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MPharm2 SL22106 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What is the CNS?

A

Brain
Spinal Cord

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2
Q

What is the PNS?

A

Cranial nerves - 12 pairs
Spinal nerves - 31 pairs

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3
Q

What is the preganglionic neurone?

A

Cell body is in the CNS
Small diameter & myelinated
Synapses at autonomic ganglia
Preganglionic fibre releases ACh
ACh acts on nicotinic receptors on the post-synaptic neuron

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4
Q

What is the postganglionic neurone?

A

Cell body in autonomic ganglion
Small diameter, unmyelinated
Synapse close to target organ

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5
Q

What are autonomic ganglions?

A
  • Interface between pre- and post- ganglionic neurons of the autonomic nervous system
  • In both Sympathetic and Parasympathetic branches
  • Acetylcholine (ACh) is the primary transmitter
  • Conducts Na+ in, K+ out
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6
Q

What is the Autonomic Regulation of the Peripheral Organs?

A

Sympathetic and parasympathetic stimulation often has opposing actions:
Smooth muscle of gut & bladder
Heart
Some organs - Sympathetic only
- Sweat glands
- Blood vessels
Others - Parasympathetic only
- Ciliary muscle of eye

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7
Q

What is Cardiovascular regulation by the ANS?

A

Control of heart rate
- Contraction & relaxation of smooth muscle in blood vessels & organs
- Most blood vessel have NO parasympathetic innervation
- Regulation of glandular secretion

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8
Q

What are the 3 physiological consequences of ganglionic nicotinic receptor stimulation?

A
  • Sympathetic and parasympathetic post-synaptic nerve activation
  • Secretion of adrenaline from the adrenal medulla
  • Sympathetic responses dominate
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9
Q

What are ganglion blocking drugs?

A

Hexamethonium
- Non depolarising nicotinic antagonist
- no clinical uses

Local anaesthetics
- Sympathetic ganglion block (sympathetically-mediated pain pathways)
- e.g. Lidocaine
- co-administered with adrenergic agonist

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10
Q

What chemical is produced by postsynaptic parasympathetic fibres?

A

Noradrenaline

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11
Q

How is noradrenaline synthesised?

A

Multi-enzyme synthetic pathway:
Initial stages of synthesis in cytoplasm
Final stage of synthesis on membrane of synaptic vesicle.

Precursor molecule is the amino acid L-tyrosine

Final product regulates synthesis via a negative feedback process on initial step of synthesis.

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12
Q

What is metirosine?

A
  • The inhibitor of the initial enzyme that forms NA
  • Possible clinical use in pheochromocytoma
  • Side fx include: headaches, heavy sweating, tachycardia, high blood pressure, a pale face, nausea, anxiety, tremor
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13
Q

What is carbidopa?

A
  • the inhibitor of the second stage of sythesis of NA
  • Used in Parkinson’s disease to prevent peripheral effects of levodopa
  • does not cross BBB
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14
Q

How is noradrenic release regulated?

A
  • Depolarization of nerve ending opens calcium channels
  • Leads to vesicle exocytosis, NA released
  • Released NA activates presynaptic receptors that inhibit adenylyl cyclase
  • This prevents calcium channel opening and limits further release of NA
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15
Q

What is methyldopa?

A
  • used for high blood pressure had perioheral and central effects). It is one of the preferred treatments for high blood pressure in pregnancy, it relaxes blood vessels
  • inhibits release of NA
  • Metabolised to methyl-NA
  • False precursor molecule
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16
Q

What is guanethidine?

A
  • Inhibits NA release
  • Substrate for NET and VMAT
  • Accumulates in vesicles and stabilises
  • Displaces NA
  • High doses – destroys neuron
  • Overall effect: block of adrenergic neurons
  • Historically used as antihypertensive but obsolete clinically
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17
Q

What is reserpine?

A
  • inhibits release of NA and VMAT
  • prevents transport of NA into vesicles
  • Cytoplasmic NA metabolised by MAO
  • Vesicular levels fall
  • antihypertensive but clinically obsolete
  • side effects similar to methyldopa
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18
Q

What are the side effects of inhibiting NA release?

A
  • Hypotension
  • Bradycardia
  • Digestive disorders
  • Nasal congestion
  • Sexual dysfunction
  • Sedation
  • Mood disturbances
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19
Q

What is the action of b-adrenoceptor receptor activation in the heart?

A

Increase in cardiac myocyte Ca2+, contractility, pacemaker activity in SA node, rate and force

In smooth muscle
Decrease in intracellular Ca2+, inhibition of MLCK, relaxation of smooth muscle, vasodilator

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20
Q

What is the function of α1 agonists?

A

constrict most smooth muscle
vasoconstrictor
except in GI tract where they relax

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21
Q

What is the function of α2 agonists?

A

mediate presynaptic inhibition of neurotransmitter release
sympathetic and parasympathetic neurons
prevent noradrenaline release and hence reduce BP

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22
Q

What is the function of β1 agonists?

A

increase heart rate and force of contraction

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23
Q

What is the function of β2 agonists?

A

dilate/relax smooth muscle
increase cardiac contractility

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24
Q

What is the function of β3 agonists?

A

stimulate thermogenesis in skeletal muscle
found in adipose tissue

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25
Q

What do amphetamines do?

A

Structures similar to NA but do not activate receptors
Substrates for NET and VMAT
Prevent NA accumulation in vesicle
Inhibit MAO
Promotes NA export via NET
increase cytosol NA
Increase NA outflow into synapse

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26
Q

What are α-adrenoceptor antagonists?

A
  • Phenoxybenzamine long lasting, covalent binding also blocks other classes of receptor, irreversible (new receptors take 24 hours)
  • Phentolamine more selective, but short acting (reversible around 4hours)

Treatment of pheochromocytoma

Cause hypotension, postural hypotension
Induced tachycardia / arrythmia

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27
Q

What are α1-antagonists?

A

Cause vasodilatation and fall in arterial pressure
Clinically used as antihypertensive drugs
e.g. prazosin, doxazosin
Less tachycardia than non-selective
Still cause postural hypotension, headaches

Relax bladder neck smooth muscle and prostate capsule
Clinically used to treat urinary retention associated with prostatic hypertrophy (enlarged prostate) esp. tamsulosin

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28
Q

What are α2-antagonists?

A

Yohimbine and synthetic analogue idazoxan are mainly experimental - effects debated

Yohimbine has vasodilator and stimulant effects
Reverse sedative effect in animals

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29
Q

How do β-adrenoceptor antagonists work?

A

Decreased heart rate and reduce contractibility. Decrease Cardiac Output, and decrease oxygen demand heart muscle
In hypertensive arterial pressure drops over several days;
Reduction of cardiac output (CO)
Reduction of renin release
CNS: Propranolol can cross the BBB treatment of migraine
Prevent tremor - skeletal muscle β-receptor
Banned in target sports (e.g. snooker, darts, shooting,
golf), ski jumping, snowboarding, automobile sports

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30
Q

What are the unwanted side effects of β-adrenoceptor antagonists ?

A

Bronchoconstriction (via β2 antagonism)
- can be significant even with “selective” β1 antagonists in asthmatics
Cardiac failure
- Reduce sympathetic tone required to maintain CO
- but generally useful in heart failure because of reduced work
Bradycardia
Hypoglycaemia
- Glucagon release and glycogenolysis normally stimulated by circulating adrenaline (b2 receptor)
- Blocked by b-antagonists
- ‘hypoglycaemic unawareness’
- Symptoms of hypoglycaemia (tremor and tachycardia) blocked by b-antagonists, rescue strategies missed
- But NOT contraindicated in diabetes – use with caution b1 selective antagonists may be preferred
Fatigue
- Due to reduced cardiac output and muscle perfusion during exercise
Cold extremities
- Loss of β2 -induced dilatation of subcutaneous blood vessels
Erectile dysfunction
Lucid dreams

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31
Q

Which disorders can be caused by GH deficit?

A

Dwarfism - may be
- general anterior pituitary dysfunction -
- specific GH deficit
- normal GH but heriditary somatomedin deficit
Accelerated aging - loss of growth hormone after adolescence
- decreased protein synthesis

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32
Q

Which disorders can be caused by GH excess?

A

Gigantism – early life pituitary tumour
Acromegaly- pituitary tumour after adolescence

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33
Q

What is acromelagy?

A

Caused by excess production of growth hormone
Most commonly affects middle-aged
Can result in premature death
Due to slow onset it is frequently incorrectly diagnosed
Most common symptoms are abnormal growth of hands & feet.

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34
Q

How is acromelagy treated?

A

Aim is to reduce GH production:
Surgical removal of tumour
Drug therapy
octreotide & lanreotide (somatostatin analogues, somatostatin receptor ligands SRLs)
pegvisomant (growth hormone receptor antagonist)
bromocriptine (dopamine agonist)
Radiation therapy

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35
Q

What is prolactinoma?

A

Benign pituitary tumours (adenomas) are the most common cause
Prolactin is the ‘milk hormone’
Common presentation:
Galactorrhoea - milky secretion from the breasts
Amenorrhoea – females absence of periods
Hypogonadism – diminished production of sex hormones, diminished function of gonads in males & females
Erectile dysfunction - males
Vision loss, due to compression of the optic chiasm, is a common comorbidity

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36
Q

How is prolactinoma treated?

A

dopamine agonists
Prolactin inhibiting factor (PIF) is dopamine

Dopamine acts at D2 receptors in the pituitary gland to inhibit prolactin release

Cabergoline and bromocriptine are dopamine agonists that inhibit prolactin production and can reduce the size of a prolactinoma

Antipsychotics that are D2 receptor antagonists can cause hyperprolactinaemia

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37
Q

What is Hypopituitarism?

A
  • Rare - results from a deficiency in one or more pituitary hormones
  • Panhypopituitarism – a deficiency in all anterior pituitary hormones
  • Multiple causes (acquired more often than congenital)
  • Symptoms mirror those of a primary deficiency in hormone secretion by the target endocrine gland
  • Managed by replacement therapy with the appropriate hormone(s)
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38
Q

What is Hypothyroidism?

A
  • One of the most common endocrine disorders
    overall UK prevalence > 2% in women, but under 0.1% in men
    mean age at diagnosis around 60 years
  • Usually primary (disease of the thyroid) but can be secondary (↓ TSH)
  • Most common form is atrophic (autoimmune) hypothyroidism
    antithyroid autoantibodies
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39
Q

What are 6 symptoms of Hypothyroidism?

A
  • fatigue
  • weight gain
  • cold intolerance
  • dry hair and skin
  • mental slowness
  • bradycardia
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40
Q

How is Hypothyroidism diagnosed?

A
  • Elevated serum TSH
  • Low free T4 confirms and excludes TSH deficiency (2o hypothyroidism)
  • Replacement therapy with levothyroxine (lifelong)
  • Adequacy assessed clinically and by tests of thyroid function (TSH)
  • Complete suppression of TSH should be avoided
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41
Q

What is hyperthyroidism?

A
  • Common, affecting 2-5% of all females between ages of 20-40 years
  • F:M of 5:1
  • Grave’s disease is the most common form
  • usually accompanied by thyroid eye disease
  • 60% exhibit pattern of alternating relapse and remission
  • many eventually become hypothyroid
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42
Q

What are the 6 symptoms of hyperthyroidism?

A
  • weight loss
  • increased appetite
  • irritability
  • heat intolerance
  • tremor
  • tachycardia or AF
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43
Q

How is hyperthyroidism diagnosed and managed?

A
  • Low serum TSH
  • A raised T3 (more sensitive) or T4 confirms the diagnosis

Three possible treatments
- Antithyroid drugs: e.g., Carbimazole (UK)
- clinical benefit delayed (10-20 days) due to long half-life of T4 (7 days)
- rapid partial symptomatic relief obtained by coadministration of a beta-blocker
- Radioiodine (only in patients previously rendered euthyroid, common in USA)
- contraindicated during pregnancy and whilst breast-feeding
- Surgery (only in patients previously rendered euthyroid)

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44
Q

What are goitres?

A

Thyroid enlargement
Present on examination in ≈ 9% of UK population
Majority are painless and cause no symptoms

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45
Q

What is alderosterone?

A

The body’s main mineralocorticoid
- Promotes the reuptake of sodium, and hence water, by the kidney
- Increased reabsorption of Na+ is associated with increased secretion of K+ and H+

Mineralocorticoid receptor is a member of the nuclear receptor superfamily (NR3C2)
- MR restricted distribution - predominantly in kidney, colon, bladder

Synthesis and secretion regulated by renin-angiotensin system

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46
Q

What are the three triggers for renin release?

A

↓ BP in afferent arteriole
↑ sympathetic nervous activity
↓ [NaCl] in distal convoluted tubule

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47
Q

What is spironolactone?

A

Competitive antagonist of aldosterone
Also has some blocking action on androgen/progesterone receptors (side effects)
Primary/secondary hyperaldosteronism and resistant hypertension

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48
Q

What is fludrocortisone?

A

Increases Na reabsorption in the distal tubules (and increases K+/H+ efflux into the tubules)
Used in replacement therapy e.g. Addison’s disease (with a glucocorticoid)

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49
Q

What is primary hyperaldosteronism/Conn’s syndrome?

A
  • Accounts for 1% of cases of hypertension
  • Increased risk of stroke, heart disease, kidney failure
  • Typical age of onset 30 – 50 years, women > men
  • ↑ plasma aldosterone:renin ratio in diagnostic blood test
  • ↑ plasma aldosterone levels; not suppressed by saline infusion
  • ↓ serum and increased urinary K+ can lead to muscle weakness,
  • Treat with aldosterone antagonist (spironolactone) or
  • Surgical removal
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50
Q

What is cortisol?

A
  • The body’s main glucocorticoid
  • Synthetic glucocorticoids are an important class of therapeutics
  • GRs widespread distribution – essentially all cell types
  • Influences many cardiovascular, metabolic, immunologic and homeostatic functions
  • Synthesis and secretion is stimulated by ACTH from the pituitary
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51
Q

How is the hypothalamic-pituitary-adrenal axis controlled?

A

Increased ACTH levels – primary hyposecretion of GC
Decreased ACTH levels – can lead to secondary adrenal insufficiency
Increased ACTH levels – consequence of a pituitary tumour can cause hypersecretion of GC (Cushing’s syndrome)

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52
Q

What is Primary adrenal insufficiency (Addison’s disease)?

A
  • A rare, life-threatening condition
  • Incidence of 3-4/million population/annum
  • Most prevalent aged 30 to 50 years
  • More common in women than men
  • In UK most often caused by autoimmune disease (> 90%)
  • Clinical features don’t appear until at least 90% of tissue destroyed
  • Early signs include chronic worsening fatigue, loss of appetite, generalized weakness, hypotension
  • Characterised by increased production of ACTH
  • Increased ACTH production/ also melanocyte stimulating hormone is responsible for hyperpigmentation
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53
Q

What are the 3 symptoms and signs of addisons disease?

A
  • weight loss
  • weakness
  • postural hypotension
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54
Q

What is secondary adrenal insufficiency?

A
  • Adrenal hypofunction because of impaired ACTH release
  • Long-term corticosteroid medication for non-endocrine disease
  • Typically patients with chronic inflammatory diseases
  • Gradual withdrawal of corticosteroid therapy is essential
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55
Q

What is hypercortisolism/Cushing’s syndrome?

A

Cushing’s syndrome is rare
Incidence of 5/million/annum
Primary - overactivity of the adrenal gland (very rare)
- Most commonly cortisol-secreting adrenal tumour or nodular hyperplasia
- Associated with subsequent (physiological) suppression of ACTH secretion

Secondary – tumour of the pituitary gland or ACTH-dependent
- Most common cause of ‘endogenous Cushings’
- Less often ectopic ACTH-secreting tumour

Differential diagnosis includes, amongst other tests/measurements
Low or undetectable plasma ACTH levels (<10 ng/L on 2 or more occasions)

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56
Q

What is iatrogenic cushing’s syndrome?

A
  • Most common cause of Cushing’s syndrome
  • Patients receiving long-term glucocorticoid therapy
  • Type, dose and duration of exposure are critical predisposing factors
  • Infrequently when administered topically or by inhalation
  • An estimated 1% of the general population use exogenous glucocorticoids
  • Of these, 70% experience some adverse effects
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57
Q

What are the 5 symptoms of cushings syndrome?

A
  • increased abdominal fat
  • cataracts
  • buffalo hump
  • poor healing
  • easy bruising
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58
Q

How is Cushing’s syndrome managed?

A
  • Untreated Cushing’s has a vey poor prognosis
  • Main caused of morbidity - hypertension, myocardial infarction, infection and heart failure
  • Cortisol hypersecretion must be controlled prior to surgery or radiotherapy
  • All cases where a cortisol secreting tumour is the cause
  • Pharmacological inhibition of cortisol synthesis with metyrapone, 750 mg – 4g daily in 3 – 4 divided doses
  • Ketoconazole is also used and is synergistic with metyrapone
    200 mg three times daily
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59
Q

What is T1DM?

A
  • The body is unable to produce any insulin
  • Usually appears in childhood and before the age of 40
  • Sudden onset
  • Accounts for between 5-15% of all people with diabetes
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60
Q

What are the 6 symptoms of T1DM?

A
  • Increased urination
  • Increased thirst
  • Weight loss (in spite of increased appetite)
  • Fatigue
  • Nausea, vomiting
  • Coma
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61
Q

What causes T1DM?

A
  • Characterized by immune-mediated destruction of the insulin-secreting b cells of the pancreas
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62
Q

How can Islet transplantation help T1DM?

A

Risks:
Transplantation surgery risk
Immunosuppressant drugs side effects
Need 2-3x transplants

Benefits:
Live without insulin injections
Improved blood glucose control

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63
Q

What is T2DM?

A
  • The body cannot produce enough insulin OR the body cannot respond to insulin = “insulin resistance”
  • Used to appear in people > 40 yrs of age but younger people are increasingly diagnosed with the condition
  • Can go undiagnosed for a long time
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64
Q

What are the 6 symptoms of T2DM?

A
  • Increased urination
  • Increased thirst
  • Increased appetite
  • Fatigue
  • Blurred vision
  • Slow-healing infections
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65
Q

What are the risk factors for T2DM?

A
  • Family history
  • Age (over 45 yrs)
  • Ethnicity (more likely if Chinese, South Asian, Black Caribbean or Black African ethnic background)
  • Obesity
  • High blood pressure
  • High cholesterol
  • Sedentary life style
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66
Q

What are the consequences of insulin resistance?

A
  • Elevated blood sugar
  • Hyperglycaemia
  • Inflammation of the liver
  • Hypertension
  • Atherosclerosis & increased risk of CVD
  • Increased thirst
  • Increased urination
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67
Q

What is gestational diabetes?

A
  • Associated with pregnancy and usually transient
  • Body can’t produce enough insulin for mother and baby
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68
Q

What are the 4 tests for diabetes?

A
  • Glycosylated haemoglobin (HbA1c)
    • When glucose attaches to proteins they become glycated
    • Biomarker of disease and treatment response
    • HbA1c level of 6.5% (48mmol/mol) + indicates T2DM
    • HbA1c level of 6-6.4% (42-47 mmol/mol) indicates risk
  • Fasting plasma glucose test (FPG)
    • Fast for 8 h, blood sample taken, blood sugar > 7 mmol/l
  • Oral glucose tolerance test (OGTT)
    • Fast for 8h, blood sample taken, drink sugary drink
    • 2h later blood sample taken
    • Blood glucose 7.9 – 11 mmol/l = impaired glucose tolerance (IGT)
    • Blood glucose > 11 mmol/l = diabetes
  • Urine analysis
    • Glycosuria
    • Ketone bodies
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69
Q

What are the 4 metabolic complications of diabetes?

A
  • Hypoglycaemia
  • Hyperglycaemia
  • Diabetic ketoacidosis in T1DM
  • Hyperosmolar hyperglycaemic state (HHS) in T2DM
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70
Q

What are the 4 microvascular complications of diabetes?

A
  • thickening of the capillary basement membrane (microangiopathy)
  • Retinopathy
  • Nephropathy
  • Neuropathy
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71
Q

What is diabetic retinopathy?

A
  • Diabetic people 25 x more likely to lose their sight than non-diabetics
  • Tiny bulges develop in the blood vessels, which may bleed slightly but don’t usually affect vision – background retinopathy
  • More severe and widespread changes affect the blood vessels, including more significant bleeding– pre-proliferative retinopathy
  • Scar tissue and new blood vessels, which are weak and bleed easily, develop on the retina– proliferative retinopathy
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72
Q

What is diabetic nephropathy?

A
  • Damage to the capillaries in the glomerulus leads to breakdown of filtration barrier and more protein than normal collects in the urine
  • Exacerbated by hypertension
  • Develops very slowly and over time, the kidneys ability to function starts to decline, which may eventually lead to chronic kidney failure
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73
Q

What is diabetic neuropathy?

A
  • Peripheral nerve dysfunction
  • Capillary damage can lead to nerve damage and loss of sensation, particularly in the extremities
  • Begins as loss of sensation e.g. in the toes and leads to injury
  • Loss of sensation and circulation problems leads to increased risk of infection, ulcers, gangrene “diabetic foot”
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74
Q

What are the macrovascular complications of diabetes?

A
  • Atherosclerosis
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75
Q

What are the 4 key features of metabolic syndrome?

A
  • Insulin resistance
  • Elevated fasting blood glucose
  • Hypertension
  • Dyslipidaemia
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76
Q

What are the risk factors for metabolic syndrome?

A
  • Visceral obesity
  • Age
  • Weight
  • Race (higher in Afro-Caribbean, Asian)
  • Non-alcoholic fatty liver
  • History of gestational diabetes
  • PCOS
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77
Q

How does smoking affect the body?

A
  • Activation of sympathetic system (via nicotinic receptors in sympathetic ganglia and adrenal medulla)
  • Likely to be seen with e-cigarettes and patches
  • Insulin resistance
  • Decreased HDL, increased triglycerides
  • Elevated cortisol
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78
Q

What are the 4 sources of glucose?

A

Dietary intake of carbohydrate

Gluconeogenesis
- liver & kidney
- lactate
- amino acids
- glycerol
- pyruvate

Glycogenolysis
- liver & kidney
- skeletal muscle

Fatty acid catabolism (via pyruvate)
- adipose tissue

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79
Q

What are the two uses of glucose?

A

Glycogenesis (liver & skeletal muscle)
- Glycogen to replenish stocks

Glycolysis (all cells) to generate
- Pyruvate
- ATP
- Chemical synthesis
- Glycerol

  • Fatty acid synthesis (liver and adipose tissue via glycerol)
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80
Q

What is brown fat?

A

High levels in neonates
Key role in thermogenesis
Levels fall (dramatically) with age

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81
Q

What is leptin?

A
  • An adipokine
  • Hormones secreted by adipose tissue
  • Primary action: hypothalamus
  • Stimulates satiety – suppresses hunger
  • Metraleptin – synthetic analogue
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82
Q

What is Adiponectin?

A
  • An adipokine
  • Secreted by adipose tissue but decreased in obesity
  • Low plasma adiponectin is risk factor for metabolic syndrome
  • Stimulates fatty acid catabolism ( => decreased triglycerides)
  • Decreases hepatic glucose production
  • Increases insulin sensitivity
  • Increases glucose uptake by energy-requiring cells
  • Increases energy expenditure
  • Increased by thiazolidinediones (glitizone drugs)
  • Enhanced insulin sensitivity
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83
Q

What are the mechanisms of vascular dysfunction in metabolic syndrome?

A
  • Decreased nitric oxide signalling
  • Increased oxidant stress
  • Triglyceridaemia
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84
Q

What are the recommended therapies for metabolic syndrome?

A
  • exercise
  • gastric bypass
  • transfer of microbiota
  • Pharmacology
    • Cholesterol lowering drugs, Antihypertensives, Insulin sensitizers
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85
Q

What are the 4 components of blood vessels?

A
  • Endothelial cells
  • Basement membrane
  • Smooth muscle cells
  • Sympathetic nerve ending
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86
Q

How is relaxation of blood vessels facilitated?

A
  • A decrease in the phosphorylated state of MLC via two principle mechanisms:
  • Inhibition of MLCK by PKA-dependent phosphorylation (Gs-receptor-coupled, AC/cAMP/PKA dependent pathway)
  • Activation of MLCP by cellular cGMP/PKG stimulated by
    NO via sGC in smooth muscle cells
    GC-coupled receptors (e.g. Natriuretic peptide receptors)
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87
Q

What are the mechanisms of decrease of cytosolic calcium in vascular SM?

A

Reduction of agonist-activated Ca2+ release
Reduction of calcium influx via L-type VACCs:
Hyperpolarisation-mediated (opening of K+ channels by voltage, phosphorylation, NO)
Phosphorylation dependent inhibition (e.g. via PKA & PKG pathways)
Re-uptake by SERCA2 (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase) into the Sarcoplasmic Reticulum (SR) (major mechanism to reduce cellular calcium levels in blood vessels)
Up-take by mitochondria (minor in healthy vessels)
Extrusion via:

Plasmalemmal Ca++-ATPase (Ca-Pump) (major Ca extrusion mechanism)
Na+-Ca++ exchanger (NCX) (minor role in healthy vessels)

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88
Q

What are endothelium-derived vasodilators?

A

Prostaglandins:
PGI2 or prostacyclin;
(others: PGE2, PGD2)
Nitric oxide (NO) or EDRF (Endothelium-Derived Relaxing Factor)

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89
Q

What are the three Nitric Oxide Synthase Isoforms?

A

Neuronal NOS (nNOS or NOS I): Calcium dependent
- CNS: Neurotransmission, LTP, plasticity
- Peripheral NS: Gastric emptying, penile erection

Inducible NOS (iNOS or NOS II) (calcium independent)
- Macrophages, neutrophils, leukocytes: Host defence

Endothelial NOS (eNOS or NOS III): Constitutively expressed; calcium dependent
- Effect on blood vessels (via NO): Vasodilatation
- Effect on platelets (via NO): Reduced platelet adhesion/aggregation

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90
Q

What activates eNOS?

A

Shear Stress (via PKA/Akt)
Insulin (AMPK / Akt)
Agonists (Gq/11–coupled;
via Ca++-CaMK):
- Acetylcholine (M3)
- Bradykinin (B2)
- Histamine (H1)
- Endothelin-1 (ETB)

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91
Q

What types of drug work on pulmonary hypertension?

A

CCBs
Prostaglandin agonists
Endothelin receptor antagonists
PDE5 inhibitors

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92
Q

What are the 4 main functions of the kidney?

A
  • Regulation of extracellular (body) fluid volume
  • Maintenance of ion balance and pH
  • Excretion of foreign substances
  • Renin secretion & activation of the RAAS
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93
Q

What is ultrafiltration?

A

Driving force:
PGC - Glomerular Capillary hydrostatic pressure
πBS - oncotic pressure in the Bowman’s Space
(negligible in normal kidney)

Opposing forces:
πGC - oncotic pressure of blood plasma
PBS - Pressure in the Bowman’s Space
Net Glomerular Filtration Pressure PGC - πGC - PBS
Glomerular Filtration Rate (GFR)

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94
Q

Where does tubular sodium reabsorption occur?

A
  1. The Proximal Convoluted Tubule (PCT) 60-70%
  2. The Thick Ascending Limb (TAL) of the loop of Henle 20-30%
  3. The Distal Tubule (DT) 5-10%
  4. The Collecting Tubule (CT) & the Collecting Duct (CD) 1-3%
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95
Q

What are the 5 types of diuretics?

A
  1. Loop Diuretics
    Act on Thick Ascending Limb (TAL) of Loop of Henle
  2. Thiazides and Thiazide-like
    Act on Distal Tubule
  3. Potassium Sparing Diuretics
    Act on: Collecting Tubule & Collecting Duct
  4. Osmotic Diuretics
    Act on: Proximal Convoluted Tubule & Thin Descending Limb of the loop of Henle
  5. Carbonic Anhydrase Inhibitors
    Act on Proximal Convoluted Tubule
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96
Q

How is sodium reabsorbed in the PCT?

A

On the Basolateral membrane:
- Na+-K+-ATPase (active Na+ reabsorption)
- Renal K+ channels

On the Luminal membrane:
- Na+/H+ exchanger (H+ secretion)
- Na+-coupled co-transporters
(X = glucose, amino acids…)

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97
Q

What is Acetazolamide?

A

Carbonic Anhydrase Inhibitor
Mechanism: Inhibition of carbonic anhydrase in the PCT
Renal effects of acetazolamide:

Moderate decrease in Na+ reabsorption (5%) & mild diuresis

Mild plasma acidosis (due to H+ retention)

Urine alkalosis (due to increased bicarbonate secretion)
Uses:
Little clinical use as a diuretic:
Weak diuretic (~5% Na excretion)
Self-limiting action
Altitude sickness
In glaucoma

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98
Q

What is the therapeutic relevance of urine alkalinisation?

A

Reduces formation of uric acid and cystine stones
Increases excretion of weak acids (e.g. salicylates, barbiturates)
Decreases crystallisation of weak acids in the urine (e.g. anti-bacterial sulphonamides)

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99
Q

What is mannitol?

A

Mechanism of diuretic action:
Freely filtered in the glomerulus
Pharmacologically inert and not reabsorbed
Increases osmolarity of the tubular filtrate
Decreases water reabsorption
Increases sodium excretion (by retaining sodium ions in diluted filtrate – secondary effect)
Act on the parts of the nephron which are freely permeable to water:
Proximal Convoluted Tubule (PCT)
Descending Limb of the loop of Henle
Cerebral oedema (to reduce intracranial pressure)
Glaucoma (to reduce intraocular pressure)
May be used in acute renal failure
Weak diuretics

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100
Q

What is the mechanism of loop diuretics?

A

Inhibition of the luminal
Na+/K+/2Cl- co-transporter

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101
Q

What are the renal effects of loop diuretics?

A

Renal effects:

↓ Na+ reabsorption
↓ Cl- reabsorption

↑ K+ excretion (moderate)

↑ Ca++ & Mg++ secretion (increased excretion)

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102
Q

What are the PK of loop diuretics?

A

Absorbed in the gut
In plasma, strongly bound to albumin
Secreted into the tubular filtrate by OAT in the PCT
Excreted in the urine

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103
Q

What are the uses of loop diuretics?

A

Acute pulmonary oedema
Diuretic resistant oedemas
Resistant hypertension
Patients with impaired kidney function or with CHF
Liver cirrhosis with ascites

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104
Q

What is the mechanism for thiazides?

A

Inhibition of the luminal
Na+/Cl- co-transporter (NCC)

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105
Q

What are the renal effects of thiazides?

A

↓Na+ reabsorption
↓ Cl- reabsorption

↑K+ excretion (moderate)

↑ Ca++ reabsorption (reduced excretion

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106
Q

What are the three uses of?

A
  • Hypertension
  • Mild heart failure
    Severe resistant oedema (thiazide-like + loop diuretics  synergistic effect)
  • Prevention of kidney stone formation in idiopathic hypercalciuria
    (thiazides; by reducing calcium excretion in the DT)
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107
Q

What are the 8 common side effects of loop and thiozide diuretics?

A
  • Gout due to hyperuricaemia
  • Hypotension
  • Loss of hearing (at high doses)
  • Hypersensitivity reactions
  • Blood disorders
  • Hypokalaemia
  • Tachyarrhythmias
  • Hyperglycaemia
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108
Q

What are the three effects of aldosterone?

A
  • Increases activation & surface expression of the luminal renal Na+ channels (ENaC)
  • Increases translocation of renal K+ channels (ROMK) to the luminal membrane
  • Increased synthesis of the basolateral Na+-K+-ATPase
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109
Q

What are the mechanisms of potassium-sparing diuretics?

A
  1. Mineralocorticoid (aldosterone) Receptor Antagonists (MRAs):
    - Spironolactone (pro-drug) (active metabolite Canrenone)
    - Eplerenone
  2. Renal Na+ channel (ENaC) blockers:
    - Amiloride
    - Triamterene
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110
Q

What are the uses of potassium-sparing diuretics?

A
  • To treat hypokalaemia (with thiazides or loop diuretics)
  • Heart failure (MRAs to improve survival)
  • Resistant essential hypertension (e.g. due to low renin)
  • Aldosteronisms (spironolactone & eplerenone):
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111
Q

What is the mechanism of ADH?

A

Increases the expression of Aquaporin-2 on the luminal membrane

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112
Q

What are the renal effects of ADH?

A

Increases water absorption
Controls the rate of urine formation

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113
Q

What is diabetes insipidus?

A

Production of copious amount of diluted urine

114
Q

What is Neurohypophyseal (central) Diabetes Insipidus?

A

Reduced ADH secretion, normal kidney response
Causes: Brain trauma; surgery; genetics
Therapy: Desmopressin (synthetic ADH)

115
Q

What is Nephrogenic Diabetes insipidus?

A

Normal ADH levels, impaired kidney response
Causes: Lithium poisoning; kidney diseases; genetics
Therapy: Thiazides
Paradoxically reduce urine volume by interfering with production of hypotonic fluid in the distal tubule

116
Q

What are the three types of hypertension?

A

Essential (primary) hypertension (no cause)
Secondary hypertension (other factor)
White-coat hypertension

117
Q

What are the three goals for treating htn?

A
  • Reduce TPR (↓ afterload)
  • Reduce SV (↓ blood volume & ↓ preload)
  • Reduce HR
118
Q

What are the 4 types of drugs that work of the RAAS?

A
  • Renin inhibitors: ALISKIREN
  • ACE inhibitors (ACEIs)
  • AT1 receptor blockers (ARBs)
  • Mineralocorticoid Receptor Antagonists (MRAs)
119
Q

What are the 5 side effects of ACEIs?

A
  • hypotension
  • reflex tachycardia and palpitations
  • hyperkalaemia
  • taste disturbances
  • persistant dry cough
120
Q

What are the two common ace inhibitors?

A

Captopril
Enalapril

121
Q

What are the benefits of switching to an ARB?

A

No cough
Reduced risk of angioedema
Improved tolerance

122
Q

What are the common three ARBs?

A

Losartan
Candesartan
Valsartan

123
Q

What must you be aware of when giving and ACEI with a diuretic?

A

If patient takes an NSAID, it may result in dangerously low GFR and acute kidney injury

124
Q

What is the exception in which a patient would need a CCB instead of ACEI or ARB?

A

If the patient doesn’t have T2DM and is either over 55 or is of afro-carribean heritage

125
Q

What other conditions can be aided by the drugs that work on the RAAS?

A
  • Systemic hypertension
  • Ischaemic heart disease and myocardial infarction
  • Heart failure
  • Diabetic nephropathy
  • Progressive renal insufficiency
126
Q

Which two anti-hypertensive drugs act on blood vessels?

A

Direct-acting vasodilators
- CCBs and potassium channel openers
Vasodilators of unknown mechanism of action:
- hydralazine

127
Q

What is the MoA of CCBs?

A

Block the L-type voltage-activated calcium influx in vascular and smooth muscle cells

128
Q

What are the three classes of CCBs?

A

Vascular (anti-htn)
Intermediate (Anti anginal/arrythmic)
Cardiac (anti-arrhthmic)

129
Q

What are the 7 common side effects of vascular CCBs?

A
  • Hypotension
  • Postural hypotension
  • Tachycardia and palpitations
  • Ankle oedema
  • Headache & flushes
  • Myocardial ischaemia
  • Constipation
130
Q

What is the cellular mechanism and the antihypertensive MoA of Potassium Channel Activators?

A

Cellular mechanism:
- Opening of ATP-sensitive potassium channels in the vasculature
- KATP are regulated by the intracellular ATP:ADP ratio
- Higher cytosolic ATP keeps KATP channels closed

Antihypertensive MoA:
- Activation of KATP in vascular smooth muscles
- Membrane hyperpolarisation
- Closure of L-type VACCs
- Vasorelaxation

131
Q

What are the 3 adverse effects of Potassium Channel Activators?

A

Reflex tachycardia
Fluid retention
Diabetes mellitus

132
Q

What is the systemic effects of hydralazine?

A

Dilation of arteries and arterioles, decrease in TPR & cardiac afterload

133
Q

What are the 2 therapeutic uses of hydralazine?

A
  • In severe hypertension in pregnancy (with a beta-blocker and a diuretic)
  • In heart failure in patients of African-Caribbean origin (with nitrates)
134
Q

What are the 3 side effects of hydralazine?

A
  • Lupus syndrome (~5-10% patients)
  • Tachycardia & palpitations
  • Hypotension and peripheral oedema
135
Q

What is the cellular mechanism of b-blockers?

A

Block b1-adrenoceptors in the heart and in the kidney

136
Q

What are the three most popular b-blockers?

A

Atenolo(β1)
Metopralol (β1)
Propranolol (non-selective)

137
Q

What are the theapeutic uses of b-blockers?

A

In resistant hypertension (in addition to first-line drugs & diuretics)
In severe hypertension in pregnancy (only Labetalol)

138
Q

What are the adverse affects of b-blockers?

A
  • Bronchoconstriction (more frequent with non-selective)
  • Reduced awareness of hypoglycaemia
  • Bradycardia
  • Negative inotropic effect in the heart
  • Fatigue
  • Cold extremities
  • Erectile dysfunction
139
Q

What is the mechanism for α1–adrenoceptor antagonists?

A

Inhibition of postsynaptic α1-adrenoceptors on vascular smooth muscle cells

140
Q

What are the antihypertensive systemic effects of α1–adrenoceptor antagonists?

A

Arterial dilatation – reduced TPR and cardiac afterload
Venodilatation – reduced cardiac preload and SV

141
Q

What are the therapeutic uses of α1–adrenoceptor antagonists?

A

In resistant hypertension

142
Q

What are the adverse effects of α1–adrenoceptor antagonists?

A
  • First-dose hypotension; orthostatic hypotension
  • Reflex tachycardia, palpitations
  • Peripheral oedemas
  • Dizziness
  • Fatigue
  • Sexual dysfunction
143
Q

What are the three common central-acting drugs and their therapeutic actions?

A

Moxonidine
- In resistant hypertension (when first-line drugs do not work)

α-methyldopa
- In severe hypertension in pregnancy

Clonidine
- Rarely used as an antihypertensive drug
- Other uses include a treatment of:
- Migraine
- Insomnia
- Opioid detoxification

144
Q

What are the 6 adverse effects of central-acting drugs?

A
  • Rebound hypertension upon withdrawal
  • Dry mouth
  • Sedation & drowsiness
  • Respiratory depression
  • Immune haemolytic reactions
  • Liver toxicity
145
Q

What is the mechanism of ganglion blocking drugs?

A
  • Competitive nicotinic acetylcholine receptor antagonist at the autonomic ganglia (a non-depolarising blocker)
  • Does not cross BBB
  • Acts on both sympathetic and parasympathetic ganglia
  • Now is largely obsolete as an antihypertensive drug
146
Q

What are the 3 adverse effects of ganglion blcoking drugs?

A
  • Reflex tachycardia
  • Postural hypotension
  • Cycloplegia
147
Q

What are the two adrenergic neuron blocking drugs

A

Guanethidine
Mechanism:
Taken up by the NET & the VMAT, depleting vesicles of NA in the adrenergic synapse.

Reserpine
Mechanism: Taken up by the NET & irreversibly inhibits the VMAT, preventing the uptake & accumulation of NA in the adrenergic synapse.

148
Q

What is atherosclerosis?

A
  • A progressive disease of large and medium-sized muscular arteries characterised by inflammation and dysfunction of the lining of the involved blood vessels and the build up of cholesterol, lipids and cellular debris.
  • This results in the formation of a plaque (atheroma), obstruction of blood flow and diminished oxygen supply to target organs.
149
Q

What is the anatomical distribution of atherosclerosis?

A
  • Stenosis of the right internal carotid artery
  • Stenosis of the proximal left anterior descending
    coronary artery
  • Stenosis of the proximal left renal artery
  • Thrombi aspirated from the affected vessel
150
Q

What are the modifiable risk factors for atherosclerosis?

A
  • Hypertension
  • Diabetes mellitus (uncontrolled)
  • Smoking
  • Alcohol excess
  • High-fat diet
  • Lack of exercise
  • Obesity (associated with metabolic syndrome)
151
Q

Which 5 things is dyslipidaemia secondary to?

A

Liver diseases (jaundice)
Nephrotic syndrome
Anorexia nervosa
Hypothyroidism
Drugs:
- Anabolic steroids
- Diuretics
- Immunosuppressants (cyclosporine and tacrolimus)
- Beta-blockers

152
Q

What is the normal level of total cholesterol and triglycerides in blood plasma?

A

Total Cholesterol (TC): <= 5 mmol/L (non-fasting)
Triglycerides (TG): <= 2 mmol/L (on a fasting sample)​

153
Q

What is LDL?

A

Low-Density Lipoprotein (bad cholesterol)

154
Q

What is HDL?

A

High-Density Lipoprotein (good cholesterol)

155
Q

What are Chylomicrons?

A

Mainly dietary triglycerides + esterified cholesterol

156
Q

What are VLDL?

A

Very Low-Density Lipoprotein: Cholesterol esters + newly synthesised triglycerides

157
Q

What is IDL?

A

Intermediate-Density Lipoprotein are remnants of VLDL stripped of TG by Lipoprotein lipase (LPL): Mainly cholesterol

158
Q

What is the TC:HDL-C ratio?

A

TC:HDL-C ratio =< 4 good
TC:HDL-C ratio > 6 bad

159
Q

How is an atheromatous plaque formed?

A

Endothelial cell dysfunction (Initiation):
- Reduced bio-availability of NO
- Upregulation of endothelial adhesion receptors
- Increase endothelial permeability to LDL particles
- Release of chemokines and cytokines

Lipid accumulation and oxidation:
- LDL particles accumulate in sub-endothelial space
- LDL retained by ApoB100 binds to negatively charged extracellular matrix proteoglycans
- LDL oxidised by reactive oxygen species or enzymes (e.g. myeloperoxidase or lipoxygenases) secreted from inflammatory cells

  • Formation of oxidised LDL particles
  • Formation of non-esterified cholesterol crystals

Immune cell accumulation:
- Adhesion and infiltration of monocytes into the arterial wall
- Differentiation of monocytes into macrophages (driven by macrophage colony-stimulating factor, M-CSF)
- Internalisation of oxidised LDL by class B (SR-B or CD36) and class A (SR-A) scavenger receptors on the surface of macrophages
- Formation of foam cells & fatty streaks

  • Increased pro-inflammatory IL-1β
    (via activation of cholesterol crystals - NLRP3 inflammasome and caspase 1 activation in macrophages)

SM cell recruitment:
- Proliferation & migration of SMC into sub-endothelial space
- Increased matrix protein synthesis & deposition
- Formation of a stable fibrous cap

Unstable atheromatous plague:
- Increased cell apoptosis & formation of lipid necrotic core (a plaque)
- Calcification
- Rapture of fibrous cap
- Thrombus formation and activation of coagulation cascade

160
Q

What is the MoA of statins?

A

Competitive and reversible inhibition of
3-Hydroxy-3-Methylglutaryl (HMG)-CoA Reductase
Rate limiting step in formation of cholesterol

161
Q

What are the main lipid-lowering effects of statins?

A

Reduction of circulating LDL
(due to increased LDL surface receptors & LDL particle clearance)
Modest increase in plasma HDL

162
Q

Which two drugs do statins commonly interact with?

A

CYP3A4 inhibitors (increase statin levels)
CYP3A4 inducers (reduce statin levels)

163
Q

What are the clinical uses of statins?

A

Secondary prevention of CHD
Primary prevention of CHD in patients with other risk factors:
- Chronic Kidney Disease
- Diabetes
In familiar hypercholesterolaemia

164
Q

What are the ADRs to statins?

A
  • Asthenia
  • Myalgia
  • Nausea, dizziness, headache
  • Constipation, diarrhoea
  • Flatulence and GI discomfort
  • Thrombocytopenia
165
Q

What is the mechanism of Ezetimibe?

A

Inhibition of Niemann-Pick C1-like 1 (NPC1L1) membrane transport protein in enterocytes in the gut

166
Q

What are the main lipid lowering effects of ezetimibine?

A

Inhibition of cholesterol absorption in the gut
Reduction of LDL

167
Q

What are the clinical uses of ezetimibine?

A

In various hypercholesterolaemias

168
Q

What are the 4 adverse effects of ezetimibine?

A

Diarrhoea
Abdominal pain
Headache
Myalgia

169
Q

What is the mechanism of Fibrates?

A

Fibrates are agonists at Peroxisomal Proliferator Activator Receptor a (PPARa), a nuclear transcription factor
Binds to and activates PPARa
Activated PPARa dimerises with the Retinoid X Receptor (RXR)
The PPARa/RXR heterodimer activates transcription of the lipoprotein lipase (LPL)
Also increased expression of Apo-A1 and Apo-A2 (HDL lipoproteins)

170
Q

What are the main lipid-lowering effects of Fibrates?

A

↑ Plasma HDL (due to Apo A1/A2 expression)
↑ FA uptake & β-oxidation (due to LPA)

↓ Plasma VLDL & TG
↓ Plasma LDL (moderate)

↓ Inflammation (due to decreased expression of proinflammatory cytokines)

171
Q

What are the clinical uses of fibrates?

A

In mixed dyslipidaemia (cholesterol + triglycerides)
In patients with high risk of atherosclerosis and low HDL
In severe treatment-resistant dyslipidaemia (with statins)

172
Q

What are the 4 adverse effects of Fibrates?

A
  • Abdominal distension
  • anorexia
  • diarrhoea
  • nausea
173
Q

What is the mechanism of bile acid-binding resins?

A

Bind bile acids in the gut and reduce reabsorption of cholesterol via enterohepatic circulation

174
Q

What are the 3 clinical uses of bile acid-binding resins?

A
  • In patients with liver diseases
  • In dyslipidaemia non-responsive to diet
  • In pregnancy with caution (not absorbed)
175
Q

What are the 3 adverse effects of bile acid-binding resins?

A

GI disturbances
Constipation
Bleeding (Vitamin K deficiency)

176
Q

What are the lipid-lowering mechanisms of nicotinic acid?

A

Activates the Gi/o coupled Hydroxy-Carboxylic Acid type 2 (HCA2) receptor in adipocytes (known before as an orphan GPR109A).

177
Q

What is the clinical use of Nicotinic acid?

A

Dyslipidaemia

178
Q

What are the ADRs of niacin?

A

Facial & skin flashes
Nausea & vomiting
Severe allergic reaction
Light headedness & syncope
Tachycardia & palpitations

179
Q

What are the 2 lipid-lowering effects of Fish-oil derivatives?

A

Reduction of triglycerides
Reduction in LDL cholesterol

180
Q

What are the clinical uses of Fish-oil derivatives?

A

In hypertriglyceridaemia, types IIb and III, (adjunct to diet and statin)
In hypertriglyceridaemia type IV (adjunct to diet)

181
Q

What is coronary blood flow?

A

Left coronary artery supplies
the left & right heart (~85% of CBF)
Right coronary artery supplies
the SAN & AVN & the right heart
Venous blood returns into:
the RA (~95%) via the coronary sinus & anterior cardiac vein;
the heart chambers directly via thebesian veins
Presence of collateral vessels

182
Q

How is CBF autoregulated metabolically?

A

Release of Cardiac Metabolites
- Adenosine
- Potassium
Hypoxia (decreased pO2)

183
Q

What is the main cause of stable angina?

A

Atheromatous disease of the coronary arteries

184
Q

What is the main symptom of stable angina?

A

Chest pain
- feels tight, dull or heavy – although some people (especially women) may have sharp, stabbing pain;
- spreads to your left arm, neck, jaw or back;
- is triggered by physical exertion or stress;
- stops within a few minutes of resting.

185
Q

What are the 4 other symptoms associated with stable angina?

A
  • breathlessness;
  • nausea
  • pain in your lower chest or belly – similar to indigestion;
  • fatigue
186
Q

What are the two therapeutic strategies for treating stable angina?

A

Reduce oxygen demand
- reduce heart rate
- reduce cardiac preload

Increase O2 supply
- increase coronary blood flow
- increase regional collateral blood flow

187
Q

What are the 2 first line treatments of stable angina?

A
  • b-blocker
  • CCB
188
Q

What are the top three second line treatments for stable angina?

A
  • A beta-blocker + a dihydropyridine CCB
  • long lasting organic nitrate vasodilator
  • Nicorandil
189
Q

What are the two types of organic nitrate vasodilator?

A

short-acting
- GTN

Long acting
- Isosorbide dinitrate

190
Q

What are the common adverse effects of organic nitrate vasodilators?

A

Dizziness
Postural hypotension
Reflex tachycardia (could be controlled with a β-blocker)
Headache (due to cerebral vasodilation)

191
Q

What is the MoA of Nicorandil?

A

A nicotinamide ester with a dual action:
Nitrate-like action (NO group)
An activator of vascular ATP-sensitive potassium channels (higher doses)

192
Q

What are the benefits of Nicorandil

A

Systemic venodilatation (a decrease of cardiac preload)
Arteriodilatation (an increase in CBF and decrease in TPR)
No effect on cardiac contractility (as seen with beta-blockers)

193
Q

What are the adverse reactions of Nicorandil?

A

Dizziness, headache, flushes, tachycardia (at high doses)
Ulcerations (skin, mucosa, eye, GI, anal ulcerations)

194
Q

What is the mechanism of ivabradine?

A

Inhibition of the pacemaker current in the Sinoatrial Node

195
Q

What are the anti anginal effects of ivabradine?

A

Decrease in HR; no negative inotropic or lusitropic effects

196
Q

What is the therapeutic use of Ivabradine?

A

In stable angina in patients with normal sinus rhythm

197
Q

What are the adverse reactions to ivabradine?

A

Bradycardia (risk increased when used with beta-blockers)
AV block
Visual disorders (blurred vision, photopsia)
Dizziness

198
Q

What is the cellular mechanism of Ranozaline?

A

Inhibits the late sodium current that is activated by ischaemia in cardiac myocytes.

199
Q

What are the common side effects of Ranozaline?

A

Asthenia
Constipation
Headache
Vomiting

200
Q

What is Prinzmetal’s angina?

A

Ischaemia and angina symptoms occur at rest due to coronary vasospasm

201
Q

What is the first line treatment of Prinzmetal’s angina?

A

Nitrate vasodilator with a CCB

202
Q

What is unstable angina?

A

Ischaemia due to thrombus formation
Partial artery occlusion: NSTEMI
Complete artery blockade: STEMI

203
Q

What are the three reperfusion therapies offered when presenting with a STEMI?

A

Primary Percutaneous Coronary Intervention (PCI)
- Coronary angioplasty
- Thrombus extraction
- Stenting

Coronary Artery Bypass Grafting (CABG)
Fibrinolysis with antithrombin therapy

204
Q

What are the lifestyle changes recommended as secondary prevention of MI?

A

Mediterranean-type diet
(more bread, fruit, vegetables, fish; less meat; replacement butter & cheese with products based on plant oils)

Regular exercise (20-30 min/day)

Alcohol consumption within the limits

Quit smoking

Weight control

205
Q

What is the drug therapy recommended as secondary prevention of MI?

A
  • ACEi
  • b-blocker
  • dual antiplatelet therapy
  • statin
206
Q

What are the stages of platelet activation and thrombus formation?

A
  • Trigger (von Williebrand Factor)
  • Platelet adhesion
  • Platelet shape change
  • Secretion of granule contents
  • Synthesis and release of Platelet-activating factor (PAF)
  • Aggregation
  • Exposure of acidic phospholipids
207
Q

What is the anti-platelet mechanism of Aspirin?

A

Irreversible COX inhibition by acetylation of serine residues
Aspirin also blocks synthesis of endothelial PGI2 ( anti-thrombotic effects).

208
Q

What is the cellular mechanism of P2Y12 receptor antagonists?

A

Inhibition of P2Y12 receptors on platelets (which control shape change of platelets)

209
Q

What are the two types of P2Y12 receptor antagonists?

A

Irreversible antagonists
- Clopidogrel
- Prasugrel

Direct-acting reversible antagonists
- Ticagrelor
- Cangrelor

210
Q

What are the three types of glycoprotein IIb/IIIa receptor inhibitors?

A

Abciximab - chimeric monoclonal antibody
Eptifibatide - synthetic cyclic heptapeptide
Tirofiban - synthetic non-peptide agent

211
Q

What is the MoA of dipyridamole?

A

Inhibition of platelet aggregation
Vasodilatation

212
Q

What are the common side effects of anti-platelets?

A

GI bleeding (ASPIRIN)
Bronchospasm (ASPIRIN)
Hypersensitivity (ASPIRIN)
Thrombocytopenia (ABCIXIMAB)
GI discomfort, diarrhoea (CLOPIDOGREL)
Rashes (CLOPIDOGREL, PRASUGREL)
Thrombotic Thrombocytopenic Purpura (with thienopyridines)
Neutropenia (with TICLOPIDINE)

213
Q

What are the symptoms of Thrombotic Thrombocytopenic Purpura?

A
  • Thrombotic refers to the formation of a blood clot inside a blood vessel (shown as red & purple dots known as petechiae).
  • Thrombocytopenic refers to a condition in which the number of platelets in the blood is lower than normal.
  • Purpura refers to purple bruises caused by bleeding underneath the skin.
214
Q

What are the two types of TTP?

A

Inherited:
- Mutations in the ADAMTS13 gene or immunodeficiency in the ADAMTS13 enzyme that breaks down the VWF

Acquired (more common):
- Drug-induced (antiplatelet thienopyridines TICLOPIDINE, CLOPIDOGREL, PRASUGREL; chemotherapy; quinine)
- Diseases and conditions (pregnancy; viral infections, HIV; hepatitis, combined contraceptives)

215
Q

What are the clinical uses of dipyridamole?

A

For prevention of atherosclerotic events in
- Ischaemic stroke
- Transient ischaemic attack (TIA) (<24 hours)
(as modified release tablets with aspirin or when aspirin/clopidogrel are contraindicated)

216
Q

What are the adverse effects of dipyridamole?

A

GI (stomach upset, diarrhoea, vomiting);
Dizziness, headache, angina pectoris, skin reactions, myalgia

217
Q

What are the steps in the extrinsic coagulation cascade?

A
  • Tissue factor (TF) released by leukocytes due to EC layer damage
  • TF binds Factor VII → FVII activated by FIIa/FXa
  • The TF:FVIIa complex cleaves & activates Factor X
  • Factor Xa cleaves Prothrombin (II), activating Thrombin (IIa) (requires FVa, PL & Ca++)
  • Thrombin converts Fibrinogen to Fibrin
  • Thrombin activates Factor XIII
  • Factor XIIIa cross-links soluble fibrin into a matrix stabilising the thrombus.
218
Q

What are the LMWH?

A

Enoxaparin
Dalteparin
Tinzaparin

219
Q

What is the antidote to heparin?

A

Protamine sulfate
It is a polycationic, highly positively charged protein derived from salmon sperm protein, with MW~ 4.5 kDa
It binds to negatively charged UFH forming stable inactive ion pairs

220
Q

What is the MoA of Fondaparinux?

A

A synthetic pentasaccharide anticoagulant
Mimics the unique binding sequence of heparin to ATIII
Enhance interactions of ATIII with active site of the Factor Xa

221
Q

What is the MoA of DOACs?

A

Selective direct inhibitors of the Factor Xa
Block conversion of prothrombin to thrombin

222
Q

What is the MoA of Hirudin peptide analogues?

A

Natural HIRUDIN (full length 65 AA) is a mixture of various isoforms
(hence different recombinant forms).
Binds and inhibits only active thrombin (IIa)
LEPIRUDIN is an irreversible thrombin inhibitor
BIVALIRUDIN can be cleaved and the N-terminal decapeptide displaced by fibrinogen (becomes a competitive reversible inhibitor)

223
Q

What is the antidote to Dabigatran?

A

Idarucizumab

224
Q

What are the pros and cons of using Warfarin?

A

Pros:
- Cost effective,
- Has an antidote, Vitamin K

Cons:
- Complex pharmacokinetics & liver metabolism (CYP450 dependent)
- Polymorphism in VKORC1
- Polymorphism in CYP2C9

225
Q

How can plasma levels of Warfarin be increased?

A

ACUTE ALCOHOLISM
(due to reduced liver metabolism)

DRUGS THAT DISPLACE WARFARIN FROM ALBUMIN
(e.g. Aspirin, NSAIDs; Clofibrate)

DISEASES
Liver diseases
Hyperthyroidism

226
Q

How can plasma levels of Warfarin be decreased?

A

DRUGS THAT REDUCE GI ABSORPTION (e.g. colestyramine)
CHRONIC ALCOHOLISM (increases activity of P450 enzymes)
DISEASES (e.g. Hypothyroidism)
DIET Effect of warfarin is decreased with excessive consumption of green plant food, source of phylloquinones (Vitamin K)

227
Q

What are the common adverse effects of anticoagulants?

A

BLEEDING
SUBCUTANEOUS HAEMORRHAGE
IMMUNE THROMBOCYTOPENIA (due to a complex formed between HEPARIN/LMWHs and Platelet Factor 4; uncommon with FONDAPARINUX)
Hyperkalaemia (suppression of aldosterone production in the adrenal gland with prolonged use of LMWHs and UFH)
Osteoporosis (with chronic use of HEPARIN)
Hypersensitivity & anaphylactic reactions (with PROTAMINE)
Teratogenicity (Warfarin)

228
Q

What are the common therapeutic applications of anticoagulants?

A

Treatment of unstable angina and prevention of STEMI
(with aspirin + antiplatelets)
Prophylaxis of stroke (e.g. in patients with non-vulvar AF) and in TIA
Prophylaxis and treatment of deep-vein thrombosis (DVT) & pulmonary embolism (PE)
Thromboprophylaxis (e.g. in heart surgeries and in rheumatic heart disease – WARFARIN; in haemodialysis patients – HEPARINs; after hip/knee replacement surgeries)

229
Q

What are the common side effcts of DOACs?

A

Anaemia
Nausea
Skin reactions
GI discomfort
Hypotension
Headache
Dizziness
Fever
Oedema
Pain in extremities
Wound complications

230
Q

What are the common therapeutic applications of thrombolytic agents?

A

In Acute Myocardial Infarction (main use)
(to dissolve thrombus & prevent further ischaemic damage)
In acute thrombotic stroke (recombinant tPA)
In life-threatening thromboembolisms (streptokinase)

231
Q

What is the MoA of tranexamic acid?

A

A synthetic derivative of amino acid lysine.
A competitive inhibition of plasminogen activation by blocking the lysine binding sites on plasminogen
Also, can block plasmin noncompetitively at high concentrations.

232
Q

What are the therapeutic uses of tranexamic acid?

A

In haemorrhage complications associated with thrombolytic therapy
For prophylaxis and treatment in patients at high risk of pre- and post-operative haemorrhage (e.g. in dentistry, in patients with haemophilia, prostatectomy, and in cervical cancer biopsies)
Heavy menstrual bleeding

233
Q

What are the common adverse effects of tranexamic acid?

A

Nausea, vomiting & diarrhoea (dose-dependent)

234
Q

What are the conduction pathways of the heart?

A

SA NODE EXCITATION - Slow (0.05 m/s)
AV NODE EXCITATION - Slow (0.02-0.05 m/s)
HIS BUNDLE & BRANCHES - Rapid (2-4 m/s)
PURKINJE FIBRES - Rapid (2-4 m/s)
ATRIAL EXCITATION & CONTRACTION - Rapid (1 m/s)
VENTRICULAR EXCITATION & CONTRACTION - Rapid (0.3-1.0 m/s)

235
Q

What are the ion mechanisms of the cardiac AP?

A

0: Rapid Na+ influx via voltage-activated sodium channels, INa
(Activation threshold -65 mV)
1: Transient K+ efflux, iTO1
2: Ca2+ influx via L-type voltage-activated calcium channels, ICa(L)
3: K+ efflux via slow (IKs) & rapid (IKr) delayed rectifier potassium channels, also background IK1
4: K+ efflux via an inwardly rectifying potassium channel, IK1
(resting potential -85 mV)

236
Q

What are the two refractory periods and the mechanism?

A

ABSOLUTE or EFFECTIVE refractory period is when generation of the 2nd AP is not possible even at the strongest consecutive stimulus.
RELATIVE refractory period is
when generation of the 2nd AP is possible, but requires a stronger stimulus.
Mechanism: Rapid inactivation of the fast voltage-activated sodium channels by maintained depolarisation.

237
Q

What are the key features of the ‘funny’ current?

A

Channel type:
- Hyperpolarisation-activated Cyclic Nucleotide-Gated channel (HCN; main cardiac isoform HCN4).

Selectivity:
- Non-selective cation current, permeable to both Na+ and K+,
BUT… at physiological potentials, mainly sodium influx

Activation:
- By membrane repolarisation, &
- Directly by increased intracellular cAMP

Modulation:
- Sympathetic +ve via β1- and β2- adrenoceptors (β2 mainly at the SAN & atria)
- Parasympathetic -ve via muscarinic M2 receptors (Gi/o - coupled)

Role in the normal heart:
- Cardiac automaticity
- Heart rate control by the autonomic NS & by circulating adrenaline
Pharmacology:
- Direct inhibition: Selectively by IVABRADINE (SL22106 L: CHD & Antianginal drugs in week 5)
- Indirect effect: via a decrease in sympathetic (beta-blockers, a Class II antiarrhythmics) or via an increase in parasympathetic (DIGOXIN) inputs; ADENOSINE -ve (via A1 adenosine Gi/o receptors)

238
Q

What are the 4 classifications of Arrhythmia?

A

By the effect on the heart rate:
- Bradycardia
- Tachycardia (Tachyarrhythmia)

By the effect on the heart rhythm:
- Regular
- Irregular

By the site of origin in the heart:
- Supraventricular (SAN, atria & AVN)
- Ventricular (His Bundles, Purkinje fibres and ventricles)

By the type of QRS complex:
- Narrow complex
- Broad complex (> 120 ms in duration on ECG)

239
Q

What are the symptoms of arrhythmias?

A

Palpitations
Shortness of breath and fatigue
Chest pain
Pre-syncope
Syncope
Cardiac arrest

240
Q

What are the causes of bradycardia?

A

Sinus bradycardia (physiological causes):
Increased vagal tone
In trained athletes

Extrinsic (non-cardiac) causes:
Endocrine disorders (hypothyroidism)
An electrolyte imbalance (severe hyperkalaemia, hypo- & hyper- calcaemia)
Drugs: anti-arrhythmic (beta-blockers, CCBs, digoxin); antihypertensive (clonidine)
Hypothermia

Intrinsic (degeneration & diseases of the SAN, the atrium and the AVN):
Sick Sinus Syndrome (ischaemia & infarction of the SAN)
Atrioventricular blockade or heart block (ischaemia; fibrosis, congenital heart defects; infections & inflammations such as myocarditis, diphtheria, rheumatic fever)

241
Q

What is Sick Sinus Syndrome?

A

A group of heart rhythm disorders due to malfunction of the SA node that may present on the ECG as:
Sinus pause
Sinus arrest (pause for > 3 sec)
Bradycardia-Tachycardia syndrome

242
Q

What are the types of AV block?

A

Fist-degree:
a slower AV conduction
(PR interval > 0.2 sec)

Second-degree:
Missed beats to the ventricles

Third-degree (complete block):
No conduction to ventricles (P waves & QRS complexes randomly separated).

243
Q

What is the treatment for AV block?

A

Treatment (in emergencies): Atropine (IV) or isoprenaline (IV)

Long term solution: Implantable TCP in cases of the 2nd & 3rd degree block

244
Q

What are the 4 classes of anti-arrhythmic drugs?

A
  1. Sodium channel blockers
  2. Beta-blockers
  3. Drugs that prolong AP duration
  4. CCBs
245
Q

What is the MoA of sodium channel blockers?

A

Block the fast voltage-activated sodium channels (rapid depolarisation phase 0).
Slow down the upstroke of the cardiac AP, hence slow down AP conduction (Ia & Ic).
Most effective in ventricular myocytes, Purkinje fibres and in the atria.
The block is use-dependent (i.e. it increased with increased HR, thus reducing AP frequency)

246
Q

What are the adverse effects of sodium channel blockers?

A

1a. Atropine-like effects (if given orally)
Myocardial dysfunction (reduces cardiac contractility)
1b. CNS effects: drowsiness, disorientation, convulsions, respiratory depression
1c. Caution: Flecainide can cause sudden cardiac death in patients with MI

247
Q

What is the MoA and the effects of drugs that prolong AP duration and the two most common?

A

Block of voltage-activated potassium channels in repolarisation phase 3 of the action potential.

Effects:
Prolong the duration of the cardiac AP
Prolong the QT interval
Increase refractoriness of the heart

Amiodarone
Sotalol

248
Q

What are the adverse effects of Amiodarone?

A

Arrhythmias
Thyroid abnormalities
Corneal deposits
Pulmonary disorders
Skin pigmentation

249
Q

What is the anti-arrythmic MoA of CCBs?

A

Block L-type voltage-activated calcium channels
Slow down conduction at the AV node

250
Q

What are the adverse reactions of CCBs?

A

Bradycardia
Reduced myocardial contractility (negative inotropic effect)
Constipation (more common with verapamil)
Hypotension

251
Q

What are the unclassified drugs for anti-arrythmia?

A

Atropine
Isoprenaline
Adrenaline
Adenosine
Digoxin
Magnesium sulfate

252
Q

What are the two types of tachyarrythmias?

A

Supraventricular tachycardia (SVT):
- Paroxysmal SVT (PSVT)
- Atrial Fibrillation (AF)
- Atrial Flutter

Ventricular:
- Ventricular Tachycardia (VT)
- Ventricular Fibrillation (VF)

253
Q

What are the causes of tachyarrythmias?

A

Certain disease & conditions:
- Congenital heart defects
- Hyperthyroidism
- Pheochromocytoma (increased circulating catecholamines)

Electrolyte imbalance:
- Hypokalaemia

Drugs:
- Inhalers
- Anti-arrhythmic drugs
- Anti-hypertensive
- Antifungal drugs
- Antibiotics
- Antihistamines

Genetic disorders:
- Channelopathies
- Abnormal conduction pathways (WPW)

254
Q

What are the two main mechanisms that can cause tachyarrythmias?

A

Re-entry (AVNRT & AVRT)
Triggered (EAD & DAD)

255
Q

What is the re-entry mechanism?

A

Atrioventricular nodal re-entrant tachycardia (AVNRT)
Presence of the two conducting pathways in the AVN:
1 - A slow conducting but with a faster recovery (accessory)
2 - A fast conducting with a longer refractory period (normal)

Atrioventricular Reciprocating Tachycardia (AVRT)
Re-entry via congenital accessory pathway(s) between atria and ventricles.

256
Q

What is the difference between macro and micro re-entry?

A

Macro re-entry:
Conduction from the atrium to the ventricle via accessory pathway (unilateral or bilateral)
Rare occurrence

Micro re-entry:
Caused by ischaemic damage of Purkinje fibres in the ventricles
Two pathways with different properties (similar to the slow and fast pathways in the AVNRT) but at micro level
Most common cause of VT

257
Q

What is the triggered mechanism?

A

Early after depolarisation (EAD)
Reactivation of L-VACCs during plateau phase of the cardiac AP
Factors which could promote EAD:
- Slow HR
- Drugs that prolong the QT interval
- Genetics (LQT or Brugada syndromes)

Delayed after depolarisation (DAD)
Build in intracellular Ca++ and activation of electrogenic 3Na+/1Ca++ exchanger leading to membrane depolarisation during diastole
Factors which could promote DAD:
- Fast HR
- Drugs (e.g. Digoxin)
- Genetics (CPVT)

258
Q

What is the difference between AF and Flutter?

A

AF - Fast irregularly irregular heartbeat.
Causes: Random ectopic activity from the pulmonary vein in the left atrium

“Flutter” – Fast regular heartbeat (HR may be within normal range – due to a decremental pulse conduction at the AVN)
Causes: One or more foci of re-entrant excitation in the atria

259
Q

How is AF treated?

A

Rhythm control:
Electrical cardioversion
Pharmacological cardioversion:
- Class Ic: Flecainide
- Class III: Amiodarone

Rate control:
- Class II: Beta-blockers
- Class IV: Diltiazem (Verapamil, a potent negative inotrope, is not recommended)
- Digoxin

260
Q

What are the key stages of Calcium entry & Calcium-Induced Calcium Release (CIRC)?

A
  1. Rapid depolarisation due to fast Na+ influx (Phase 0) via Na+ channels (NaV1.5) (STIMULUS)
  2. Depolarisation dependent activation of L-VACCs (CaV1.2) and influx of extracellular Ca++ (Phase 2) (TRIGGER)
  3. Ca++ induced activation of ryanodine receptors (RyR2) on the SR and Ca++-induced Ca++ release (CICR) (MAIN SOURCE of Ca++cyt )
  4. Ca++ influx via Na+-Ca++ exchanger (NCX) via the reverse mode of the NCX (MINOR ROLE IN NORMAL CONTRACTION)
261
Q

What is the Ryanodine Receptor (RyR)?

A

Three main isoforms:
- RyR1 – skeletal muscles
- RyR2 – cardiac muscles
- RyR3 – brain & other tissues

RyR is a large (~2 MDa) homotetrameric protein complex with a large cytoplasmic N-terminus domain (regulatory function)
RyR is an intracellular calcium release channel on the SR

262
Q

What are the key features of the Ryanodine Receptor (RyR)?

A
  • Contain cytoplasmic Ca++ binding sites: activated by low cytosolic Ca++ (Ca++cyt, 1-10 µM range) and inhibited by high cytosolic Ca++ (1-10 mM);
  • Calstabin-2 (FKBP12.6), endogenous stabiliser that keeps the RyR2 channel closed;
  • Calmodulin (CaM) inhibits opening of RyR2 in Ca++cyt-independent manner
  • Phosphorylation sites for PKA (sympathetic NS) and for CaMKII (enhanced with increased Ca++cyt) – increased opening of RyR2
  • In the SR lumen: Calsequestrin-2, a low affinity, high capacity Ca++ binding protein (binds up to 40-50 Ca++)
263
Q

What causes the RYR to become ‘leaky’?

A

Excess of caffeine
Immunosuppressants
Cardiac glycosides (e.g. Digoxin - mechanism discussed in the last lecture)

264
Q

What are the stages of calcium re-uptake and extrusion?

A
  1. Ca++ reuptake into the SR by a Sarcoplasmic/Endoplasmic Reticulum
    Calcium ATPase (SERCA) (70-80%)
  2. Ca++ extrusion by the Na+-Ca++ exchanger (20-30%)
  3. Ca++ extrusion by the Ca2+ ATPase (Ca-Pump) (~ 1% of Ca2+ removal)
  4. Ca2+ uptake into mitochondria by the mitochondrial Ca2+ uniporter (~ 1% of Ca2+ removal)
265
Q

How is cardiac relaxation regulated?

A

by Phospholamban

Activation by:
- incr. in cytosolic Ca++ directly
- phosphorylated form of phospholamban (PLB)

PLB is phosphorylated by:
- PKA (Protein Kinase A) (main)
- CaMKII (Ca++-Calmodulin-depended Kinase II)

266
Q

What are positive inotropic and lusitotropic effects?

A
  • Catecholamines (via Gαs-coupled β1-adrenoceptors on cardiac myocytes) increase both the force of contraction and the rate of relaxation via PKA-dependent phosphorylation to maintain adequate cardiac output when the heart rate is increased.
  • Increased force of contraction (positive inotropic effect) is enabled by more rapid increase in [Ca++]cyt due to enhanced activity of:
    • L-VACCs (greater calcium influx),
    • RyR2 (more calcium is released from the SR),
    • Increased Ca-sensitivity of the tropomyosin complex via phosphorylation of the regulatory Troponin I
  • Increased rate of relaxation (positive lusitropic effect) via accelerated reuptake of
    cytosolic Ca++ into the SR due enhanced activity:
    • SERCA as a result of increased phosphorylation of phospholamban (PLB) (This enables a stronger force of contraction at increased HR).
267
Q

What is the definition of heart failure?

A

Heart failure is a common complex clinical syndrome of symptoms and signs caused by impairment of the heart’s action as a pump supporting the circulation. It is caused by structural or functional abnormalities of the heart.

The demonstration of objective evidence of these cardiac abnormalities is necessary for the diagnosis of heart failure to be made.

The symptoms most commonly encountered are breathlessness (exertional dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea), fatigue, and oedema.

Signs in heart failure could be due to pulmonary and systemic congestion, or the structural abnormalities either causing or caused by heart failure.

268
Q

What are the pathogenic signs and symptoms of CHF?

A
  • Impaired cardiac contractility & reduced CO
  • Increased sympathetic activity (due to reduced CO & activation of baroreceptors)
  • Activation of the RAAS
  • Fluid and salt retention
  • Breathing difficulties on exertion or at rest or in sleep, cough
  • Abdominal & peripheral oedema
  • Fatigue & exercise intolerance
269
Q

What is the first line therapy for CHF?

A

ACE Inhibitor (or ARB) + beta-Blocker + Diuretic

270
Q

Why are beta-blockers used in treatment of heart failure?

A
  • Inhibition of cardiotoxicity of catecholamines
  • Increase of the density of β-adrenoceptors (increased contractility)
  • Anti-hypertensive, antianginal and anti-arrhythmic effects
  • Antioxidant and anti-proliferative effects (Carvedilol, Nebivolol
271
Q

What are the three kinds of positive inotropic agents used in CHF?

A
  • Catecholamines
  • Phosphodiesterase type-3 inhibitors
  • Cardiac glycosides
272
Q

What are the benefits of phosphodiesterase type-3 inhibitors?

A

Increased CO
Reduction in right atrial pressure (less risk of pulmonary oedema)
Reduced TPR and reduced cardiac preload (due to peripheral arterial and venous dilatation)

273
Q

What are the adverse effects of phosphodiesterase type-3 inhibitors?

A

Lethal arrhythmias with prolonged use of MILRINONE
Hypotension
Headache

274
Q

What is the mainly used cardiac glycoside for CHF?

A

digoxin

275
Q

What is the MoA of cardiac glycosides?

A

Inhibition of the Na+/K+ ATPase (Na-Pump) by binding competitively to an extracellular K+ binding site.

276
Q

What are the therapeutic uses of cardiac glycosides?

A

In worsening or severe HF
In HF patients with atrial fibrillation

277
Q

What are the benefits of cardiac glycosides?

A

Anti-arrhythmic (central action, increases vagal tone (Heart-2))
Positive cardiac inotrope
Mild diuretic effect in CHF patients
Reduces sympathetic activity (indirectly, due to improved CO and fluid loss and, as a result, improved haemodynamic)

278
Q

What are side effects of cardiac glycosides?

A

Cardiac tachyarrhythmias (due to DADs from cardiac calcium overload)
GI (gastric irritations, diarrhoea, nausea, vomiting)
CNS:
Yellow vision (xanthopsia)
Blurred vision
Dizziness
Headache
Bradycardia (central action, increased vagal tone)

279
Q

What can effect the plasma levels and toxicity of digoxin?

A

Hypokalaemia (e.g. caused by diuretics or hyperaldosteronism)
(Increased binding to the Na-Pump: more CV effects)
Hyperkalaemia (e.g. caused by aldosterone antagonists, ACEIs/ARBs) (Increased plasma levels: more CNS & GI effects)
Hyperthyroidism
(If untreated, needs high doses than when treated
Impaired kidney function
(less excretion, increased plasma levels)
Drugs affecting renal excretion
(P-gp substrates or inhibitors (e.g. Amiodarone, Spironolactone, CCBs e.g. Verapamil, Nifedipine)

280
Q

How is digoxin toxicity prevented and treated?

A

Use a lower dose monitoring plasma levels (e.g. with any CCBs)
or withdrawal
Use oral K+ supplements (if hypokalaemia)
Steroid-binding resins, activated charcoal
Digoxin-specific antibody fragments (Digifab, IV)

MPharm2 SL22106 (4 decks)

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