (ryanodine) receptor –> SR Ca release –> Cardiomyocyte contraction

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23
Q

What is reserpine and what is its mechanism of action?

A

Monoamine reuptake inhibitor
Blocks vesicular monoamine transporter 2 –> catecholamines and serotonin lingers in the cytoplasm and is destroyed by cytoplasmic monoamine oxidase –> depletion of catecholamine and serotonin stores in central and peripheral nerve terminals

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24
Q

What are the clinical effects of reserpine

A 
Hypotension
Sedation 
Bradycardia
Depression
(Can be used as antipsychotic)
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25
Q

Summarise the Juxta-glemrular apparatus structure and function

A

Structure of Juxtaglomerular apparatus

  1. Juxtaglomerular (granular) cells (part of afferent a. –> contain prorenin –> renin)
  2. Macula densa (cells at start DCT –> sense NaCl)
  3. Agranular lacis cells (or extraglomerular mesangial cells) (between afferent and efferent arteriole cells)

Increased renin from agranular cells:

  1. Reduced RBF
  2. Reduced Na at macula densa
  3. Beta 1 adrenoreceptor stimulation

Reduced RBF and Na delivery to macular densa –> contraction of extraglomerular mesangial cells reduces the surface area available for GFR. Reduced GFR –> Reduced filtration fraction –> Fluid retention

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26
Q

What is the half life of renin

A

80 minutes

27
Q

What does renin do

A

Splits the angiotensin 1 from circulating angiotensinogen (made in liver)

28
Q

What is ANG 1 and ANG 2

A

ANG 1 is a decapeptide

ANG 2 is an octapeptide

(ACE converts in lungs and also inactivates bradykinin

29
Q

How is ANG 2 metabolized

A

Broken down in kidney to inactive metabolites and ANG 3 (which retains minor activity)

30
Q

What is the mechanism of action of ANG2

A

There are AT 1 and AT 2 receptors

ANG 2 has greater affinity for AT 1 which is G protein coupled.

31
Q

What are the effects of angiotensin

A
  1. Vasoconstriction (5 x potency of noradrenalin)
  2. SNS activation - inhibition of NA re-uptake
  3. CNS - Increase thirst / ADH / ACTH
  4. Adrenals - Increase aldosterone release
  5. Decrease GFR
32
Q

Which population group is ACE resistant

A

Black population (thiazides better)

33
Q

Classify the ACEI in terms of their metabolism

A

Group 1:
Captopril - active drug metabolized into active metabolites

Group 2
Enalapril / Ramipril - Prodrugs requiring hepatic metabolism for activation

Group 3
Lisinopril - Active drug. Excreted unchanged in urine

34
Q

What are the renal considerations with ACEI and ARB

A

Suppression of efferent arteriolar tone for the maintenance of GFR in poor perfusion states.

  • Low renal perfusion –> renal failure
  • Bilateral renal artery stenosis is contraindication
  • Unilateral renal artery stenosis to single functioning kidney is also contraindication
35
Q

What are the potential metabolic effects of ACE

A

Reduced aldosterone

  • -> hyponatraemia
  • -> hyperkalaemia
  • -> Raised urea and creatinine
36
Q

What are the relevant drug interactions with ACEI and ARB

A

Potassium sparing diuretics

NSAIDS relative

37
Q

What are common side effects of ACEI

A

Cough (no inactivation of bradyknin in lungs)
Angiodema (0.2%)
Agranulocytosis
Tthrombocytopaenia

38
Q

What is the elimination half life and duration of action of analaprilat

A

4 - 10 hours.

DOA - 20 hours

39
Q

Discuss the metabolites of losartan

A

Losartan has an active metabolite 40 x more potent than losartan at the AT1 receptor. Hence, losartan is considered a prodrug

40
Q

How does losartan affect angiotensin levels and why

A

Increases them. Blocks negative feedback of ANG 2 on renin. Increased renin and increased ANG 2 result. This has little effect due to comprehensive block at AT1 receptors

41
Q

What is the name of the losartan active metabolite with 40 x potency of losartan at AT 1 receptors

A

Carboxylic acid losartan metabolite (acts non-competitively)

42
Q

What are common contraindications for both ACEI and ARBs

A

Pregnancy

Bilateral Renal Artery Stenosis

43
Q

Why are ARBs considered superior to ACE I

A
  1. AT1 blockade more complete as ANG 2 can be synthesized via non ACE pathways
  2. AT2 not block. AT 2 believed to have cardioprotective properties
  3. Cough / Angioedema almost never occurs –> better compliance
44
Q

List the alpha 2 agonists and there alpha receptor selectivity ratio

A

Agent (alpha 2 : alpha 1)

Alpha methyldopa (10 : 1)

Clonidine ( 200 : 1)

Dexmedetomidine ( 1600 : 1)

45
Q

When is alpha methylodopa used and what is its dose

A

Used in hypertensive diseases of pregnancy

Dose 250 mg tds –> 3 g/day

46
Q

Describe alpha methyldopa mechanism of action

A

Crosses BBB –> alpha - methyl - noradrenalin –> stimulation of presynaptic alpha 2 adrenergic receptors –> reduced centrally mediated SNS tone and NA release

47
Q

describe the presentation of clonidine

A

Tablets: 25 - 300 ug
Injection: clear and colourless (150 ug/ml)
Transdermal patch (takes 48 hours peak levels)

48
Q

What is clonidine used for

A

HPT
Acute and chronic pain
Suppression of symptoms of opioid withdrawal
Augment sedation during ventilation in critically ill patients
PAeds - premed

49
Q

Describe the CVS effects clonidine

A
  1. Decrease BP
  2. Decrease HR
  3. CO maintained
  4. PR lengthened
  5. AV conduction slowed
  6. Sensitized BR reflex
  7. coronary VC offset by release of local Nitric Oxide
  8. Rebound HPT –> if stopped abruptly
50
Q

What is the treatment of clonidine withdrawal rebound HPT.What should not be admininstered

A

Phentolamine

DO not give beta blockers

51
Q

What are the CNS effects of Clonidine

A

Sedation –> reduce MAC up to 50%
Anxiolytic (low doses)
Anxiogenic (high dose)

52
Q

Describe the mechanism, effects and use of clonidine as an analgaesic agent

A

Mechanism

  1. Spinal cord: Augment endogenous opioid release
  2. Spinal cord: Modulate descending noradrenergic nociceptive pathways

Effects

  1. Prolonged analgaesia with no resp. depression
  2. Synergistic with concurrent opioids
  3. No motor or sensory blockade
  4. Reduce post-op opioid requirement
53
Q

How does clonidine affect the renal system

A

Diuresis –> ? inhibition ADH release

54
Q

What are the effects of clonidine on the RSP system

A

No resp depression

55
Q

What endocrine effects does clonidine have

A
  1. Inhibited stress response to surgery

2. Inhibition insulin release

56
Q

What type of adrenoreceptors occur on platelets and does clonidine affect these

A

alpha 2 receptors which cause platelet aggregation

Clonidine does not promote platelet aggregation.
Clonidine’s sympatholytic effects blocked adrenalin induced platelet aggregation.

57
Q

Describe the pharmacokinetics of clonidine

A

A: Bio 100% oral
D: 2 L/kg
M: 50 % liver to inactive. and 50% unchanged in urine
E: elimination half life 9 - 18 hours

58
Q

Compare the route of administration of midazaolam to dexmedetomdine

A

Midazolam
Oral 44% bioavail (double dose required vs IV) / IV / SC / Intranasal / buccal /

Dexmedetomidine
IV / Buccal / Intranasal / Intrathecal
Oral Bio is 16% (significant 1st pass)

59
Q

Compare the protein binding and Vd of dexmed to midaz

A

Midaz 96% PB Vd 1.5

Dexmed 96% PB Vd 1.5

60
Q

Compare the metabolism and elimination of dexmed to midazolam

A

Midaz
Liver
- Hydroxylated to 1 alpha hydroxymidaz (active) - accumulates in renal failure
- Other Inactive compounds glucoronidated and excreted renal

Dexmed
- Hydroxylation P450
- Glucoronidation
Both excreted renal

61
Q

Compare the mechanism of action of midaz to dexmed

A

Dexmed
Presynaptic alpha 2 adrenergic agonist –> G protein linked receptor –> Negative feedback system promoted –> inhibition of SNS tone and inhibition of NA output. Analgaesia: central modulation of descending NA nociceptive pathways vs peripheral sensitization of opioid receptors vs increase endogenous opioid release.

Midaz
Allosteric modulator of GABA A –> increase effect of GABA at GABA A receptor in CNS –> Increase Cl- into cell –> cell hyperpolarization. Reduced AP generation as further from threshold. Sedation.

62
Q

Compare the effects of Midaz and Dexmed

A

Midaz

  1. Sedation / hypnotic –> reduce MAC
  2. Amnesia (anterograde)
  3. Anticonvulsant
  4. Anxiolysis
  5. Muscle relaxation
  6. Resp depression
    - Lost airway reflexes
    - Reduced hypercapnoiec response of Ve
    - Resp drive suppressed (not as much as opioids)
  7. Mild CVS affects: SNS suppression - mild decrease BP and HR
  8. No effect ICP. Mild decrease CMRO2

Dexmed

  1. Sedation (like natural sleep)
    - preserved airway reflexes
  2. Analgaesia (mild)
  3. No RESP depression (even at high doses)
  4. Low HR and Low BP with decreased CO (sympatholytic !)
63
Q

What is the dose of administration of dexmedetomidine

A

Load 0.5 ug/kg/dose over 10 minutes

0.2 - 1 ug/kg/HOUR titrated to effect

Pharmacology for Anaesthetists (37 decks)

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