Nervous System and Drugs Flashcards
(139 cards)
1
Q
Describe the branches of the nervous system.
A
Main divisions of the NS:
Somatic nervous system - controls organs under voluntary control (mainly muscles), and
Autonomic nervous system (ANS) - regulates organ function and homeostasis, mostly under involuntary control.
ANS further divided into:
Sympathetic nervous system - response to stress, danger, other alerts; and
Parasympathetic nervous system - background housekeeping functions (digestion…)
2
Q
Describe the reflex arcs of the autonomic nervous system.
A
Afferent autonomic nerves:
Transmit information from the periphery to the CNS (to inform activity of efferent system),
Sensors in many organs, notably the baroreceptors (sense stretch from arteries due to blood pressure) and chemoreceptors (sense oxygen content in blood),
Information is carried to the CNS by major autonomic nerves (vagus, splanchnic, pelvic nerves…).
Efferent autonomic nerves:
Transmit impulses from the CNS to the peripheral organ systems,
Control heart, blood vessels, gut, bladder, eyes, exocrine/endocrine glands,
Responses include smooth muscle contraction/relaxation, glandular secretion…
Afferent and efferent limbs form reflex arc that enable instantaneous adjustments of physiology to respond to changing conditions.
3
Q
What is the anatomy of the Autonomic Nervous System?
A
Parasympathetic NS: parasympathetic preganglionic fibres, parasympathetic postganglionic fibres, preganglionic nerves (from brainstem).
Sympathetic NS: sympathetic preganglionic fibres, sympathetic postganglionic fibres, preganglionic fibres that don’t synapse in sympathetic chains (terminate in separate cervical/abdominal ganglia or travel in greater splanchnic nerve and synapse directly with adrenal medulla chromaffin cells).
4
Q
What is the anatomy of the parasympathetic nervous system?
A
Parasympathetic preganglionic fibres: myelinated, leave the brainstem (midbrain, pons, medulla) and sacral segment of spinal cord (S2-S4), travel long distances to synapse with postsynaptic fibre in ganglia (cluster of synapses) located near/within effector organs.
Preganglionic nerves that arise from brainstem, travel in cranial nerves like oculomotor nerve [CN III] (innervates sphincter muscles of iris and ciliary muscles of eye), facial nerve [CN VII] (innervates lacrimal, nasal, palatine, sublingual/submandibular glands), glossopharyngeal nerve [CN IX] (innervates parotid glands), vagus nerve [CN X] (travels through thoracic/abdominal cavities, innervates heart, lungs, GI tract, kidneys).
The preganglionic fibres synapse with the postganglionic fibres.
Parasympathetic postganglionic fibres: unmyelinated, much shorter than preganglionic fibres, mostly located near/within effector organ.
5
Q
What is the anatomy of the sympathetic nervous system?
A
Sympathetic preganglionic fibres: myelinated, cell bodies in lateral cords of spinal segments T1-L2 (‘thoraco-lumbar outflow’), sympathetic paravertebral ganglioninc chains (run from cervical to sacral region), only travel short distance and synapse in ganglia with postsynaptic fibre.
Sympathetic postganglionic fibres: unmyelinated, much longer than preganglionic fibres, at the same dermatologist level as the preganglionic they synapse with (+/- 1 level), run all the way to the effector organ.
Some preganglionic fibres don’t synapse in sympathetic chains but terminate in separate cervical/abdominal ganglia, or travel in greater splanchnic nerve and synapse directly with adrenal medulla (chromaffin cells).
6
Q
How is the adrenal medulla involved in the sympathetic nervous system?
A
Andrenal glands are located on superior aspect of each kidney; adrenal medulla (centre of gland) chromaffin cells synthesise and store catecholamines (in a similar way to sympathetic postganglionic nerve endings).
Presence of an additional enzyme converts majority of noradrenaline to adrenaline.
This responds to impulses in the sympathetic nervous cholinergic preganglionic fibres by transforming the neural impulses into hormonal secretion into the circulation.
Allows large quantities of of catecholamines to be released in situations involving physical/psychological stress.
7
Q
What are the main endogenous mediators and regulators involved in the regulation of the parasympathetic nervous system?
A
Preganglionic parasympathetic nerves:
Acetylcholine (ACh) is the neurotransmitter,
Nicotinic receptors at the preganglionic synapse are where it acts.
Binding causes postsynaptic Na+ ion channels to open, leading to depolarisation.
Postganglionic parasympathetic nerves:
Acetylcholine (ACh) is the neurotransmitter,
Muscarinic receptors at the effector organs are where it acts.
Binding to M1, M3, M5 leads to G-protein (inositol triphosphate) to activate, creating an excitatory response.
Binding to M2, M4 causes decreased cyclic AMP levels, creating an inhibitory response.
8
Q
What are the main endogenous mediators and regulators involved at the synapses of the preganglionic parasympathetic nervous system?
A
Preganglionic parasympathetic nerves:
Acetylcholine (ACh) is the neurotransmitter,
Nicotinic receptors at the preganglionic synapse are where it acts.
Binding causes postsynaptic Na+ ion channels to open, leading to depolarisation.
9
Q
What are the main endogenous mediators and regulators involved at the synapses of the postganglionic parasympathetic nervous system?
A
Postganglionic parasympathetic nerves:
Acetylcholine (ACh) is the neurotransmitter,
Muscarinic receptors at the effector organs are where it acts.
Binding to M1, M3, M5 leads to G-protein (inositol triphosphate) to activate, creating an excitatory response.
Binding to M2, M4 causes decreased cyclic AMP, creating an inhibitory response.
10
Q
What is acetylcholine?
A
Cholinergic neurotransmitter, synthesised in neurons from acetyl-CoA and cholinergic by choline acetyltransferase (enzyme).
This generates free coenzyme A which is regenerated to acetyl-CoA by pyruvate decarboxylation and the supply of acetate anions.
ACh is stored in vesicles and released into synaptic cleft following electrical stimulation.
Action of ACh is terminated by diffusion from site of action, or metabolism by acetylcholinesterase (AChE) followed by re-uptake of choline and acetate back into presynaptic nerve ending.
11
Q
What are cholinergic receptors?
A
Cholinoreceptors are specific postsynaptoc cell surface receptors that mediate the actions of acetylcholine.
Pharmacologically subdivided into 2 groups:
Nicotinic receptors - ligand-gated ion channel directly coupled to increased permeability of cation channels (Na+, K+) which depolarise post-synaptic membrane when 2 ACh bind, reside at autonomic ganglia (and neuromuscular junction) as well as on the presynaptic membrane to provide negative feedback down regulation of further ACh release.
Muscarinic receptors - G-protein-coupled receptors, coupled to second messenger or ion channel; M1 (neural) and M3 (glandular secretion/smooth muscle contraction) are stimulatory and coupled to phospholipase C which generates IP3 or DAG; M2 (cardiac) inhibits adenylate cyclase enzyme reducing cAMP availability; M2 also coupled to reduction in conductance of Ca2+ channels and activation of K+ channels which is inhibitory on cardiac conduction tissue; also reside on the presynaptic membrane to provide negative feedback down regulation of further ACh release.
12
Q
What are Muscarinic receptors?
A
G-protein-coupled receptors, coupled to second messenger or ion channel; M1 (neural) and M3 (glandular secretion/smooth muscle contraction) are stimulatory and coupled to phospholipase C which generates IP3 or DAG; M2 (cardiac) inhibits adenylate cyclase enzyme reducing cAMP availability; M2 also coupled to reduction in conductance of Ca2+ channels and activation of K+ channels which is inhibitory on cardiac conduction tissue; also reside on the presynaptic membrane to provide negative feedback down regulation of further ACh release.
Acetylcholine, muscarine and carbachol are agonists.
Atropine and Ipratropium are antagonists.
Mainly involved in the parasympathetic nervous system - only exception is sweat glands.
13
Q
What are Nicotinic receptors?
A
Ligand-gated ion channel directly coupled to increased permeability of cation channels (Na+, K+) which depolarise post-synaptic membrane when 2 ACh bind, reside at autonomic ganglia (and neuromuscular junction) as well as on the presynaptic membrane to provide negative feedback down regulation of further ACh release.
Acetylcholine, nicotine and carbachol are agonists.
Hexamethonium and bupropion are antagonists.
Postganglionic receptors for sympathetic and parasympathetic nervous systems.
14
Q
What are common agonists and antagonists at Nicotinic and Muscarinic receptors?
A
Nicotinic agonists: acetylcholine, nicotine, (carbachol)
Nicotinic antagonists: (hexamethonium), (bupropion)
Muscarinic agonists: acetylcholine, muscarine, (carbachol)
Muscarinic agonists: atropine, ipratropine
15
Q
What are the main endogenous mediators and receptors involved in the regulation of the sympathetic nervous system?
A
Preganglionic sympathetic nerves:
Acetylcholine is the neurotransmitter,
Nicotinic receptor at the preganglionic synapse is where it acts,
The adrenal medulla is innervated by preganglionic fibres and therefore adrenaline is released from the gland by stimulation of Nicotinic ACh Receptors.
Binding of ACh to the Nicotinic receptor causes postsynaptic Na+ and K+ ion channels to open, leading to influx and eflux respectively, causing depolarisation.
Postganglionic sympathetic nerves:
Noradrenaline is the chemical transmitter,
Alpha- or beta- adrenoreceptors is where the NA acts (in various tissues - heart, lungs, blood vessels, kidneys, eyes…),
Sweat glands are an exception - postganglionic sympathetic fibres release ACh at Muscarinic cholinergic receptors.
Alpha-1 receptors are liked to IP3 (inositol triphosphate) as a secondary messenger and cause constriction in smooth muscle cells,
Beta receptors are linked to cAMP (cyclic adenosine monophosphate) as a secondary messenger and cause smooth muscle relaxation.
Pre-synaptic alpha-2 adregenergic receptors cause negative feedback down regulation of noradrenaline release.
16
Q
What are the main endogenous mediators and receptors involved at the synapses of the preganglionic sympathetic nerves?
A
Acetylcholine is the neurotransmitter,
Nicotinic receptor at the preganglionic synapse is where it acts,
The adrenal medulla is innervated by preganglionic fibres and therefore adrenaline is released from the gland by stimulation of Nicotinic ACh Receptors.
Binding of ACh to the Nicotinic receptor causes postsynaptic Na+ and K+ ion channels to open, leading to influx and eflux respectively, causing depolarisation.
17
Q
What are the main endogenous mediators and receptors involved at the synapses of the postganglionic sympathetic nerves?
A
Noradrenaline is the chemical transmitter,
Alpha- or beta- adrenoreceptors is where the NA acts (in various tissues - heart, lungs, blood vessels, kidneys, eyes…),
Sweat glands are an exception - postganglionic sympathetic fibres release ACh at Muscarinic cholinergic receptors.
Alpha-1 receptors are liked to IP3 (inositol triphosphate) as a secondary messenger and cause constriction in smooth muscle cells,
Beta receptors are linked to cAMP (cyclic adenosine monophosphate) as a secondary messenger and cause smooth muscle relaxation.
Pre-synaptic alpha-2 adregenergic receptors cause negative feedback down regulation of noradrenaline release.
18
Q
What is noradrenaline?
A
The catecholamine neurotransmitter for most sympathetic postganglionic neurones, formed from precursor molecules including amino acids phenylalanine and tyrosine, and dopamine beta-hydroxylase.
Monoamine oxidase (MAO) is enzyme that degrades NA intracellularly. Catechol-O-methyl transferase (COMT) degrades it in the synaptic cleft.
Adrenaline is formed from NA.
19
Q
What are adrenergic receptors?
A
Adrenoreceptors, specific postsynaptic cell surface receptors that mediate catecholamines (noradrenaline, adrenaline).
Pharmacologically subdivided into two groups (based upon differential effect at peripheral sympathetic sites);
Both alpha and beta increase rate and force of contraction of the heart but adrenaline vasodilator and noradrenaline vasoconstrictor.
They are further divided:
Alpha-1-adrenoreceptors cause vasoconstriction to blood vessels, through IP3 second messenger;
Alpha-2-adrenoreceptors cause negative feedback by NA alone at presynaptic terminal receptors by;
Beta-1-adrenoreceptors increase force and rate of contraction of the heart, through cAMP second messenger, adrenaline and noradrenaline have equal effects on this;
Beta-2-adrenoreceptors cause bronchial smooth muscle relaxation through cAMP second messenger and vasodilate blood vessels, more sensitive to adrenaline than noradrenaline.
20
Q
What drugs act on adrenoreceptors?
A
Alpha-1 agonists: noradrenaline, phenylephrine, adrenaline.
Alpha-1 antagonists: doxazosin.
Alpha-2 agonists: (clonidine).
Alpha-2 antagonists: (yohimbine).
Beta-1 agonist: adrenaline, dobutamine, noradrenaline.
Beta-1 antagonists: atenolol.
Beta-2 agonist: adrenaline, salbutamol.
Beta-2 antagonists: (butoxamine).
21
Q
What drugs act on alpha-1-adrenoreceptors?
A
Alpha-1 agonists: noradrenaline, phenylephrine, adrenaline.
Alpha-1 antagonists: doxazosin.
22
Q
What drugs act on alpha-2-adrenoreceptors?
A
Alpha-2 agonists: (clonidine).
Alpha-2 antagonists: (yohimbine).
23
Q
What drugs act on beta-1-adrenoreceptors?
A
Beta-1 agonist: adrenaline, dobutamine, noradrenaline.
Beta-1 antagonists: atenolol.
24
Q
What drugs act on beta-2-adrenoreceptors?
A
Beta-2 agonist: adrenaline, salbutamol.
Beta-2 antagonists: (butoxamine).
25
What neurotransmitters are used in the autonomic nervous system?
In parasympathetic, the same neurotransmitter acetylcholine is secreted at both pre- and post-ganglionic synapses. Preganglionic it acts on Nicotinic receptors, postganglionic is acts on Muscarinic.
In sympathetic, acetylcholine is secreted pre-ganglionic to activate post-synaptic neurones (or the adrenal medulla) by acting on Nicotinic cholinergic receptors; but post-synaptic neurones secrete noradrenaline which acts on a variety of adrenergic receptor sub-types (alpha-1, alpha-2, beta-1, beta-2), except at the sweat glands where acetylcholine acts on Muscarinic receptors.
26
What does activation of the parasympathetic nervous system do?
The actions of the parasympathetic system can be seen as maintaining the general 'housekeeping' activities of the body, and antagonises the sympathetic nervous system (which prepares the body for instantaneous/energetic protective action when danger threatens).
This involves decreasing heart rate, thereby reducing cardiac output and blood pressure, promoting conservation of energy, promoting the activity of the gastrointestinal tract (increasing glandular secretions, increasing peristalsis and promoting emptying of bowel), promoting emptying of the bladder, constricting the bronchial airways, and constricting the pupils (to protect the retina from excess light).
The activity of the parasympathetic system predominates during periods of sleeping or rest while the sympathetic nervous system predominates during periods of exercise or other kinds of stress.
27
What does activation of the sympathetic nervous system do?
The sympathetic system has evolved in the animal kingdom to enable the body to prepare instantaneously for protective action when danger threatens. Therefore, the actions of the sympathetic system can be seen as preparation for what is sometimes encapsulated in the phrase 'fear, fight or flight'.
This involves increasing the circulation of blood carrying oxygen and nutrients to exercising muscle, releasing energy stores (e g. glucose, free fatty acids) for exercising muscle, diverting blood flow from less important circulations (e.g. skin, splanchnic) to make it available for muscles, dilating bronchi to allow for increased ventilation of the lungs, dilating pupils to allow more light into the eye, constructing the sphincters, and inhibiting the functions of the gastrointestinal system.
Sympathetic activation not only occurs as a physiological response to danger encountered from time-to-time in every day life but also as part of the pathophysiology of many disease presentations such as heart failure and haemorrhage.
The activity of the parasympathetic system predominates during periods of sleeping or rest while the sympathetic nervous system predominates during periods of exercise or other kinds of stress.
28
What are the parasympathetic and sympathetic nervous system’s affect on the heart?
*Cardiac output (CO) = heart rate (HR) x stroke volume (SV)* remember
Parasympathetic:
At Muscarinic (M2) receptors decreases heart rate by acting on the pacemaker cells in the sino-atrial and atrioventricular nodes, and alters the conduction rate of electrical impulses through Purkinje fibres and the atrial/ventricular muscle.
It does this by decreasing cAMP (inhibits adenylate cyclase), decreasing Ca2+ conductance, and increasing K+ conductance. This leads to reduced CO (volume of blood pumped out per minute = HR x SV).
Atropine is an antagonist to this.
Sympathetic:
At Beta-1 receptors, increases heart rate by acting on pacemaker cells in the sine-atrial and atrioventricular nodes, and increases conduction rate of electrical impulses. This effect on heart rate called a positive chronotropic effect.
Also at Beta-1 receptors, increases contractility (force of contraction) of ventricular muscle.
This increases the SV (volume of blood pumped out per beat) and increases CO.
This effect on contractility called a positive inotropic effect.
Adrenaline is an agonist and atenolol is an antagonist to this.
29
What are the parasympathetic and sympathetic nervous system’s affect on the blood vessels?
Blood pressure (BP) = cardiac output (CO) x systemic vascular resistance (SVR)
Parasympathetic postganglionic neurone:
Increased nitric oxide (NO) synthase activity (from L-arginine) by endothelial cells when M3 is bound to by ACh. The increased NO stimulates guanylate cyclase which generates cyclic guanylate monophosphate (cGMP), which causes smooth muscle relaxation and vasodilation, increasing blood flow.
Parasympathetic vasodilation is relevant in some vascular beds - salivary and GI glands (increases production of watery secretions), erectile tissues.
Sympathetic (bigger influence):
Vasoconstriction - Alpha-1 receptor binding by NA causes smooth muscle contraction in most arterial circulations, increasing resistance, thus reducing local blood flow. This increases SVR and BP. Doxazosin is an antagonist to (a1) vasoconstriction.
Vasodilation - Beta-2 receptors lead to smooth muscle relaxation in large arteries and arterioles supplying skeletal muscles. This increases blood flow to muscles.
Venoconstriction - Alpha-1 in smooth muscle contracts veins, mobilising blood from venous reservoir into the circulation. This increases venous return to the heart, important when blood volume is depleted (like haemorrhage).
30
What are the parasympathetic and sympathetic nervous system’s affect on the lungs?
Parasympathetic:
Bronchoconstriction - when M3 is activated, smooth muscle surrounding bronchi and bronchioles contracts, decreasing diameter of bronchi/bronchioles, increasing airflow resistance to reduce ventilation in the alveoli. Ipratropium is an antagonist to this (M3) bronchial muscle contraction.
Glandular secretion - mucus secretion from glands lining bronchioles and upper airways when M3 is activated.
Sympathetic:
Bronchodilation - beta-2 receptors activation causes smooth muscle around bronchi/bronchioles to relax, increasing diameter of bronchi/bronhioles, reducing resistance to airflow, improving ventilation of alveoli. This causes more effective transfer of oxygen into the body and carbon dioxide out, increasing exercise capacity. Salbutamol is an agonist to bronchial muscle relaxation.
31
What are the parasympathetic and sympathetic nervous system’s affect on the GI tract?
Parasympathetic:
Glands (submandibular salivary/parotid salivary/ pharyngeal/oesophageal) - M3 activation (coupled to phospholipase C, upregulating inositol triphosphate) stimulates secretion. Hycosine is an antagonist to watery salivary secretion (M3).
Stomach - M3 activation stimulates motility of the stomach and secretion of gastric acid.
Gallbladder/bile duct - M3 activation stimulates gallbladder contraction.
Bowel wall - M3 activation stimulates smooth muscle to increase peristalsis and stimulates digestive secretions. Atropine, hycosine, and propantheline are antagonists to increased motility from the M3 receptor.
Sphincters - M3 activation relaxes smooth muscle sphincters to permit onward transition of food and bowel contents.
Sympathetic:
Salivary glands - alpha-1 activation stimulates viscous rather than watery secretions.
Bowel wall - alpha-1 and beta-2 activation relaxes smooth muscle of the gut wall to decrease peristalsis.
Sphincters - alpha-1 constricts smooth muscle in sphincters to reduce onward transition of food/bowel contents.
Liver - beta-2 activation stimulates glycogenolysis, mobilising glucose into circulating blood from glycogen stores and stimulates gluconeogenesis, synthesising glucose from its precursors.
32
What are the parasympathetic and sympathetic nervous system’s affect on the bladder and genitalia?
Parasympathetic:
Bladder wall - M3 activation constricts smooth muscle (detrusor) to initiate voiding. Oxybutynin is an antagonist of this.
Sphincters - M3 relaxes smooth muscle in sphincters to allow voiding to occur.
Genitalia - M3 dilates blood vessels supplying clitoris and penis to promote erection.
Sympathetic:
Bladder wall - beta-2 activation relaxes smooth muscle of bladder wall, reducing possibility of voiding.
Sphincters - alpha-1 causes constriction of smooth muscle in sphincters, reducing possibility of voiding. Tamsulosin is an antagonist of this.
Male prostate - alpha-1 constricts male prostate smooth muscle, more difficult to urinate.
Female reproduction - alpha-1 activation causes contraction of myometrium of pregnant uterus during labour, beta-2 causes relaxation of myometrium.
Male reproduction - alpha-1 causes ejaculation.
33
What are the parasympathetic and sympathetic nervous system’s affect on the eyes?
Parasympathetic:
Lacrimal glands - M3 activation causes secretion of tears.
Iris (pupil) - M3 activation causes contraction of the (circular) constrictor pupillary muscle of the iris, causing miosis. Tropicamide is an antagonist to this.
Ciliary muscle - M3 causes contraction of the ciliary muscle which adjusts the curvature of the lens, by relaxing tension on suspension ligaments, altering its refraction as lens becomes more rounded with shorter focal length, accommodating near vision.
Sympathetic:
Iris (pupil) - alpha-1 and beta-2 activation causes relaxation of (circular) constrictor pupillae muscle of iris, causing mydriasis (dilation), more light.
34
What is the sympathetic nervous system’s affect on the kidneys?
Renal blood vessels: alpha-1 activation constricts renal arterioles reducing blood flow and this urine production.
Renin secretion: beta-1 and beta-2 stimulates release of renin (an enzyme) from the juxtaglomerular apparatus, renin catalyses conversion of angiotensinogen into angiotensin I, subsequently converted to angiotensin II, which is a potent vasoconstrictor and stimulates aldosterone release, main Na retaining hormone in the body. This contributes to rise of blood pressure, favouring maintenance of extracellular fluid volume.
35
What is the sympathetic nervous system’s affect on adipose tissue?
Adipocytes: beta-3 activation stimulates lipolysis (increases action of the enzyme lipase), process of breaking down triglyceride stores to release free fatty acids, which are muscle energy source.
36
What are some sympathetic nervous system effects that don’t have a parasympathetic equivalent?
Beta-2 activation causes a muscle tremor.
Alpha-2 activation causes platelets aggregation.
Muscarinic activation causes sweating in the skin.
37
What are some drugs that affect the autonomic nervous system?
Atropine - antagonises M2 receptors in the heart that decrease heart rate (parasympathetic).
Adrenaline - agonist to beta-1 and beta-2 receptors in heart that increase heart rate (sympathetic).
Atenolol - antagonist to beta-1 and beta-2 receptors in heart that increase heart rate (sympathetic).
Doxazosin - antagonises alpha-1 receptors that cause constriction in arteries (sympathetic).
Ipratropium - antagonises M3 receptors that cause bronchial muscle contraction (parasympathetic).
Salbutamol - agonist to beta-2 receptors that cause bronchial muscle relaxation (sympathetic). Also an agonist to relax the pregnant and non-pregnant uterus by the same mechanism.
Atropine, hycoscine, propantheline - antagonists to M3 receptor that causes increased motility in GI tract (parasympathetic).
Oxybutynin - antagonist to M3 receptor that causes detrusor contraction in the bladder (parasympathetic).
Tamsulosin - antagonist to alpha receptor that causes contraction of sphincters in the bladder (sympathetic).
Tropicamide - antagonist to the M3 receptor that constricts the pupil (parasympathetic).
Hyoscine - as well as antagonising GI motility, also antagonises M3 watery salivary secretions (parasympathetic).
38
What are some respiratory functions?
Gas exchange: alveoli
Ventilation of alveoli: breathing (diaphragm innervated by C3-C5); chemoreceptors (carotid sinus, brainstem)
Protection of the airways: humidification of air (nasal passages); prevention of obstruction (larynx, epiglottis); removal of particulates (nose, cilia); protective reflexes (bronchospasm, laryngospasm, cough)
Preventing infection: immune system
Endocrine function: angiotensin-converting enzyme
39
What is the anatomy of the bronchiole, including endogenous receptors and mediators?
Made of ciliated columnar endothelial cells surrounded by smooth muscle, surrounded by blood vessels within the adventitia.
Airway tone is regulated by:
Autonomic nerves via autonomic nerves (Muscarinic cholinergic receptors):
The parasympathetic postganglionic nerve releases ACh which acts on M3 receptors in the smooth muscle, causing contraction.
Local mediators:
Leukotrienes, prostanoids, histamine, nitric oxide. These act on LT-R.
Circulating hormones:
Adrenaline from blood stream acts on beta-2 receptors (sympathetic).
Physical features:
Temperature, particulates.
40
What are the main diseases affecting the respiratory system?
Asthma (10%) - bronchial hyper-reactivity, allergy, bronchoconstriction;
Chronic obstructive pulmonary disease (5%) - airways inflammation, bronchoconstriction, mucous secretion, alveolar destruction, emphysema;
Interstitial lung disease - Inflammation and fibrosis lung parenchyma;
Infections - bacterial pneumonia, bronchiectasis (cystic fibrosis), viral pneumonitis, aspergillosis;
Other diseases - lung cancer, pleural fibrosis, pulmonary embolism, pulmonary hypertension.
41
Which drugs act as bronchodilators and what do they do?
Bronchodilators decrease smooth muscle tone, increase airway diameter, decrease resistance to air flow. Indicated for asthma, COPD.
4 types:
Beta-2 agonist:
SABAs (short acting) - terbutaine, salbutamol
LABAs (long acting) - formoterol, salmeterol
Antimuscarinics:
SAMAs - ipatropium bromide
LAMAs - aclidinium bromide, tiotropium
Phosphodiesterase inhibitors:
Methylxanthines - theophylline, aminophylline
PDE4 inhibitors - roflumilast
Others - Magnesium sulfate, montelukast
42
How and why are drugs delivered by inhalation?
Rationale: drug delivered directly to its site of action so limited collateral effects on other tissues
Inhaler devices:
Metered-dose inhaler (MDI) - inhaler technique is critical for success, spacer devices useful;
Dry powder inhaler (DPI)
Nebuliser devices: Aerosolised solution, driven by air or oxygen.
43
What are beta-2 agonists?
Examples
Short-acting: salbutamol, terbutaline;
Long-acting: salmeterol, formoterol
Mechanism of action: Agonists at beta-2 adrenoceptors → activates adenylate cyclase, which increases cAMP generation → decreasing smooth muscle contraction.
Indications: Asthma/COPD, hyperkalaemia, premature labour (tocolytic)
Administration:
Salbutamol 100-200 micrograms INH as required
Salbutamol 2.5-5 mg NEB as required
Adverse effects: tremor, palpitations, arrhythmias, hypokalaemia, hyperglycaemia
44
What are antimuscarinics?
Examples
Short-acting: ipratropium bromide
Long-acting: tiotropium, aclidinium bromide
Mechanism of action: muscarinic M3 receptor (PNS) antagonists → decreased PLC (phospholipase C) → decrease IP3 (inositol triphosphate) → decrease Ca2+, this decreases smooth muscle contraction and decreases glandular secretion.
Indications: COPD/(asthma)
Administration:
Ipratropium bromide 20-40 micrograms INH 3-4 times daily,
Ipratropium bromide 250-500 micrograms NEB 3-4 times daily,
Tiotropium 5 micrograms INH once daily
Adverse effects: dry mouth, blurred vision, tachycardia, constipation, urinary retention, glaucoma.
45
What are phosphodiesterase inhibitors?
Examples
Methylxanthines: theophylline, aminophylline, (caffeine)
Phosphodiesterase type-4 inhibitor: roflumilast
Mechanism of action: increased cAMP generation → decreased smooth muscle contraction; adenosine receptor antagonism, anti-inflammatory (PDE4).
Indications: chronic asthma/chronic obstructive pulmonary disease
Administration: Theophylline m/r 200-400 mg PO twice daily
Adverse effects: tachycardia, palpitations, cardiac arrhythmia, tremor, hypokalaemia, nausea, anxiety, headache, insomnia.
46
What is magnesium?
Example: magnesium sulfate
Mechanism of action: inhibits the action of calcium ions leading to relaxation
Indications:
Severe acute asthma,
Treatment and prevention of seizures in pre-eclampsia,
Hypomagnesaemia
Administration: intravenous (IV)
Adverse effects:
Vascular smooth muscle relaxation: hypotension, flushing;
Electrolyte disturbances: hypocalcaemia, hyporeflexia, weakness, drowsiness.
47
What are leukotriene receptor antagonists?
Examples: montelukast
Mechanism of action: inhibition of leukotriene receptors, anti-inflammatory, bronchodilatation
Indications: prophylaxis of asthma, seasonal allergic rhinitis
Administration: montelukast 10 mg PO daily
Adverse effects: neuropsychiatric reactions (rare)
48
Which drugs are used to reduce bronchial inflammation?
Corticosteroids.
Diseases that involve regular inhaled corticosteroid therapy include chronic asthma and COPD.
Pathophysiology: airways inflammation → bronchoconstriction; excessive mucous secretion
Inhaled corticosteroids (e.g. beclometasone, budesonide):
Administered daily to reduce inflammation and disease activity ('preventer' therapy),
Inhalation enables high concentrations to be delivered to bronchial mucosa but avoid the systemic effects off corticosteroids,
Low dose and high dose therapy
Systemic corticosteroids for acute exacerbations: prednisolone PO, hydrocortisone IV
49
What are corticosteroids (used for respiratory)?
Examples
Inhaled: beclometasone, fluticasone
Oral: hydrocortisone, prednisolone
IV/IM: hydrocortisone, methylprednisolone, dexamethasone
Topical: hydrocortisone, betamethasone
Mechanism of action: bind to intracellular receptors to alter translation of DNA, macrophages and T cells are key cell targets in inflammation
Indications; inflammatory diseases such as asthma, COPD exacerbations, RA, SLE, inflammatory bowel disease and many more; allergic emergencies, adrenal insufficiency
Administration: beclometasone 200-400 micrograms INH twice daily, prednisolone 5-40 mg PO
Adverse effects: oral candidiasis, dysphonia, pneumonia, growth suppression, taste alteration, cataract, (skin changes, osteoporosis, myopathy, weight gain, diabetes, hypertension, decreased healing, infection, fluid retention, dyspepsia, psychosis)
Monitoring and follow-up important whenever prescribed long-term, use at lowest dose for shortest period of time.
50
Summarise respiratory therapeutics.
Chronic asthma:
Beta-2 agonists (SABA), corticosteroids (inhaled), beta-2 agonists (LABA), leukotriene antagonist, methylxanthine, sodium cromoglicate, corticosteroid (oral)
Acute asthma:
Oxygen, beta-2 agonist, antimuscarinic (SAMA), corticosteroid (oral), menthylxanthine, magnesium
COPD:
Beta-2 agonists (SABA), antimuscarinic (SAMA), beta-2 agonist (LABA), antimuscarinic (LAMA), corticosteroid (inhaled), PD4 inhibitor, methylxanthine, corticosteroid (oral), oxygen
Acute exacerbation COPD:
Oxygen, antibiotics, beta-2 agonist (SABA), antimuscarinic (SAMA), corticosteroid (oral)
Acute anaphylaxis:
Oxygen, adrenaline, histamine-1 antagonist, corticosteroid (IV), beta-2 agonist (SABA)
Pulmonary thromboembolism:
Anticoagulants (heparin, warfarin, apixaban)
Cyclic fibrosis:
Mucolytics (dornase alpha), antibiotics (penicillins, cephalosporins, macrolides), CFTR potentiator (ivacaftor)
51
What adverse effects on the lungs can drugs have?
Bronchoconstriction: imbalance between factors affecting contraction and relaxation of vascular smooth muscle
Pneumonitis and fibrosis: drugs that cause an inflammatory reaction in the lung that may progress to scarring
Respiratory suppression: inhibition of the respiratory centre in the central nervous system, paralysis of the respiratory muscles
Other effects: laryngeal myopathy, mucosal congestion
52
What drugs cause bronchoconstriction?
Bronchoconstriction due to an imbalance between factors affecting contraction and relaxation of vascular smooth muscle. Caused by:
Beta-blockers:
Non-selective (e.g. propranolol),
Beta-1 selective (e.g. atenolol, bisoprolol)
Non-steroidal anti-inflammatory drugs (NSAIDs):
Aspirin,
Others (e.g, ibuprofen, diclofenac)
Cholinesterase inhibitors:
Neostigmine,
Organophosphates
Beta-2 agonists (paradoxical bronchospasm):
Salbutamol
53
What drugs are directly toxic to the lung?
Antibiotics - nitrofurantoin
Anti-rheumatic drugs - methotrexate, sulfasalazine
Biological agents - adalimumab, etanercept
Cancer chemotherapy - bleomycin, busulphan, carmustine, cyclophosphamide
Cardiovascular drugs - amiodarone
Ergot derivatives - methysergide, bromocriptine, cabergoline
Susceptibility factors: age, sex, genetics, dose, pre-existing disease, oxygen
54
What drugs suppress respiration?
Opioid analgesics - codeine, tramadol, morphine, oxycodone, fentanyl
Hypnotic drugs - Benzodiazepines (e.g. diazepam), Z-drugs (e.g. zopiclone), Barbiturates
Ethanol
Oxygen
Drugs that cause paralysis - non-depolarising neuromuscular blockers (e.g. atracurium), depolarising neuromuscular blockers (e.g. succinylcholine)
55
What is the function of different aspects of the cardiovascular system?
Pulmonary circulation: low pressure, right heart
Heart: ‘pump’ depends on venous return, right ventricle to pulmonary artery, left ventricle to aorta
Veins: return blood to heart, thoracic pump, muscle pump, valves, reservoir function, low pressure
Arteries: elastic properties, conduit vessels, high pressure
Arterioles: major source of systemic circulation, vascular resistance, regulateblood flow
Capillaries: nutrient/gas exchange, equilibrate with EC fluids
56
How is capillary fluid equilibrium maintained?
Oncotic pressure is 25 mmHg (created by draw due to high concentration of albumin/other proteins in plasma).
Hydrostatic pressure in the arterioles is 35 mmHg so filtration occurs as O2 and nutrients flow out to lower pressure.
Hydrostatic pressure in the venules is 15 mmHg so oncotic larger so CO2 and waste products are reabsorbed.
In the interstitial fluid, both hydrostatic and oncotic pressures are 1 mmHg.
57
Why does oedema occur?
Decrease in plasma oncotic pressure: malnutrition, liver disease, nephrosis
Increased interstitial oncotic pressure: inflammation
Increased venular hydrostatic pressure: deep vein thrombosis
Increased arteriolar hydrostatic pressure: vasodilator drugs
58
How is blood pressure regulated?
Afferent information from: the arterial baroreceptors.
Efferent signals from: the autonomic nervous system (sympathetic and parasympathetic); circulating hormones (renin-angiotensin system {angiotensin II}, adrenaline, vasopressin); and local factors (nitric oxide, endothelin, kinins, prostglandins, renin-angiotensin).
Effector organs: heart, arterioles.
Response time: seconds-minutes.
59
How is blood volume regulated?
Afferent information from: the volume stretch receptors, and juxtaglomerular cells.
Efferent signals from: the autonomic nervous system (sympathetic only); circulating hormones (renin-angiotensin system {aldosterone}, natriuretic peptides, vasopressin).
Effector organs: kidneys.
Response time: minutes-hours.
60
What is blood pressure controlled by?
ABP = CO x SVR
Arterial BP = cardia output (stroke volume x heart rate) x systemic vascular distance (mainly provided by arterioles; R=Ln/(πr^4); so radius has biggest effect)
So ABP dependant on HR, contractility, arteriolar tone.
61
What controls the heart?
Heart rate:
Increased by noradrenaline (NA), adrenaline (A), beta-1 adrenoreceptors.
Decreased by acetylcholine, muscarinic receptors.
Myocardial contractility:
Increased by noradrenaline (NA), adrenaline (A), beta-1 adrenoreceptors.
62
What controls the blood vessel tone?
Sympathetic NS releases noradrenaline (NA) which binds to alpha-1 adrenoreceptors to vasoconstrict.
Circulating factors - adrenaline (A) released from medulla causes vasodilation by acting on beta-2 adrenoreceptors. Other circulating factors include angiotensin II (from activated RAAS), vasopressin (from posterior pituitary gland due to reduced plasma volume/increased osmolality).
Local factors are endothelin (vasoconstrictor), and NO (vasodilator).
63
What is the baroreceptor reflex?
Critical in regulating second-to-second BP and protecting cerebral perfusion.
Afferent information from arterial baroreceptors:
Carotid sinus - glossopharyngeal nerve (CN IX),
Aortic arch - vagus nerve (CN X).
Central nervous system: ‘Vasomotor Centre’.
Efferent signals:
*Sympathetic nerves (NA):
Heart - tachycardia (beta-1), increased contractility (beta-1);
Blood vessels - arteriolar constriction (alpha-1), venoconstriction (alpha-1);
Adrenal medulla - secretion of catecholamines (A, NA);
Kidney - arteriolar constriction (alpha-1), renin-secretion (beta-1).
*Parasympathetic nerves (ACh):
Heart - bradycardia (muscarinic).
Phenylepharine is an alpha-1 vasoconstrictor.
Glyceryl trinitrate is a vasodilator.
Tilt table test activates baroreflex. Causes increased HR to increase BP when quickly go from lying down to upright.
In elderly, less sensitive baroreflex so harder to respond to increase BP by increasing heart rate.
64
What is blood volume and how is it maintained?
In 70kg man:
Blood (intravascular) = 4L
- heart/arteries/arterioles/capillaries (equilibrium with extracellular fluid) /veins (50-60% blood volume).
Extracellular (interstitial) fluid = 12L
Intracellular fluid = 32L
Blood volume dependant on overall hydration of the body, regulated by the kidney:
Renal blood flow ~1.25 L/min (25% of CO), from which,
Glomerular filtration rate (GFR) ~125 mL/min (180 L/day), from which,
Urine output ~1 mL/min (1.5L/day).
65
How is blood volume regulated?
Blood volume required to maintain venous return to heart to enable to to produce adequate CO.
Volume sensors are in the kidneys (juxtaglomerular cells sense low Na+ delivery and urine flow) and the heart (low pressure stretch receptors in the aorta).
Efferent signals:
Renin-angiotensin system releases Ang II
- efferent arteriolar and vaso -constriction (angiotensin II acts on AT1 receptors) locally and systemically,
- aldosterone release from adrenal cortex (AT1) which conserves Na in exchange for loss of H+/K+ (Ang II stimulates),
- vasopressin released from posterior pituitary gland (due to Ang II stimulation) which conserves water, vasoconstricts, and makes thirsty.
Sympathetic nerves:
- NA at beta-1 adrenoreceptors in heart causes tachycardia and increase contractility,
- NA at alpha-1 in blood vessels increases SVR by causing arteriolar constriction and venoconstriction,
- arteriolar constriction in kidneys (alpha-1) to decrease renal blood flow and glomerular capillary pressure to reduce glomerular filtration/urine production, and renin is secreted at juxtaglomerular cells (beta-1) to activate RAAS and release vasoconstriction Ang II.
Circulating factors:
- vasopressin, atrial and brain natiuretic peptides increase Na and water retention.
66
What is the renin-angiotensin system?
Defence of renal blood flow and extracellular fluid volume. Controls blood pressure over minutes-hours.
Hypotension and decreased NaCl cause renin release from juxtaglomerular cells.
Renin acts on angiotensinogen to make angiotensin I (Ang I).
Angiotensin converting enzyme acts on Ang I to make angiotensin II (Ang II).
Ang II causes:
Arteriolar vasoconstriction - preserves ABP and glomerular perfusion,
Aldosterone release (from adrenal cortex) - stimulates Na (and water) retention,
Vasopressin secretion - stimulates water retention,
And Thirst.
67
What are the physiological responses to acute haemorrhage?
Immediate consequences (due to injury, surgery, GI bleed, obstetric bleed…) is decrease in:
Intravascular volume, venous return, ventricular filling, CO, BP, renal perfusion, capillary hydrostatic pressure.
This activates Afferent sensors:
Carotid baroreceptors, aortic arch baroreceptors, atrial volume stretch receptors, juxtaglomerular sensors.
This leads to immediate Efferent signals:
Beta-1 adrenoreceptors - tachycardia, increased contractility;
Alpha-1 adrenoreceptors (NA) - vasoconstriction, venoconstriction;
Other affects - catecholamine secretion (A from adrenal medulla), sweating.
…and later Efferent signals:
Renin released due to sympathetic activation (Beta-1 adrenergicreceptors at juxtaglomerular cells) and sensed decreased Na and water delivery to the distal convoluted tubule,
This promotes AngII activation, causing AngII-mediated vasoconstriction, aldosterone release, vasopressin release (AT1 receptors),
Also reduced arteriolar (and venular) pressure reduces hydrostatic pressure in capillary beds and favours reabsorption into intravascular from interstitial.
68
What is hypovolaemic shock?
Depleted blood volume due to haemorrhage but body’s response to loss of blood volume isn’t enough.
As well as tachycardia, pale skin, cold peripheries, sweating, continued blood loss leads to:
Arterial hypotension - increased CO and TPR can’t offset intravascular volume loss,
Renal perfusion compromised - due to hypotension, causes reduction/caseation of urine output,
Cerebral perfusion compromised - can’t be maintained even with auto-regulatory mechanism so confusion, syncope.
Treatment: IV fluid, blood transfusion.
Rapid is crucial.
69
What does cardiac damage cause?
Cardiovascular risk factors and damage (atherosclerosis…) cause decreased cardiac performance,
This leads to:
Sympathetic NS activation which increased BP (afterload), [beta-blockers]
RAAS activation which leads to increased volume (preload), [ACE inhibitors]
These cause increased cardiac work which further decreases cardiac performance so cycle continues and worsens.
Maladaptive regulatory responses - increases in sympathetic NS and renin-angiotensin system activity which can exacerbate impaired cardiac function,
Endothelial dysfunction - impairs vascular function,
Volume overload - notably in heart failure,
Hypertension,
Cardiac ischaemia,
Changes in the structure of blood vessels - increased resistance since ‘stiffer’,
High levels of circulating lipids (cholesterol),
Platelet activation - stickiness,
Thrombosis - clot formation.
70
What are drug solutions to cardiovascular disease?
Diuretics (e.g. furosemide) - reduce sodium and water overload,
Beta-blockers (e.g. atenolol) - reduce the effects of sympathetic nervous system activation, especially the work and oxygen demands of the heart,
Alpha-blockers (e.g. doxazosin) - reduce sympathetic vasoconstriction in arterioles,
Calcium channel blockers (e.g. amlodipine) - relax arteriolar smooth muscle,
Angiotensin-converting enzyme inhibitors (e.g. ramipril) - reduce the effects of renin-angiotensin system activation,
Nitrates (e.g. glyceryl trinitrate) - relax veins and arteries to reduce the work of the heart,
Lipid-lowering drugs (e.g. statins) - reduce cholesterol levels in the circulation,
Anti-platelet drugs (e.g. aspirin) - reduce platelet adherence to the vascular wall,
Anticoagulants (e.g. warfarin) - reduce the tendency towards blood clot formation in diseased vessels.
71
What is the renin-angiotensin system?
The renin-angiotensin system is the primary defence of renal glomerular filtration rate and is activated in circumstances where this is threatened (e.g. hypovolaemia, hypotension), acting to preserve extracellular fluid volume and blood pressure.
The jutaglomerular cells of the macula densa are sensitive to the concentration of sodium chloride in tubular fluid, the pressure in the afferent artery and efferent signals from the sympathetic nervous system (beta-1).
A decrease in sodium chloride concentration stimulates the release of the enzyme renin, which cleaves off the decapeptide angiotensin I from circulating angiotensinogen.
Angiotensin I is converted to the octapeptide angiotensin II by the actions of the angiotensin-converting enzyme (ACE).
Angiotensin II acts locally to constrict the efferent arteriole, which increases glomerular capillary pressure, favouring increased glomerular filtration.
Angiotensin II acts systemically to cause vasoconstriction in arteriolar resistance vessels (increasing systemic vascular resistance and blood pressure), stimulate the release of the water conserving hormone vasopressin at the posterior pituitary gland, and stimulate the release of the sodium-conserving hormone aldosterone from the adrenal cortex.
72
What is the management plan for hypertension?
Step 1:
If T2DM or < 55 (and not of Black African/African-Caribbean family origin) then ACEi/ARB.
If > 55 (or any age Black African/African-Caribbean family origin) then CCB.
Step 2:
If on ACEi/ARB then add CCB or thiazides-like diuretic.
If on CCB then add ACEi/ARB or thiazides-like diuretic.
Step 3:
ACEi/ARB + CCB + thiazides-like diuretic.
Step 4:
Confirm resistant hypertension - confirm elevated BP with ABPM or HBPM, check for postural hypotension and discuss adherence.
Consider seeking expert advice or adding a -
Low-dose spironolactone if blood potassium level is ≤4.5 mmol/l,
Alpha-blocker or beta-blocker if blood potassium level is >4.5 mmol/I.
Seek expert advice if BP is uncontrolled on optimal tolerated doses of 4 drugs.
73
What are angiotensin-converting enzyme inhibitors?
ACEi examples: ramipril, lisinopril, perindopril, enalapril.
Main actions:
Inhibit angiotensin-converting enzyme (kininase II),
Decrease angiotensin II, vasopressin, and aldosterone,
Decreases blood pressure, Na+ retention, and K+ excretion.
Indications: hypertension, chronic heart failure.
Dose: Ramipril 2.5-10 mg PO daily, Lisinopril 2.5-40 mg PO daily.
Drug interactions: Loop diuretics, other antihypertensive drugs, Potassium-sparing diuretics, Potassium supplements, NSAIDs.
Adverse effects: hypotension, hyperkalaemia, renal impairment; cough (15%), angioedema (0.1%).
Contra-indication in pregnancy.
74
What are angiotensin receptor antagonists (blockers)?
ARB examples: losartan, candesartan, valsartan, irbesartan.
Inhibit angiotensin AT1 receptors,
Decrease vasoconstriction, vasopressin, and aldosterone,
Decreases blood pressure, Na+ retention, and K+ excretion.
Indications: hypertension, chronic heart failure.
Dose: Losartan 25-100 mg PO daily, Candesartan 2-32 mg PO daily.
Drug interactions: Loop diuretics, other antihypertensive drugs, Potassium-sparing diuretics, Potassium supplements, NSAIDs.
Adverse effects: hypotension, hyperkalaemia, renal impairment; angioedema (rarely).
Contra-indication in pregnancy.
75
What are Calcium Channel Blockers?
CCB Examples:
amlodipine, nifedipine (dihydropyridines);
verapamil, diltiazem (centrally-acting).
Mechanism of action:
Decreases Ca2+ entry via L-type channels → decreased Ca2+ availability.
In arterioles decreased smooth muscle tone → vasodilatation → decreased SVR → decreased BP.
In cardiac conduction system decreased rate of phase 0 depolarisation → decreased HR.
In myocardium decreased ventricular contractility (-ve inotropy).
Indications: hypertension, angina, supraventricular tachyarrhythmias.
Administration: amlodipine 5-10 mg PO once daily.
Adverse effects:
Peripheral - flushing, headache, hypotension, oedema, constipation,
Cardiac - heart block, decreased ventricular contractility (beta-blocker interaction).
76
What are diuretic drugs?
Decrease tubular reabsorption of Na+ and Cl-, causing decreased tubular reabsorption of water, causing increased urine volume.
Clinically indicated in heart failure, renal failure, liver failure, hypertension.
Types:
Loop diuretics - furosemide, bumetanide.
Thiazide diuretics - Thiazides - hydrochlorothiazide, bendroflumethiazide.
Thiazide diuretics - Thiazide-likes - chlortalidone, indapamide.
Potassium-sparing diuretics - Aldosterone antagonists - eplerenone, spironolactone.
Potassium-sparing diuretics - sodium channel inhibitors - triamterene, amiloride.
Osmotic diuretics - mannitol.
Carbonic anhydrase inhibitors - acetazolamide, brinzolamide.
77
What are thiazide diuretics?
Examples
Thiazides: bendroflumethiazide, hydrochlorothiazide;
Thiazide-like: indapamide, chlortalidone.
Main actions:
Inhibit Na+/CI- co-transport in the distal convoluted tubule,
Maximum natriuresis of 5-10% of filtered Na+,
Vasodilation.
Indications: Hypertension (and heart failure).
Dose: bendroflumethiazide 2.5-5 mg PO daily.
Adverse effects: hypokalaemia, hyponatraemia, hypomagnesaemia, alkalosis; hyperuricaemia, hyperglycaemia; fluid depletion, incontinence, erectile dysfunction.
78
What are potassium-sparing diuretics?
Examples
Aldosterone receptor antagonists: spironolactone, eplerenone,
Sodium channel blockers: amiloride, triamterene.
Main actions:
Aldosterone binding to its receptor stimulates the formation of the Na+/K+ exchanger in the basolateral membrane of the distal convoluted tubule,
Amiloride blocks the sodium channel in the luminal membrane.
Indications: Chronic heart failure, liver failure with ascites, primary hyperaldosteronism (Conn's syndrome), resistant hypertension.
Dose: spironolactone 25-200 mg or amiloride 5-10 mg PO daily.
Adverse effects: hyperkalaemia, spironolactone oestrogenic effects (gynaecomastia).
79
What are beta-blockers?
Examples: atenolol, metoprolol, bisoprolol (relatively B1-selective).
Mechanism of action:
Decreased sympathetic (B1) activation → decreased cAMP → decreased Ca2+ availability,
Decreased ventricular response rate (-ve chronotropy),
Decreased excitability of conduction system (-ve dromotropy),
Decreased ventricular contractility (-ve inotropy).
Indications: hypertension, atrial fibrillation; angina, heart failure.
Administration: atenolol 25-100 mg PO daily, bisoprolol 2.5-10 mg PO daily.
Adverse effects: lethargy, decreased peripheral perfusion, heart block, bronchospasm.
80
How do blood vessels change with age?
<20: healthy blood vessels, fully functioning endothelium that produces nitric oxide, not vulnerable to plat adhesion/clot formation (except when injured).
>20: prolonged exposure to circulating cholesterol-rich lipids like LDL and development of abnormal endothelium (related to hypertension…) means lipid deposits start to form in sub-endothelium.
This causes further damage to endothelial function, and start to cause local inflammation - atherosclerosis.
>40: atheroma formation progresses, leaving arterial vessels vulnerable to clot formation and occlusion. If this happens, they cause ischaemia, dysfunction, and death of tissue downstream.
81
How are atherosclerotic plaques formed?
Chronic inflammatory disease of the arteries, initiated by low-density lipoprotein (LDL) accumulation in the subendothelial space;
Favoured by oxidative modification of LDL and uptake into the subendothelial macrophages by scavenger receptors (since they aren’t down-regulated by cellular cholesterol content) to create foam cells,
This is more likely if the endothelium is dysfunctional and not producing healthy amounts of nitric oxide (NO),
Endothelial dysfunction is more likely if the blood vessels are inflamed by hypertension, hyperlipidaemia, diabetes, chronic systemic inflammation and smoking.
Early signs are fatty streaks, but atherosclerosis is progressive throughout life;
Growing atherosclerotic plaques become more fibrous, calcified and potentially necrotic;
Many are stable (with fibrous cap) but some are vulnerable to cap rupture (cap weakened by uncontrolled proteolytic enzyme activity) exposing a thrombogenic surface on the intima that promotes thrombus formation and vessel occlusion.
82
What is nitric oxide (NO)?
Produced from L-arginine by the enzyme NO synthase.
NO has important antiplatelet, anti-inflammatory and vasodilatory effects.
83
What is the difference between a STEMI and NSTEMI?
Once atherosclerotic plaque ruptures, highly thrombogenic surface is exposed, promoting platelet aggregation and clot formation. This produced an occlusion if the body’s endogenous thrombolytic mechanisms don’t breakdown the clot.
If part of the clot breaks down and blocks a smaller coronary artery downstream, this creates an NSTEMI.
If the clot produces a complete blockage (occlusion) in situ then it produces a STEMI (worse).
Same situation in cerebral circulation produces a stroke/TIA.
84
Why does coronary artery atherosclerosis cause decreased cardiac performance?
Atherosclerosis of coronary arteries can lead to myocardial ischaemia and ventricular dysfunction.
Decreased left ventricular dysfunction causes a series of maladaptive responses - causing deteriorating heart failure;
Reduced CO causes activation of sympathetic and renin-angiotensin systems (via baroreceptor reflex and sensing of impaired renal function by juxtaglomerular apparatus);
SNS causes vasoconstriction in arteriolar resistance vessels, increasing BP - afterload,
RAAS promotes increase in volume, increasing BP - preload;
Both processes cause increased cardiac work more than heart can manage, so can’t support BP/renal function, so fluid accumulates in tissues as oedema.
85
What are pharmacological interventions to prevent worsening cardiac performance after coronary artery atherosclerosis?
ACE inhibitors block renin-angiotensin system, preventing increased venous return (preload);
Beta-blockers inhibit sympathetic NS, reducing arterial pressure (afterload).
Both these systems would cause increased cardiac work which the heart cannot handle, leading to deterioration and oedema.
86
What factors affect myocardial oxygen demand?
Contractility of the myocardium (force of contraction),
Heart rate (rate of it’s contraction),
Preload/venous return (the extent to which the ventricle is filled just prior to systole),
Afterload/arterial pressure (pressure that needs to be generated to pump blood into the arterial tree).
87
What factors affect myocardial oxygen supply?
Oxygen extraction (O2 carrying capacity - haemoglobin),
Coronary blood flow (coronary artery tone/vasodilation ability, atherosclerosis, thrombosis, heart rate) - also coronary perfusion is only possible in diastole (time in diastole decreases as HR increases),
Regional distribution.
88
What are therapeutic interventions help fix the mismatch of oxygen supply and demand?
Supply
89
What are clinical manifestations of ischaemic heart disease?
Angina pectoris: Stable angina, chest pain that is predictable on exertion and resolves rapidly on rest, related to a stable fixed stenosis of a coronary artery.
Unstable angina: chest pain that may come on unpredictably at rest because of an acute reduction in blood flow caused by a clot, in general unstable angina is not associated with a rise in cardiac enzymes (troponin, CK-MB) although there may be ECG changes such as ST-depression or T wave inversion.
Myocardial infarction: characterised by myocardial necrosis in the setting of myocardial ischaemia with symptoms of ischaemia (central chest pain), new ST-T changes, the development of pathological Q waves (full thickness infarct), a new regional wall motion abnormality (on echocardiogram or angiography) and a cardiac enzyme rise (CK, troponin,
ALT) - the rise in cardiac enzymes is usually too delayed to guide initial diagnosis.
90
What are the therapeutic objectives in ischaemic heart disease?
Primary prevention: Prevent the progression to symptomatic coronary disease - treat hypertension (ACE inhibitors, CCBs, thiazide diuretics), hyperlipidaemia (statins), diabetes.
Angina pectoris: Decrease oxygen demands and energy requirements of myocardium - Decrease preload (venous return) and decrease afterload (blood pressure); or undergo coronary angioplasty with stent insertion.
Myocardial infarction: restore blood flow to myocardium by promoting clot lysis (fibrinolytic drugs), prevent immediate clot extension (antiplatelet), remove the clot (primary percutaneous coronary intervention - PCI).
Secondary prevention: after myocardial event - prevent further atheroma, plaque rupture and clot formation (long-term aspirin, beta-blockers, statins).
Heart failure treatment: may develop after big MI - reduce neurohumoral activation (beta-blocker, ACE inhibitor), prevent fluid accumulation (loop diuretics).
91
What does therapeutic primary prevention of ischaemic heart disease involve?
Prevent progression to symptomatic disease:
Antihypertensives - ACE inhibitors (lisinopril)/ARAs (candesartan), calcium channel blockers (amlodipine), thiazide diuretics;
Lipid-lowering drugs - statins (atorvastatin).
92
What does therapeutic treatment and prevention of angina pectoris involve?
Decrease oxygen demand and energy requirements for myocardium - decrease preload (venous return), and decrease afterload (BP).
Nitrates (sublingual, oral, transdermal) (glyceryl trinintrate), calcium channel blockers (amlodipine), beta blockers (non-selective - propranolol, cardioselective - atenolol).
93
What does therapeutic intervention of an MI involve?
Restore blood flow to myocardium by promoting clot lysis (fibrinolytic drugs - streptokinase, alteplase), prevent immediate clot extension (antiplatelet - aspirin, clopidrogel), remove the clot (primary percutaneous coronary intervention - PCI and angioplasty).
94
What does therapeutic secondary prevention of ischaemic heart disease involve?
After myocardial event prevent further atheroma, plaque rupture and clot formation: long-term antiplatelets (aspirin, clopidrogel), beta-blockers (non-selective - propranolol, cardioselective - atenolol), statins (atorvastatin).
95
What does heart failure treatment involve?
May develop after big MI.
Reduce neurohumoral activation with beta-blocker (non-selective - propranolol, cardioselective - atenolol), ACE inhibitor (lisinopril),
Prevent fluid accumulation with loop diuretics (furosemide).
96
What is the treatment for stable angina?
Treatment for symptomatic relief of chest pain:
Sublingual glyceryl trinitrate (GTN) - rapid relief of anginal chest pain (can be use as prophylaxis before exercise), take a second dose after 5 minutes if the pain has not eased, call 999 for an ambulance if the pain has not eased 5 minutes.
Treatment to prevent chest pain:
Beta-blocker or a calcium-channel blocker (CCB) as first-line (choice depends on the comorbidities, contraindications, and preference),
If beta-blocker or calcium-channel blocker not tolerate consider: long-acting nitrate (such as isosorbide mononitrate), nicorandil, ivabradine or ranolazine.
Secondary prevention measures:
Antiplatelet treatment given to all people with stable angina - low-dose aspirin (75 mg daily) in most cases but clopidogrel preferred with stroke or PVD,
Statins for all patients with stable angina,
If patient has diabetes, consider ACE inhibitor as well (lisinopril).
97
What are the different types of nitrates?
Glyceryl trinitrate (GTN) ('nitroglycerin'):
Administered via sublingual route (400-800 micrograms) normally but there are other ways like patches,
Rapid absorption into circulation avoiding first-pass metabolism in liver,
Rapid relief of anginal chest pain (minutes) and can be used as prophylaxis,
Administered by intravenous infusion in hospital,
Indicated in myocardial ischaemia (angina), heart failure,
Side effects (typical of a vasodilator) include headaches, dizziness, weakness, flushing, syncope, tachycardia, palpitations, postural hypotension.
Isosorbide mononitrate/isosorbide dinitrate:
Indicated for chronic prevention of angina,
Administered orally (20 -120mg) in divided doses,
Long-acting modified-release (m/r) preparations available,
Overnight ‘rest’ period to avoid tolerance,
Same side effects as above.
Sodium nitroprusside:
Indicated in hypertensive emergencies,
Administered intravenously, light-sensitive, ferrous iron complexed with nitric oxide (NO) and five cyanide ions [cyanide toxicity (thiocyanate metabolite)].
With all nitrates, tolerance develops rapidly so exposure means needs 8-12 hrs nitrate-free to improve efficiency.
98
What is the effect of Nitric Oxide?
Nitric oxide activates guanylate cyclase (GC) in vascular endothelial cells, which increases the production of intracellular cyclic GMP from GTP and thereby dephosphorylating myosin light chains causing relaxation of smooth muscle cells.
The effect of nitrates is on both arteries and veins, but predominantly veins, causing venous pooling and a decrease venous return to the heart, thus decreasing cardiac preload and work.
Arteriolar relaxation reduces systemic vascular resistance and systolic blood pressure decreasing cardiac afterload. Nitrates also cause some increase in coronary blood flow.
These combined effects decrease myocardial oxygen demand and relieves ischaemia.
Key contraindication with sildenafil - too much vasodilation means heart can’t beat.
99
What are nitrates?
Examples: glyceryl trinitrate (SL, IV infusion, transdermal), isosorbide mononitrate (PO).
Main actions:
Nitric oxide (NO) donor - NO activates guanylate cyclase, Cyclic GMP deactivates phosphorylated myosin light chain, Causes smooth muscle relaxation → decreased preload and decreased afterload.
Indications:
Angina (prophylaxis and treatment), myocardial ischaemia in unstable angina/myocardial infarction, heart failure.
Dose:
Glyceryl trinitrate 400-800 ug SL as required (rapid-acting),
Isosorbide mononitrate 20-60 mg PO twice daily (prophylaxis).
Adverse effects: headache, flushing, hypotension, dizziness, tachycardia; tolerance.
Drug interactions: Other antihypertensive drugs, PDES inhibitors (e.g. sildenafil).
Nitrate tolerance: Depleted tissue sulfhydryl groups mean tissues can’t convert nitrates to NO, Neurohumoral activation (SNS) opposes action of vasodilators; so need 8-12 hrs nitrate free period daily.
100
What are examples of Calcium Channel Blockers (CCBs)?
Amlodipine:
Mainly peripheral action on arterioles,
Indicated as first-line medicine in hypertension, not often used for angina,
Rapid absorption into circulation avoiding first-pass metabolism in liver,
Rapid relief of anginal chest pain (minutes) and can be used as prophylaxis,
Daily administration by mouth.
Diltiazem:
More 'central' action on the heart,
Indicated as chronic prevention of angina, hypertension.
Short half-life long-acting modified-release (m/r) preparations twice daily.
Verapamil:
Administered by mouth or intravenously,
Indications in hypertension, angina, supraventricular tachycardia, atrial fibrillation,
Short half-life so normally given as modified-release (m/r) once or twice daily,
Cytochrome P450 inhibitor that affects metabolism of other drugs.
They all act to inhibit Ca2+ entry via L-type voltage-gated Ca channels, preventing rapid influx during depolarisation. 2 types:
Dihydropyridines (amlodipine) act peripherally on smooth muscle in vessels, mainly for hypertension, can cause reflux tachycardia;
Cardiac-selective (centrally-acting) CCBs (verapamil, diltiazem) act on pacemaker and myocardial cells - also used to treat supraventricular tachyarrhythmias like atrial fibrillation..
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How do calcium channel blockers work?
Extracellular Ca2+ around 10,000 times higher than intracellular.
Calcium channel blockers (CCBs) primarily act on voltage-gated L-type channels.
This action prevents Ca2+ binding with calmodulin and facilitating myosin light chain kinase and crossbridge formation between myosin and actin.
This reduces the contractile state of vascular smooth muscle in arterioles relaxing them to decrease vascular resistance and increase blood flow.
In the heart cardiac conduction system this reduces the rate of depolarization of conduction system (negatively chronotropic),
It also reduces the force of contraction of the myocardium (negatively inotropic).
Dihydropyridine CCBs (e.g. amlodipine, nidedipine) are much more potent in their effects on vascular smooth muscle cells than in the heart, whereas ‘centrally-acting’ CCBs (e.g. verapamil and diltiazem) are approximately equipotent in heart and vascular smooth muscle.
102
What are side effects and drug interactions of calcium channel blockers?
Very common (>10%): oedema {increased capillary hydrostatic pressures due to greater dilation of pre-capillary arterioles than post-capillary venules}, flushing {dilation};
Common (1%-10%): throbbing headache {increased blood flow}, palpitations {arterial vasodilators reduce peripheral vascular resistance, reducing BP, but baroreceptor reflex causes SNS activation so contractility increases}, dizziness, hypotension {normally want to reduce BP to an extent}, constipation {colonic smooth muscle relaxation}, bradycardia (verapamil) {sometimes causes heart block since affect SA and AV nodes}, heart failure {reduce HR and contractility - can cause heart failure if susceptible/influence drugs like beta-adrenoreceptor antagonists};
Uncommon (0.1%-1%): syncope;
Rare (0.01%-0.1%): confusion;
Very rare (<0.01%): gingival hyperplasia.
Drug interactions: antihypertensives (beta-blockers, ACE inhibitors, ARBs), bradycardia (beta-blockers), myocardium (anti-arrhythmic drugs, beta-blockers).
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What are calcium channel blockers?
Examples:
Dihydropyridines - amlodipine, nifedipine;
Centrally-acting - verapamil, diltiazem.
Mechanism of action:
Decrease Ca2+ entry via L-type channels → decreased Ca2+ availability;
In arterioles causes decreased smooth muscle tone → vasodilatation → decreased SVR → decreased BP;
In cardiac conduction system causes decrease in rate of phase 0 depolarisation → decreased HR;
In myocardium causes decreased ventricular contractility (-ve inotropy).
Indications: hypertension, angina, supraventricular tachyarrhythmias.
Administration: amlodipine 5-10 mg PO once daily.
Adverse effects:
Peripheral: flushing, headache, hypotension, oedema, constipation;
Cardiac: heart block, decreased ventricular contractility (beta-blocker interaction)
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What are types of beta-blockers?
Beta-adrenoceptor antagonists can be:
Non-selective (propranolol) - affects beta-1 and beta-2 receptors;
Cardioselective (atenolol, bisoprolol) - relatively selective for beta-1 receptors.
Both block binding of noradrenaline and adrenaline to the beta-1 receptors so inhibit response in the heart. Used for hypertension (4th line agent), angina (reduces energy requirement of the heart), anti-arrhythmic (supraventricular tachyarrythmia - AF); but cardioselective better since less side effects.
105
How to beta-blockers work?
Beta-1 adrenoceptors are in the cardiac conduction system (SA and AV nodes) and myocardium, and normally respond to post-ganglionic sympathetic secretion of noradrenalin and adrenaline secreted in the circulation by the adrenal medulla,
They are coupled to a stimulatory Gs-protein, which activates the enzyme adenylate cyclase to form cAMP from ATP,
CAMP activates protein kinase (PKA) that phosphorylates membrane L-type calcium channels (causing increased calcium entry into the cell by opening ryanodine {RY2} channels),
Increased free intracellular [Ca2+] facilitates cardiac myocyte contraction (inotropy), favours faster depolarisation of pacemaker cells (chonotropy), and favours faster electrical conduction through conduction system (dromotropy).
Thus beta-blockers slow Ca-dependent depolarisation in sine-atrial node, stabilise transmembrane potential, delaying the next depolarisation,
This reduces HR (negatively chronotropic);
Also decreases conduction velocity and automaticity, especially at AV node, and extends refractory periods.
In myocytes, force of ventricular contraction is decreased (negatively inotropic),
Reduces SV, CO (when combined with reduced HR), and so reduces energy requirement of heart.
Beta-adrenoceptor blockers:
Non-selective (e.g. propranolol) antagonise beta-1 and beta-2 receptors, or
Cardioselective (e.g. atenolol, bisoprolol) mainly antagonize beta-1 receptors.
Indications:
Hypertension - now relegated to fourth-line agents,
Angina - reduced energy requirements of the heart,
Anti-arrhythmic - supraventricular tachyarrhythmia.
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What are adverse effects and drug interactions of beta blockers?
Very common or common (up to 10%): Bradycardia, dizziness, fatigue (decreased HR, peripheral perfusion, reduced release of energy substrates by glycogenolysis/lipolysis), heart failure, peripheral coldness (inhibition beta-2 receptors on blood vessels), peripheral vascular disease, syncope; Confusion, sleep disorders.
Uncommon (0.1% to 1%): Atrioventricular block, Bronchospasm.
Rare (0.01% to 0.1%): Hallucinations.
Drug interactions:
Antihypertensives - calcium channel blockers, ACE inhibitors, angiotensin receptor blockers;
Bradycardia - so centrally-acting calcium channel blockers (e.g verapamil), digoxin;
Myocardium - calcium channel blockers, antiarrhythmic drugs - can precipitate heart failure.
107
What are beta-blockers?
Examples: atenolol, metoprolol, bisoprolol (relatively B1-selective).
Mechanism of action:
Block binding of noradrenaline and adrenaline to beta-1 receptors;
Decreased sympathetic (B1) activation → decreased cAMP → decreased Ca2+ availability;
Decreased ventricular response rate (-ve chronotropy);
Decreased excitability of conduction system (-ve dromotropy);
Decreased ventricular contractility (-ve inotropy).
Indications: hypertension, atrial fibrillation; angina, heart failure (low dose).
Administration: atenolol 25-100 mg PO daily, bisoprolol 2.5-10 mg PO daily.
Adverse effects: lethargy, decreased peripheral perfusion, heart block, bronchospasm.
108
What are some less common drugs for angina?
Nicorandil:
Vasodilation by opening ATP-sensitive K+ channels in smooth muscle,
Nitrate moiety in structure offers additional vasodilator action.
Ivabradine:
Blocks 'funny current' in sino-atrial node cells, thus reduces the rate of spontaneous depolarisation during action potential generation,
Reduce heart rate and therefore O, demand,
Fewer adverse effects than B-blockers (used as alternative or as adjunct).
Ranolazine:
Inhibits late phase of inward Na+ channels in ischaemic cardiac myocytes → decreases intracellular Na+ concentration → decreases intracellular Ca2+ influx via Na+-Ca2+ channel,
Inhibits rapid delayed rectifier K+ current, thus delaying action potential and prolonging QT interval,
Inhibits fatty acid oxidation → increases glucose oxidation and decreases lactic acid production, and improves heart function.
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What does secondary prevention for patients with angina involve?
Antiplatelet drugs:
Aspirin (75 mg PO daily) is an irreversible inhibitor of platelet cyclo-oxygenase and this reduces production of thromboxane A2 and platelet aggregation,
Clopidogrel is an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor prevents the downstream activation of the glycoprotein lIb/Illa receptor complex - less gastric upset than aspirin.
Statins (atorvastatin):
Inhibit HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol within hepatocytes → increase expression of LDL receptors on hepatocytes,
Increased uptake of cholesterol-rich LDL,
Decreases LDL cholesterol concentration by 30-50%,
Decreases CV events by 30-50%.
110
What are statins?
Examples: atorvastatin, simvastatin, rosuvastatin.
Main actions:
Inhibit enzyme HMG CoA reductase (rate-limiting of cholesterol synthesis),
Impaired hepatocyte ability to produce cholesterol (precursor in bile acid synthesis),
Stimulate production of hepatocyte LDL receptors,
Reduce LDLc by 30-50%.
Indications: hypercholesterolaemia, mixed hyperlipidaemia; primary and secondary prevention.
Dose: atorvastatin 10-80 mg PO nightly (greater impact at night), simvastatin 10-80 mg PO nightly.
Adverse effects: muscle toxicity - myalgia, myositis (increased CK), myopathy; raised liver enzymes (increased ALT).
Drug interactions: Macrolides (e.g. clarithromycin), grapefruit juice, diltiazem, amiodarone and ketoconazole; increase exposure to atorvastatin.
111
How are acute coronary syndromes treated?
Initial management:
Analgesics (morphine),
Nitrate (glyceryl trinitrate) to relieve pain,
Loading dose aspirin (300 mg).
Coronary reperfusion therapy:
Antiplatelet drugs (aspirin plus clopidogrel or prasugrel or ticagrelor),
Thrombolytic agents (streptokinase, alteplase).
Revascularisation procedures:
Percutaneous coronary intervention (PCI) with angioplasty,
Coronary artery bypass surgery (CABG).
Secondary prevention:
Dual antiplatelet therapy (aspirin plus clopidogrel or ticagrelor),
ACE (angiotensin-converting enzyme) inhibitor,
Beta-blocker,
Lipid-lowering drugs (statin).
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What are fibrinolytic drugs?
Fibrinolytic (thrombolytic drugs): important emergency drugs with the potential to induced clot lysis in a threatened acute myocardial infarction and reduce mortality.
Streptokinase, alteplase, reteplase and tenecteplase.
Most beneficial in ST segment elevation (particularly anterior infarction) and in patients with left bundle branch block.
The benefit is greatest the earlier that administration occurs after symptom onset - Alteplase and streptokinase still have value up to 12 hours after symptom onset, but ideally be given within 1 hour.
Alteplase can also be used for other thromboembolic disorders such as pulmonary embolism and acute ischaemic stroke.
Urokinase is also licensed to restore the patency of occluded intravenous catheters and cannulas blocked with fibrin clots.
Acute haemorrhage (including haemorrhagic stroke) is a predictable and potentially serious adverse effect and caution should be exercised in patients with increased risk factors for serious bleeding.
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What are anticoagulants drugs?
Unfractionated heparin is a mixture of polymorphic polysaccharide chains that significantly enhance the activity of the major natural inhibitor of coagulation, antithrombin III, which in healthy individuals
accounts for the majority of natural anticoagulation;
Antithrombin III is a serine protease inhibitor that primarily antagonises thrombin (factor lla) and factor Xa, two pivotal actors within the coagulation cascade;
After antithrombin III binds to thrombin or factor Xa, they form a complex that is rapidly degraded by the circulation.
Low-molecular-weight heparins (LMWHs) are derived from unfractionated heparin (UFH) by splitting the latter into a fraction that is approximately one-third of the original size;
The principal mechanism of action is similar for UFH and LMWHs, but LMWHs have fewer side effects and produce a more predictable anticoagulant response;
LMWHs (e.g. enoxaparin, dalteparin, tinzaparin) have now replaced UFH for most thrombotic indications;
LMWHs are injected subcutaneously in a fixed dose without the need for consistent anticoagulant monitoring, allowing some patients with venous thromboembolism to be treated as outpatients, rather than in hospital.
Fondaparinux is a small molecule with a structure that is based on the active component of heparins, and it was the first of a new class of selective antithrombin-dependent factor Xa inhibitors.
Other important oral anticoagulants are the vitamin K antagonist warfarin and direct acting oral anticoagulants (e.g. apixaban) but neither are indicated in the treatment of ACS.
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What are the antiplatelet drugs and their mechanisms?
Antiplatelet medications can be classified by their route of administration and their mechanism of action.
Aspirin was the first antiplatelet medication and is a cyclooxygenase (COX) inhibitor. Other oral antiplatelet agents include clopidogrel, ticagrelor, prasugrel and dipyridamole. Glycoprotein IIb/Illa inhibitors such as abciximab and eptifibatide are only available as parenteral agents and are used in acute coronary syndrome (ACS).
Aspirin is the most commonly prescribed oral antiplatelet drug and works by irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the prostaglandin synthesis pathway (PGH2);
This prostaglandin is a precursor of thromboxane A2 (TXA2) and prostacyclin (PGI2);
Thromboxane A2 induces platelet aggregation and vasoconstriction while PGI2 works by inhibiting platelet aggregation and induces vasodilation (the latter is mediated mainly by COX-2);
Low-dose aspirin (75 mg) can induce complete or near-complete inhibition of COX-1, thus inhibiting the production of TXA2, but larger doses are required to inhibit COX-2.
Oral thienopyridines (clopidogrel and prasugrel) selectively inhibit adenosine diphosphate-induced (ADP-induced) platelet aggregation;
These drugs are converted into the active drug with the help of the hepatic CYP450 system (CYP2C19 and CYP3A4) that can irreversibly inhibit the platelet P2Y12 receptor;
Prasugrel is the most potent, has a rapid onset of action and is superior to clopidogrel in patients undergoing coronary stenting.
Ticagrelor is an ADP analogue that also blocks P2Y12 receptors.
Glycoprotein platelet inhibitors (abciximab and eptifibatide) work by inhibiting glycoprotein IIb/Illa (GplIb-Illa) receptors on platelets, thus decreasing platelet aggregation;
Only available in an intravenous form and are therefore used as short-term therapy in ACS.
Dipyridamole has antiplatelet and vasodilating properties and inhibits platelet cyclic nucleotide phosphodiesterase;
This enzyme is responsible for the degradation of adenosine monophosphate (AMP) to 5'AMP, which increases intra-platelet cyclic AMP accumulation and inhibits platelet aggregation;
It also blocks the uptake of adenosine by the platelets, which also increases cyclic AMP;
Dipyridamole is used in the secondary prevention of stroke but not for ACS.
115
What are ACE inhibitors?
Examples: ramipril, lisinopril, perindopril, enalapril.
Main actions:
Inhibit angiotensin-converting enzyme (kininase II),
Decrease angiotensin II, vasopressin, and aldosterone,
Decreases blood pressure, Na+ retention, and K+ excretion.
Indications: hypertension (<55 or T2DM), chronic heart failure.
Dose: ramipril 2.5-10 mg PO daily, lisinopril 2.5-40 mg PO daily.
Adverse effects: hypotension, hyperkalaemia, renal impairment; dry cough (15%), angioedema (0.1%); contra-indication in pregnancy.
Drug interactions: Loop diuretics, Other antihypertensive drugs, Potassium-sparing diuretics, Potassium supplements, Non-steroidal anti-inflammatory drugs.
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What does effective cardiac function depend on?
Adequate diastolic filling:
Adequate volume returned to the heart (preload),
Regular rhythm that gives adequate filling time,
Compliant ventricular wall — no hypertrophy.
Adequate systolic emptying:
Adequate contraction - no damage + adequate perfusion,
Mobile and competent valve leaflets,
Normal arterial blood pressure (afterload)
Ejection fraction > 60% in health.
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What is preload?
Volume of blood in ventricles at end of diastole.
Determined by:
circulating blood volume,
venous 'tone' - affects the capacity of the venous circulation to hold blood.
Increased by:
Sympathetic NS activation (noradrenaline acting on alpha-1 to vasoconstrict),
Renin-angiotensin system activation (AII → aldosterone to favour Na retention),
Fluid and salt loading.
118
What is afterload?
Work heart must do to pump blood out of heart into circulation.
Determined by:
Blood pressure - aortic and pulmonary arteries,
Vascular resistance - systemic and pulmonary arterioles.
Increased by:
Sympathetic NS activation (noradrenaline on alpha-1),
Renin-angiotensin system activation (All → AT,),
Нурохіа.
119
What are HFrEF and HFpEF?
HFrEF = Heart failure with reduced ejection fraction:
Impaired contractility,
Left ventricular systolic dysfunction,
Reduced emptying of ventricle,
Most common.
HFpEF = Heart failure with preserved ejection fraction:
Impaired relaxation of the ventricle,
Impaired ventricular filling,
Left ventricular diastolic dysfunction - ('diastolic heart failure'),
Hypertension, diabetes, women,
Less common but increasingly recognised.
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What are Pathophysiological causes of heart failure?
Reduced myocardial contraction (causes reduced ejection fraction - HFrEF):
Ischaemic heart disease - most common,
Cardiomyopathy (e.g. inherited, alcoholic),
Infiltrative diseases (e.g. amyloidosis),
Myocarditis (e.g. viral).
Reduced myocardial relaxation (compliance):
Left ventricular hypertrophy (untreated hypertension).
Arrhythmias:
Tachyarrhythmias (e.g. atrial fibrillation),
Bradyarrhythmias (e.g. heart block).
Valvular disease:
Stenosis,
Regurgitation.
Increased demands:
Pressure overload,
Volume overload
121
What is heart failure presentation?
Symptoms: shortness of breath, persistent coughing or wheezing, ankle swelling, reduced exercise tolerance, fatigue.
Clinical signs: findings that suggest right ventricular failure (e.g. elevated jugular venous pressure, liver engorgement and enlargement, peripheral oedema) and left ventricular failure (bibasal fine inspiratory crepitations, more extensive pulmonary oedema, pleural effusions).
May point to non-ischaemic causes of heart failure such as anaemia, arrhythmias (e.g. atrial fibrillation), hypertension and heart murmurs (indicating valvular disease).
122
What events can cause chronic and acute heart failure?
Chronic: MI, ischaemia, arrhythmia, valvular disease.
Acute: infection, drug, arrhythmia, fluid overload, ischaemic event.
123
What are therapeutic objectives in heart failure?
Relieve symptoms: dyspnoea, persistent coughing or wheezing, ankle swelling and fatigue.
Improve exercise tolerance: improve walking distances before onset of dyspnoea and fatigue.
Prevent progression: Reduce neurohumoral activation (SNS, RAAS activation), prevent fluid accumulation.
Prevent acute exacerbations: Prevent fluid accumulation, Avoid 'decompensation'.
Reduce mortality: Reduce fatal arrhythmias and coronary disease.
124
What are the therapeutic approaches to heart failure?
Stop drugs that impair contractility (CCBs, some antiarrhythmic drugs), treat infections/chronic conditions, address ischaemia, control arrhythmias, avoid fluid overload (especially due to alcohol).
Loop diuretic (furosemide) - fluid overload.
Angiotensin-converting enzyme (ACE) inhibitor (ramipril) - preferred before beta blocker if diabetic/fluid overload but not if valve disease. ARAs (losartan) if can’t tolerate it/causes cough.
Beta-blocker (bisoprolol)
Mineralocorticoid receptor antagonists (spironolactone, eplerenone) - K sparing diuretics
Additional therapy options:
Sacubitril with valsartan (to replace ACE inhibitors) or ivabradine if EF <35%,
SGLT-2 inhibitor (e.g. dapagliflozin),
Hydralazine and a nitrate,
Digoxin
Secondary prevention: Antiplatelet drugs (aspirin), lipid-lowering drugs (statins).
125
How are loop diuretics used in heart failure?
Loop diuretics licensed for heart failure:
Furosemide - commonest and available in oral and IV formulation,
Bumetanide - better absorbed from oedematous bowel wall.
Dose and titration:
Impact on hydration, blood pressure and renal function - assess blood pressure/renal function before starting;
Furosemide 20-40 mg PO daily in the morning initially,
Titrate according to symptoms and monitoring.
Monitoring:
Blood pressure, renal function, serum electrolytes rechecked at around 1-2 weeks but earlier for those at risk of adverse effects patients vulnerable to adverse effects of loop diuretics:
• chronic kidney disease
• elderly.
• comorbidities (e.g. diabetes)
• taking other drugs affecting renal function (e.g. ACE inhibitors, AlIRAs or MRAs)
126
How do loop diuretics work?
Target the thick ascending limb of the Loop of Henle.
Furosemide inhibits the Na+/K+/2CI- co-transporter in the luminal membrane by combining with its Cl- binding site.
This action prevents the reabsorption of up to 25% of the sodium, chloride and water filtered at the glomerulus and allows it to progress to the distal convoluted tubule and collecting duct.
127
What are adverse effects and cautions of loop diuretics in heart failure?
Adverse effects:
Electrolyte losses - hyponatraemia (confusion, muscle cramps/weakness, appetite loss, dizziness, drowsiness, vomiting), hypokalaemia (lethargy, confusion, weakness, constipation, heart rhythm disturbances, increased toxicity of other drugs - digoxin, type III anti-arrythmics), hypomagnesaemia, hypocalcaemia;
Acid-base disturbances - metabolic alkalosis;
Water losses - dehydration/hypovolaemia, hypotension (postural), impaired glomerular filtration and renal function, polyuria and urinary retention;
Altered tubular excretion - hyperuricaemia and gout;
Other effects - ototoxicity.
Contra-indications: hypovolaemia, dehydration, hyponatraemia, hypokalaemia, poor renal function.
Cautions: elderly, hypotension, history of hyponatraemia/hypokalaemia, difficulty with micturition/history of urinary retention, hyperuricaemia/gout, impaired renal function.
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What are loop diuretics?
Examples: furosemide, bumetanide, torasemide.
Main actions:
Decrease Na+/K+/2Cl- absorption in thick ascending limb of Loop of Henle (target co-transporter),
Inhibits reabsorption of 15-25% of glomerular Na+ filtrate.
Indications: heart failure (acute and chronic), renal failure (including nephrotic syndrome), liver cirrhosis with ascites.
Dose: furosemide 40-80 mg PO daily (also available IV).
Adverse effects:
Hyponatraemia, hypokalaemia (lethargy, increase other drug toxicity - digoxin, type III antiarthythmics; prevented by using K sparing diuretic or giving K supplement), metabolic alkalosis;
Fluid depletion (dehydration, hypovolaemia) (hypotension, precipitate impaired renal function - reduce glomerular filtration rate), incontinence;
Ototoxicity (hearing loss),
Gout (decreased uric acid excretion, increased Ca2+/Mg2+ excretion).
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How are ACE inhibitors used in heart failure?
ACE inhibitors licensed for heart failure: ramipril, lisinopril, enalapril; decreased hospitalisation and mortality
Dose and titration:
Assess BP, renal function and electrolytes before starting,
Start with a low dose before progressive up-titration,
Beware 'first dose hypotension' if already taking loop diuretic
Monitoring:
BP, renal function and serum electrolytes should be rechecked at around 1-2 weeks but earlier for those at risk of adverse effects,
Patients vulnerable to adverse effects of ACE inhibitors - chronic kidney disease/renal artery stenosis, elderly, comorbidities (e.g. diabetes, peripheral vascular disease), taking other drugs affecting renal function (e.g. AlIRAs, MRAs, potassium supplements, vasodilators, NSAIDs).
130
What are adverse effects and cautions of ACE inhibitors used in heart failure?
Adverse effects:
Hypotension - decreased availability of angiotensin II, more likely if blood pressure more dependent on RAS (e.g. dehydration, renal artery stenosis);
Renal impairment - RAS is the defence of glomerular perfusion at times of dehydration and hypotension;
Hyperkalaemia - AII activates release of aldosterone which favours sodium retention in exchange for potassium excretion;
Cough and angioedema - ACE also breaks down kinins accumulation, in the lung causes intractable cough (15%), in the upper airways causes angioedema (0.1%);
Other effects: rash, headache, teratogenic.
Contraindications: known angioedema history, bilateral renal artery stenosis, hyperkalaemia with poor renal function, pregnancy.
Cautions: concurrent diuretics, peripheral vascular disease, impaired renal function, hypotension, heart failure not stabilised.
131
How are beta-blockers used in heart failure?
Beta-blockers licensed for heart failure: bisoprolol, carvedilol; decrease hospitalisation and mortality.
Dose and titration:
Tend to reduce contractility so the patients should be stable and started on the lowest dosage before up-titration,
May be a temporary worsening of symptoms,
Beta-blockers should not be stopped suddenly without good cause (rebound ischaemia or arrhythmias)
Monitoring:
Heart rate - Interacting drugs: diltiazem, verapamil, digoxin;
Blood pressure - Interacting drugs: nitrates, amlodipine, hydralazine;
Clinical status - Symptoms: fatigue, dyspnoea, cold peripheries.
132
What are adverse effects and cautions of beta-blockers used in heart failure?
Adverse effects:
Hypotension - decreased heart rate and contractility;
Bradycardia/heart block - deceased rate of depolarisation of the sino-atrial node and transmission through the atrioventricular node;
Peripheral vascular constriction - decreased beta-2-mediated vasodilatation - cold extremities, paraesthesia, and numbness - worse with pre-existing peripheral arterial disease;
Bronchospasm - decreased beta-2-mediated bronchodilatation;
Reduced exercise tolerance/fatigue - decreased beta-2-mediated vasodilatation, glycogenolysis and lipolysis as well as beta-1-mediated decrease in cardiac output;
Other effects - sexual dysfunction, decreased autonomic hypoglycaemia response.
Contra-indications: history of asthma/bronchospasm, significant heart block, significant hypotension, severe heart failure, severe peripheral vascular disease (PVD), vasospastic (Prinzmetal) angina.
Cautions: bradycardia, heart block, hypotension, heart failure, PVD, diabetes mellitus
133
How are mineralocorticoid receptor antagonists used in heart failure?
Potassium-sparing diuretics.
Spironolactone, eplerenone (less hormonal adverse effects);
Decreased hospitalisation and mortality in patients with persisting symptoms - NYHA classes II-IV and an EF ≤ 35% despite ACEi/ARB,
Dose and titration: prescribed for heart failure at only two doses, initially 25 mg PO daily then 50 mg PO daily
Monitoring: serum potassium and renal function 1 week after initiation, then monthly for first 3 months, then every 3 months for 1 year, and then every 6 months.
134
What is the mechanism of action of potassium-sparing diuretics?
Spironolactone is antagonist at mineralcotricoid receptors (MRAs),
Up-regulates the transcription of the basolateral membrane protein that is responsible for exchanging sodium for potassium (in the collecting duct),
Preserves potassium in the body and prevents the reabsorption of most of the remaining sodium, chloride and water filtered at the glomerulus.
Amiloride inhibits the same sodium/potassium exchange but does so by preventing the entry of sodium ions through their ion channel in the luminal membrane.
MRAs seem to have beneficial effects in heart failure, not only by reducing the tendency to accumulation of sodium and water but also be preventing some of the longer-term maladaptive responses to aldosterone. MRAs might have anti-arrhythmic effects on atrial and ventricular arrhythmias and may be helpful in prevention of myocardial fibrosis and vascular damage.
135
What are adverse effects of mineralocorticoid receptor antagonists?
Adverse effects:
Hyperkalaemia - aldosterone promotes sodium retention and potassium excretion into the lumen of the distal tubule and collecting duct, mineralocorticoid receptor antagonists interfere with this action to impair the ability of the kidneys to excrete potassium, hyperkalaemia is exacerbated in the presence of renal impairment or other drugs that favour retention (e.g. ACE inhibitors);
Anti-androgen-related effects - spironolactone cross-reaction with androgen-receptors - male breast tenderness and gynaecomastia, male erectile dysfunction, female menstrual irregularities, eplerenone has 100-1000 lower affinity for testosterone and progesterone receptors
Contra-indications: hyperkalaemia, severe renal impairment.
Cautions: elderly, reduced renal function.
136
What are mineralocorticoid receptor antagonists?
Examples: Spironolactone, Eplerenone
Main actions: decrease aldosterone receptor-mediated formation of the Na+/K+ exchanger in basolateral membrane of the distal tubule; decrease Na+ reabsorption in exchange for K+ or H+ ions.
Indications: chronic heart failure, liver failure with ascites, resistant hypertension, primary hyperaldosteronism (Conn's syndrome)
Dose: spironolactone 25-50 mg or eplerenone 25-50 mg PO daily.
Adverse effects: hyperkalaemia, acidosis; spironolactone antiandrogenic effects (breast tenderness, gynaecomastia, erectile dysfunction), menstrual irregularity
137
What re less common drugs for heart failure?
Sacubitril with valsartan:
To replace the ACE inhibitor if the ejection fraction is less than 35%,
Sacubitril (a prodrug) inhibits the breakdown of natriuretic peptides resulting in varied effects including increased diuresis, natriuresis, and vasodilation.
Sodium-glucose transporter type 2 (SGLT-2) inhibitor: dapagliflozin, empagliflozin.
Ivabradine: for people in sinus rhythm with a heart rate over 75 beats per minute (bpm) and ejection fraction less than 35%.
Hydralazine and nitrate:
Especially if of African-Caribbean descent,
Hydralazine is an arterial vasodilator (decrease afterload),
Nitrates are predominantly venodilators (decrease preload).
Digoxin: for people in sinus rhythm to improve symptoms.
138
What are cardiac glycosides?
Examples: digoxin, digitoxin
Mechanism of action:
Inhibits Na+/K+-ATPase → increases force of contraction (inotropy),
Decreases rate of SA node depolarisation (negative chronotropy),
Decreases conduction through AV node (negative dromotopy).
Indications: Atrial fibrillation, Heart failure
Administration: digoxin 62.5-250 micrograms PO daily (can be given IV), long half-life (40 hours) so loading dose required for rapid effect
Adverse effects: anorexia, nausea, vomiting, visual disturbances, AV block, arrhythmias; promoted by hypokalaemia; caution in renal failure (depends on renal excretion), low therapeutic index (digoxin concentration can be measured).
139
What is the treatment for acute heart failure?
Oxygen: to address hypoxia
Loop diuretic (e.g. furosemide): administered by intravenous bolus or infusion; monitor renal function, weight and urine output, urinary catheter may be required.
Glyceryl trinitrate: administered by intravenous bolus or infusion to reduce venous return (preload) and blood pressure (afterload); used for myocardial ischaemia, severe hypertension or regurgitant aortic or mitral valve disease; monitor blood pressure closely
Inotropes/vasopressors:
If cardiogenic shock (decreased BP, cardiac output and tissue perfusion);
Inotropes act on beta-1 receptors (adrenaline, dobutamine, dopamine) to stimulate cardiac contractility,
Vasopressors act on beta-1and alpha-1 (noradrenaline) to increase blood pressure.
