Case 9 SBA Flashcards
Describe the structure of the thyroid gland
A butterfly shaped endocrine gland. Has a left and right lobe connected by a central isthmus. Anterior to and wrapping partially around the trachea. Surrounded by the pretracheal fascia. Not visible or palpable unless pathology is present
Describe the parathyroid glands
usually two pairs of small glands, one superior and one inferior in the left and right lobes. Some people, however, have more pairs. Share a similar blood supply and lymphatic drainage to the thyroid gland. Produces parathyroid hormone in response to low blood calcium.
Embryology of thyroid
descends through thyroglossal duct which then closes over time. If it does not close, a thyroglossal cyst can form which is a differential diagnosis for a midline neck lump
Perfusion of thyroid gland
superior thyroid artery (external carotid) and inferior thyroid artery (thyrocervical trunk from subclavian artery)
Drainage of thyroid gland
superior, middle, and inferior (superior and middle to internal jugular and inferior to brachiocephalic)
Innervation of thyroid gland
sympathetic: fibres from superior, middle, inferior cervical ganglia. parasympathetic: fibres from superior and recurrent laryngeal nerves
Lymph node groups that drain thyroid gland
peri-thyroid, pre-laryngeal, pre-tracheal, paratracheal, superior and inferior deep cervical
Histology of thyroid gland
functional units of the thyroid are the follicles. A single layer of follicle cells surrounds a pool of colloid. The production and storage of thyroid hormones occurs in the colloid. C cells secrete calcitonin which is involved in calcium homeostasis
TSH normal range
0.4-4.2 mlU/L.
Free T4 normal range
0.8-2.7ng/dL
Total T4 normal range
4.5-11.7 ug/dL
T3 normal range
80-220 ng/dL
Graves’ disease investigation results
serum T4 elevated (both free and total), TSH supressed, increased iodide uptake by thyroid (123I RAIU test)
Untreated hyperthyroidism investigation results
low TSH, high free T4, high T3, high radioiodine uptake
Hyperthyroidism with thyrotoxicosis investigation results
low TSH, normal free T4, high T3, normal or high radioiodine uptake
Untreated primary hypothyroidism investigation results
high TSH, low free T4, low or normal T3, low or normal radioiodine uptake
Hypothyroidism secondary to pituitary disease investigation results
low or normal TSH, low free T4, low or normal T3, low or normal radioiodine uptake
Euthyroid on exogenous thyroid hormone investigation results
normal TSH, normal free T4 on T4, low free T4 on T3, high T3 on T3, normal T3 on T4, low radioiodine uptake
Describe levothyroxine
Hypothyroid treatment of choice. T4. Consistent potency, >99.8% protein bound (gives reservoir of T4 for conversion to T3), half-life of roughly 7 days, 5-6 weeks for new steady state, 80% oral bioavailability (reduced by gastric acidity, various foods and drugs, especially Fe and Ca supplements).
Describe liothyronine
T3, hypothyroidism. Cytomel, triostat. Quicker onset, half-life >24 hours, more variable response, frequent dosing, more expensive, increased cardiovascular events
Describe liotrix
hypothyroidism. T4/T3 combo in 4:1 ratio, brand name thyrolar. Attempts to simulate natural hormone levels, no therapeutic advantage over T4, expensive
Describe desiccated animal thyroid
hypothyroidism. 4:1 ratio of T4:T3, variable response, interchange with other therapies is problematic, allergic reactions to animal proteins. Not really used that often anymore.
Describe carbimazole
hyperthyroidism. pro-drug, meaning only active when converted in thiamazole and methimazole metabolites
T4 drug side effects (TWIST CAD)
not for treatment of obesity or for weight loss, increased risk of cardiac events in elderly (MI and A-Fib), adrenal insufficiency, decreased bone mineral density, tachycardia, tremors, insomnia, weight loss, sweating
Drug-drug interactions of T4
long list - altered absorption, protein binding, and metabolism that may alter therapeutic response, decreased conversion to T3 by beta-blockers, amiodarone, and propylthiouracil (PTU).
Thioamide side effects
agranulocytosis, liver toxicity, and congenital malformations
High iodine side effects (MIDBAD)
metallic taste, burning mouth, diarrhoea, systemic allergic reactions (fever, rash, rhinitis), severe dermatitis, iododerma eruptions can be fatal but are very rare
Indications for T3/T4 treatment
replacement/supplemental in patients with hypothyroidism of any aetiology, treatment or prevention of euthyroid goitres, adjunct to surgery and radioiodine therapy in management of TSH-dependent thyroid cancer
Goal of hypothyroidism treatment
maintain TSH in normal range for symptom relief and avoiding hypothyroidism in foetus
Thioamide mechanism of action
thiourea blocks hormone production. Bind to active site of thyroid peroxidase (TPO), complexes with iodine and converts it to iodide, this oxidases thioamide which forms disulphide bond with enzyme, causing irreversible inactivation of TPO enzyme. Decreased formation of iodotyrosine residues causes a decreased in T4 synthesis. Inhibition of peripheral deiodination of T4.
Thioamide examples
Propylthiouracil (PTU), carbimazole, and methimazole (MMI)
Indications for carbimazole
graves’ disease and toxic multinodular goitre in patients for whom surgery and radioactive iodine are not appropriate
In preparation for surgery with 131Iodine until effective
What is favoured as hyperthyroidism treatment in 1st trimester of pregnancy and thyroid storm and why?
PTU as blocks T4-T3 conversion
Treatment of Graves’ disease in pregnancy
1st trimester: PTU
2nd and 3rd trimesters: carbimazole but continue 2-3 weeks pre-birth.
Nursing: carbimazole as PTU contraindicated.
Give in low doses and monitor TSH as both can cross placenta
High iodide treatment mechanism
acute inhibition of tyrosine iodination, then decreases in iodine uptake transporter. Inhibits proteolysis and release of T4 – rapid effect but not sustained, escape after 1-2 months
Indications for high iodide treatment
Rarely used as a sole therapy: preoperative with thioamide for thyroidectomy, with PTU for thyroid storm, prevent radiation-induced thyroid cancer after nuclear fallout
Forms of high iodide treatment
SSKI, Lugol’s solution, Iodoral
131 Iodine indications and mechanism
gland ablation in hyperthyroidism. Half-life of 8 days, gamma and beta emitter – long exposure for ablation, causes cell necrosis and destroys small blood vessels, symptoms abate in 6 months – thioamides, iodide, or beta-adrenergic antagonists given over this lag period
Treatment of thyrotoxicosis (LAB)
beta adrenergic antagonists
lithium
amiodarone
Describe thyroxine
T4, major product. Daily secretion around 100 nmoles. 5-7 day half life. 0.04% free, rest bound to plasma proteins
Describe triiodothyronine
T3. 3-8 times more active than thyroxine. Daily secretion around 5 nmoles. 0.4% free, rest bound to plasma proteins. 80% derived from peripheral metabolism of T4.
Which proportion of thyroid hormone is active?
The unbound, <1%
Purpose of the bound thyroid hormone?
Acts as a reservoir in the circulation with hormone dropping off the transport protein when required to maintain the equilibrium between free and bound
70% T3 and T4 bound to
Thyroxine-binding globulin (TBG)
10% T3 and T4 bound to
Transthyretin (thyroxine-binding prealbumin)
Ten-fold greater affinity for T4
Albumin with thyroid hormones
15-20% bound to albumin, major source of free hormone from rapid dissociation as bound with relatively low affinity
Four types of thyroid hormone receptors
TRα1, β1, β2, and β3
Which thyroid hormone receptor type has a very low affinity for T3?
TRα1
What do the TRβ1, β2, and β3 have a higher affinity for?
T3
Describe the mechanism of thyroid hormone
Once inside the cell, T4 is acted upon by deiodinase enzymes which forms T3 + Iodine. Receptors are found attached to hormone response elements in DNA where they repress transcription – causes conformational change which allows gene transcription to occur. Thyroid hormones change the amount of protein in the cell and thus the function of the cell. Key target is increased transcription of genes encoding mitochondrial uncoupling proteins.
Effects of thyroid hormones
increases basal metabolic rate, increases cardiac output, enhances catecholamine actions, maintains emotional tone, effect on foetal neural development, bone growth, tooth development, permissive role in male and female reproductive organs
Synthesis of thyroid hormone
production of thyroglobulin (glycoprotein rich in tyrosine) produced by follicular cells and exocytosed across the apical membrane to be stored in the colloid. Iodide retrieved from blood by I/Na transporter, taken into colloid by protein pendrin iodide oxidized by thyroid peroxidase (TPO, expressed on follicular cell membrane) into iodine. Iodine groups are added to tyrosine on thyroglobulin (either one or two per tyrosine) under control of TPO. Coupling – T1 and T2 coupled to form T3 and T4 groups on the thyroglobulin which is stored in the colloid.
Release of thyroid hormone
pinocytosis – some of the colloid is embraced by membrane and taken into the follicular cell. Colloid acted on by lysozymes which break down the thyroglobulin molecule that frees up T1 and T2 to be recycled and T3 and T4 are free to move into the blood
HPT axis control of thyroid hormone
largely through negative feedback. In response to stimuli, the hypothalamus releases thyrotropin-releasing hormone (TRH) into the portal circulation of the pituitary stalk. TRH acts on thyrotropes in the anterior pituitary to stimulate the release of TSH. TSH travels to the thyroid to stimulate release of T3 and T4
What else stimulates TRH release?
increased cold, stress, and exercise
What inhibits TSH?
glucocorticoids and somatostatin
Actions of TSH
increases iodide uptake, increases thyroglobulin synthesis, increases iodination of tyrosine residues, increases size of thyroid cells, increases pinocytosis of colloid, and increases lysosomal activity
Conversion of T4 to T3
requires the removal of an iodine residue by action of deiodinase enzymes which results in either active or inactive T3
How is active T3 produced?
action of type 2 deiodinase which removes iodine residue from outer ring of T4
Action of type 3 deiodinase
converts T4 into reverse T3 by removing iodine from inner ring
Action of type 1 deiodinase
can remove iodine from both inner and outer rings
Neuroendocrine factors increasing mood disorders
Stress, therapeutic glucocorticoid treatment, adrenal dysfunction, altered cortisol rhythm, excess cortisol
Altered cortisol rhythm in mood disorders
stays higher than normal and the negative feedback loop doesn’t work properly causing hyperstimulation of receptors (especially common in bipolar disorder and psychotic depression
How does excess cortisol impact on brain function?
altering the expression of proteins, interfere with the action of antidepressants, decrease neuronal complexity, and affect 5-HT (serotonin) neurotransmission (HPA dysfunction).
Describe serotonin mechanism
released at both the cell body and terminals – auto-receptors on soma respond to levels and regulate firing rate
Synaptic plasticity
change that occurs at synapses depending on stimulation e.g. exercise increase and stress decreases
Neuro changes with bipolar disorder
HPA dysfunction more common, more evidence of brain structural and connectivity changes, some evidence for involvement of dopamine
Define major depressive disorder
major depression or clinical depression. Periods of extreme sadness, hopelessness, or emptiness accompanied by a variety of physical, cognitive, and emotional symptoms.
Define bipolar 1 disorder
formerly called manic depression. Mania is characterised by euphoric and/or irritable moods and increased energy or activity. During manic episodes, people also regularly engage in risky activities that can result in negative consequences for themselves and/or others.
Define bipolar 2 disorder
episodes of hypomania (a less severe form of mania) and major depression, but no history of mania.
Symptoms of MDD
depressed mood and markedly diminished interest in things that once brought enjoyment are the two key symptoms. Additional symptoms include weight loss, appetite change, insomnia, hypersomnia, psychomotor agitation/retardation, fatigue, lack of energy, feelings of worthlessness and guilt, unable to think clearly/concentrate, and thoughts of death/suicide. Need the two key symptoms plus at least another three for two weeks
Symptoms of bipolar 1
all of the depressive symptoms for the same timescale. Mania – inflated self-esteem, increased talking, decreased need for sleep, racing thoughts, easily distracted, increase in goal directed activity, psychomotor agitation, and engaging in risky behaviour. Need three or more of the mania symptoms for a week as well as functional impairment on daily life.
Symptoms of bipolar 2
same symptoms as bipolar 1. Need three or more for four days but with no functional impairment on daily life
Diagnosis of mood disorders
Patient and clinician questionnaires (BDI and HAM-D) are used for diagnosis. Results are monitored weekly to lead treatment and monitor recovery
Monoamine theory of depression
reduction in monoamines (serotonin, norepinephrine, and dopamine) causes the symptoms of depression. Also includes cofactors, precursors, receptor activity, intracellular processes, and process and degradation enzymes
Reason for believing monoamine theory
Medications that increase neurotransmitter concentrations in synaptic cleft are effective antidepressants, people with depleted tryptophan show depression symptoms
Reasons against monoamine theory
Reasons for decrease in neurotransmitters unknown, no consistent evidence of serotonin dysfunction
Serotonin mechanism of action and metabolism
tryptophan converted to 5-HTP which is then converted to 5-HT in the raphe nuclei. Sequestered into vesicles, protected from breakdown and ready for release. Released in response to action potentials, removed from synaptic cleft by reuptake transporter. Degraded by monoamine oxidase (MAO) into 5-HIAA
Thiopental pharmacokinetics
high lipid solubility, rapid action
Phenobarbital pharmacokinetics
lowest lipid solubility, lowest plasma binding, lowest brain protein binding, longest delay in onset of activity, longest duration of action. Half-life 53-118 hours (mean 79 hours), primarily metabolised by liver, excreted in urine
All SSRI side effect
risk of suicide, especially in adolescents
Citalopram side effects
one of its minor metabolites is cardiotoxic and pro-convulsant at high doses
Paroxetine side effects
most sedating, highest weight gain risk
Benzodiazepines side effects
Nausea, sexual dysfunction, agitation, weight gain, insomnia, serotonin syndrome (too much serotonin)
What can be prescribed with SSRIs in initial weeks to counteract side effects and offset delay?
Benzodiazepines
SSRI discontinuation syndrome
patients must be tapered off, except for fluoxetine where long half-life leads to natural tapering. Symptoms: fatigue, lethargy, malaise, muscle aches, headaches, diarrhoea, insomnia, nausea, gait instability, dizziness, vertigo, paraesthesia, anxiety, agitation.
Tricyclic antidepressant side effects
blurred vision, dry mouth, constipation, orthostatic hypotension, urinary retention, rash, hives, tachycardia, increased risk of seizures. Side effects severe, likely to be successful if used in an overdose attempt (cardiotoxicity, hypotension)
Barbiturate side effects
addictive with severe withdrawal symptoms, respiratory distress at high doses, lethal OD (x10 hypnotic dose) due to ability to act as direct agonist at high concentrations
Benzodiazepine withdrawal side effects
depression, suicidal behaviour, psychosis, seizures, and delirium tremens.
Benzodiazepine mechanism of action
GABA A receptor positive allosteric modulators.
GABA A
inhibitory neurotransmitter, lessens the ability of a nerve cell to receive and send chemical messages
Clinical use of benzodiazepines
Short term for anxiety, only antidepressant/anxiolytic with immediate effect. can be useful to treat muscle spasms as have strong muscle relaxant effects but tolerance often develops
Benzodiazepine examples
diazepam, alprazolam, temazepam, midazolam
SSRI mechanism of action
Blocks the reuptake of serotonin leaving more in the synapse (eventually, initially causes a decrease in serotonin because of the feedback mechanism): 5HT1A receptors act as inhibitory somato-dendritic auto-receptors on 5HT neurons → blockage of 5HT uptake → elevated 5HT in raphe nuclei → reduced expression of inhibitory 5HT1A receptors → 5HT neuron disinhibited → 5HT output enhanced. Efficacy takes 4-6 weeks
Citalopram
SSRI, 2nd most serotonin selective
Escitalopram
S enantiomer of citalopram, more potent and selective, reduced side effects
Fluoxetine
1st SSRI, very long half life, potent CYP2D6 inhibitor
Sertraline
SSRI, most widely prescribes, mildest side effects, moderate CYP2D6 inhibitor
Paroextine
possibly more effective, potent CYP2D6 inhibitor
Tri-cyclic antidepressant mechanism of action
serotonin-norepinephrine reuptake inhibitors act by blocking the serotonin transporter (SERT) and norepinephrine transporter (NET) → elevation of synaptic concentrations of these and an enhancement of neurotransmission
SNRIs mechanism of action
tend to have a higher affinity for SERT than NET. Potent inhibitors of serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake. Minimal or no pharmacological action and adrenergic, muscarinic, histamine, dopamine, or post-synaptic serotonin receptors
SNRI examples
venlafaxine and duloxetine
Venlafaxine at low doses (37.5mg daily)
functions like an SSRI
Venlafaxine at high doses (above 225mg daily)
dual mechanism agent affecting serotonin and noradrenaline
Atypical antidepressants
buspirone, mirtazapine, and trazodone
Buspirone
5-HT1A receptor partial agonist. Antidepressant and anxiolytic. Dopamine agonist at D2, D3, and D4 receptors, primarily acting on presynaptic inhibitory auto-receptors. Depresses serotonin and enhances dopamine release. Generally used for anxiety but also relieves depressive symptoms in anxious patients
Mirtazapine mechanism
potent antagonism of central alpha-2 adrenergic receptors (blockade of presynaptic auto-receptors and thus enhanced noradrenaline release) and antagonism of 5-HT2 (net increase in 5-HT mediated transmission), 5-HT3 (antiemetic), and H1 receptors
What dose should mirtazapine not be given lower than and why?
15mg to avoid excessive sedation as has antihistaminergic effects
Low dose trazodone
Hypnotic due to blockade of 5-HT2A receptors, as well as H1 and alpha-1 adrenergic receptors
High dose trazodone
Recruits blockade of SERT and has antidepressant effects
Why does trazodone have limited use in the elderly?
Can cause orthostatic hypotension
Describe barbiturates
sedative, hypnotic, anaesthesia inducing, anticonvulsant. Positive allosteric modulators of GABA A receptors
Barbiturate examples
pentobarbital, butobarbital, phenobarbital, and sodium thiopental.
Describe Z drugs
show preference for alpha-1 subunits of BZ receptors. Similar action to benzos. Zolpidem (Ambien), eszopiclone (Lunesta – additional activity in alpha 2 and 3 receptors), and zaleplon (Sonata, shorter half-life so fewer hangover effects)
Describe flumazenil
BZD antagonist – binds to GABA A receptor. Repeat doses may be required to prevent overdose symptoms re-occurring once the initial dose wears off (shorter half-life than many benzos). May get benzo withdrawal symptoms like seizure in patients who are physically dependent on benzos upon rapid administration
Specific phobia
childhood onset, isolated fear of specific object/event with avoidance. Occurs for >6 months.
Describe anxiety
feeling of worry, nervousness, or unease about something with an uncertain outcome. May be normal, necessary, appropriate, and entirely rational. A psychological, physiological, and behavioural state induced in animals and humans by a threat to well-being or survival, either actual or potential
Social phobia
slightly higher in females, emerges in teens. Fear of social situations or being focus of attention (public speaking, small groups e.g. parties, meetings), fear of behaving in an embarrassing way or humiliating oneself (blushing). Avoidance behaviours, >6-month duration.
Agoraphobia
around 1.8:1 F:M, emerges early-mid twenties to mid-thirties. Fear of leaving the home, travelling alone, crowds, and public places. Avoidance behaviours, >6-month duration.
Panic disorder
panic attacks that start abruptly. Discrete episodes of intense fear that last for some minutes. Fear of catastrophic outcome. Random, not situational. Four of the anxiety symptoms not caused by substances, medications, medical conditions, or another mental disorder.
Generalised anxiety disorder
a period of at least six months with prominent tension, worry, and feelings of apprehension about everyday events and problems. Difficulty controlling the worry. Four or more of restlessness, easy fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbances that are not explained by something else. Chronic but fluctuating and not situational. Excessive, persistent, and unreasonable
OCD
either obsessions or compulsions present on most days for a period of at least two weeks. Obsessions (thoughts, ideas, or images) and compulsions (acts) share the following features, all of which must be present: originate in the mind of the patient, are repetitive and unpleasant, individual tries to resist them unsuccessfully, and carrying out the obsessive thought or compulsive act is not in itself pleasurable. Obsessions and compulsions cause distress or interfere with the subject’s social or individual functioning, usually by wasting time
PTSD
: exposure to a stressful event or situation of exceptionally threatening or catastrophic nature which is likely to cause pervasive distress in almost anyone. Persistent remembering or reliving the stressor by intrusive flashbacks, vivid memories, recurring dreams, or by experiencing distress when exposed to circumstances resembling or associated with the stressor. Actual or preferred avoidance of circumstances resembling or associated with the stressor not present before exposure to the stressor. Symptoms: inability to recall some important aspects of the incident, sleep problems, irritability, outbursts of anger, difficulty concentrating, hyper-vigilance, exaggerated startle response
GAD pathophysiology
hypofunction of serotonergic neurons, hypofunction of GABAergic neurons (less inhibition of emotions), and hyperactivity of noradrenergic neurons arising from the locus coeruleus may produce excessive excitation in the brain areas implicated in GAD. During anxiety, the hippocampus-amygdala circuit amplifies the aversive events of anxiety disorder. Changes in dopamine and serotonin in the circuit impact anxiety disorders
Causes of anxiety
hyperthyroidism, caffeine, substance abuse, medication
Limbic system in anxiety
more active than normal (hyperactive amygdala)
Which nervous system component is important in anxiety?
sympathetic
Psychological symptoms of anxiety
worry, hypervigilance, depersonalisation/derealisation, irritability, and dread.
Physical symptoms of anxiety
light headedness, fatigue, sweaty, hot flashes, chills, twitching, blushing, nausea, chest pain, difficulty breathing, numb hands, weakness, trembling, muscle tension, muscle aches, frequent urination.
Behavioural symptoms of anxiety
avoidance
Primary treatment hyperthyroidism
Carbimazole
