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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
Summarise the Juxta-glemrular apparatus structure and function
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
26
What is the half life of renin
80 minutes
27
What does renin do
Splits the angiotensin 1 from circulating angiotensinogen (made in liver)
28
What is ANG 1 and ANG 2
ANG 1 is a decapeptide ANG 2 is an octapeptide (ACE converts in lungs and also inactivates bradykinin
29
How is ANG 2 metabolized
Broken down in kidney to inactive metabolites and ANG 3 (which retains minor activity)
30
What is the mechanism of action of ANG2
There are AT 1 and AT 2 receptors ANG 2 has greater affinity for AT 1 which is G protein coupled.
31
What are the effects of angiotensin
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
Which population group is ACE resistant
Black population (thiazides better)
33
Classify the ACEI in terms of their metabolism
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
What are the renal considerations with ACEI and ARB
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
What are the potential metabolic effects of ACE
Reduced aldosterone - -> hyponatraemia - -> hyperkalaemia - -> Raised urea and creatinine
36
What are the relevant drug interactions with ACEI and ARB
Potassium sparing diuretics | NSAIDS relative
37
What are common side effects of ACEI
Cough (no inactivation of bradyknin in lungs) Angiodema (0.2%) Agranulocytosis Tthrombocytopaenia
38
What is the elimination half life and duration of action of analaprilat
4 - 10 hours. | DOA - 20 hours
39
Discuss the metabolites of losartan
Losartan has an active metabolite 40 x more potent than losartan at the AT1 receptor. Hence, losartan is considered a prodrug
40
How does losartan affect angiotensin levels and why
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
What is the name of the losartan active metabolite with 40 x potency of losartan at AT 1 receptors
Carboxylic acid losartan metabolite (acts non-competitively)
42
What are common contraindications for both ACEI and ARBs
Pregnancy | Bilateral Renal Artery Stenosis
43
Why are ARBs considered superior to ACE I
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
List the alpha 2 agonists and there alpha receptor selectivity ratio
Agent (alpha 2 : alpha 1) Alpha methyldopa (10 : 1) Clonidine ( 200 : 1) Dexmedetomidine ( 1600 : 1)
45
When is alpha methylodopa used and what is its dose
Used in hypertensive diseases of pregnancy | Dose 250 mg tds --> 3 g/day
46
Describe alpha methyldopa mechanism of action
Crosses BBB --> alpha - methyl - noradrenalin --> stimulation of presynaptic alpha 2 adrenergic receptors --> reduced centrally mediated SNS tone and NA release
47
describe the presentation of clonidine
Tablets: 25 - 300 ug Injection: clear and colourless (150 ug/ml) Transdermal patch (takes 48 hours peak levels)
48
What is clonidine used for
HPT Acute and chronic pain Suppression of symptoms of opioid withdrawal Augment sedation during ventilation in critically ill patients PAeds - premed
49
Describe the CVS effects clonidine
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
What is the treatment of clonidine withdrawal rebound HPT.What should not be admininstered
Phentolamine DO not give beta blockers
51
What are the CNS effects of Clonidine
Sedation --> reduce MAC up to 50% Anxiolytic (low doses) Anxiogenic (high dose)
52
Describe the mechanism, effects and use of clonidine as an analgaesic agent
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
How does clonidine affect the renal system
Diuresis --> ? inhibition ADH release
54
What are the effects of clonidine on the RSP system
No resp depression
55
What endocrine effects does clonidine have
1. Inhibited stress response to surgery | 2. Inhibition insulin release
56
What type of adrenoreceptors occur on platelets and does clonidine affect these
alpha 2 receptors which cause platelet aggregation Clonidine does not promote platelet aggregation. Clonidine's sympatholytic effects blocked adrenalin induced platelet aggregation.
57
Describe the pharmacokinetics of clonidine
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
Compare the route of administration of midazaolam to dexmedetomdine
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
Compare the protein binding and Vd of dexmed to midaz
Midaz 96% PB Vd 1.5 Dexmed 96% PB Vd 1.5
60
Compare the metabolism and elimination of dexmed to midazolam
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
Compare the mechanism of action of midaz to dexmed
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
Compare the effects of Midaz and Dexmed
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
What is the dose of administration of dexmedetomidine
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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