Systems Pharmacology PED2006 Flashcards
1
Q
What are the 2 main parts of the GI tract
A
Lower and upper part
2
Q
Describe the upper tract of the GI tract
A
Mouth oesophagus stomach and duodenum
Aid in the ingestion and digestion offood
3
Q
Describe the lower tract of the GI tract
A
Small and large intensities
Digestion is completed and absorption of nutrients
4
Q
Describe the circular muscle of the gut
A
Between the inner and outer part of the gut
Circular structures that are able to narrow and restrict the lumen
5
Q
Describe the longitudinal muscles
A
Muscles arranged lengthwise
Constriction causes of intestines
6
Q
What are sphincters
A
Valves formed from circular muscle
Constriction determines the closure or natural opening of a passage
7
Q
What causes peristaltic waves
A
The circular and longitudinal muscles constrict and release in coordinated waves
8
Q
What factors are involved in peptic ulcer formation
A
Imbalance between aggressive and defensive factors
Breakdown of the mucosal barrier and excess acid secretion
9
Q
What are the 3 major pathways for regulating acid secretion
A
Neural stimulation via vagus nerve
Endocrine stimulation via gastric release
Paracrine stimulating by histamine release
10
Q
What are anatacids used for
A
Gastritis and duodenal ulcers
11
Q
Describe antacid composition
A
Basic compounds composed of a metal ion and a base
12
Q
What are the 3 principal secretagogues
A
Histamine
Acetylcholine
Gastrin
13
Q
How is the action of the secretagogues synergistic
A
A small dose of one potentiates the response bought about by a small dose of another
14
Q
What receptor does histamine activate in the parietal cells
A
H2 receptors
15
Q
Why do H2 receptor antagonist do not interfere with other receptors in different tissues
A
Highly selective
16
Q
What affect do H2 antagonists have on gastric secretion
A
Reduce gastric acid secretion
Decrease H+ concentration in gastric lumen
Decrease volume of acid secretion
17
Q
Why do H2 antagonists in the gut develop rapid tolerance
A
Due to elevation of cAMP in parietal cells
18
Q
how do the secretagogues increase acid within the stomach lumen
A
Activate by cAMP pathway (histamine)
Activate calcium sensitive pathways (muscarinic and gastrin receptors)
Triggers H+/K+ ATPase pump
Active transport of H+ into lumen
19
Q
How do proton pump inhibitors work
A
Selectively block the action of the H+/K+ ATPase pump
20
Q
How are PPIs specific
A
Requirement for an acidic condition in order to activate, trap and protonate the drug
21
Q
How is acid secretion affected by PPIs
A
Inhibition is permanent and is only resumed after the insertion of new molecules
22
Q
Why are PPIs better than H2 antagonists
A
More rapid in producing relief
Don’t develop tolerance as rapidly
No difference in inhibiting nocturnal vs day acid secretion
23
Q
What is the 2 cell hypothesis
A
Ach and gastrin stimulate mast cells to make more histamine
24
Q
What is the 1 cell hypothesis
A
Mast cells make more histamine
Lead to more proton pump stimulation
25
How its the frequency of stomach contractions controlled
Pacemaker cells in the fundus region
Critical in setting a slow depolarisation of the tissue to start contraction
26
How is the force of stomach contraction controlled
Increases vagal afferent activity to create stronger muscle contraction
Decreased by adrenergic activity
27
How does gastrin affect contraction of the stomach
Increases the force of contraction
Also increases the volume of HCL
28
Describe receptive relaxation
When the stretch receptors in the stomach turn off the afferent vagal nerve
Slows down smooth muscle contraction
Allows food to enter the large intestine
29
What is emesis
Forceful evacuation of stomach contents
30
What controls emesis
In the medulla:
Vomiting centre and chemoreceptor trigger zone (CTZ)
31
Why are alkaloids not the standard procedure to vomit when something toxic has been ingested
Patients can inhale the vomit as the sphincter that closes of the lungs doesn’t shut
32
What are H1 receptor antagonists effective in treating
Ocular issues e.g motion sickness
Not centrally active agents as they act on vestibular nuclei
33
Whats a side effect to H1 antagonists
Cause drowsiness and sedation
Helps with motion sickness and they don’t register the ocular disruption
34
Describe the use of muscarinic antagonists in treating emesis
Potential to interact w other systems
No CNS effects
Anti cholinergic affects e.g dry mouth, blurred vision and slight sedation
35
When are D2 receptor antagonist used to treat emesis
Severe forms of emesis
Given to only those who’s emesis is caused by the CTZ
Therefore CNS side effects
36
When are 5-HT3 antagonists used to treat emesis
Very severe forms of sickness
37
What is the mechanism of opiates in anti-diarrhoeals
Increase activity of receptors
Hyperpolarisation = inhibition of ACH release
No stimulation and contractility
Reduced bowel motility
38
What are the cons of using opiates in treatments
Can be misused and are a class of drug where you have to take more each time to be bale to stimulate the receptor the next time
39
How can the abuse potential of opiates be reduced in anti-diarrhoeals
The use of synthetic analogues e.g codeine
Less likely to cause dependent and no CNS effects
Use atropine to discourage base to make the patient feel queasy
40
Describe bulk forming laxatives
Contain undigestable cellulose components
Therefore retain fluid and increase fecal bulk
Stimulate stretch receptors = peristalsis
41
How do osmotic laxatives work
Salt present in gut lumen
Osmosis sucks in water into fecal matter
Softer bulkier stool
42
How do stimulant laxatives work
Stimulate the intramural plexus i.e neuronal firing
43
What is the downfall of using stimulant laxatives
Degree of colonic atrophy over time
If nervous system stimulated too often it can’t stimulate on its own
44
How doe fecal softners work
Coats the stool in non ionic surfactant
Reduces surface tension of stol
Allows the penetration of fluid in the stool
45
Describe dopamine
Inhibitory neurotransmitter
2 dopamine receptors: D1 and D2
46
Describe noradrenaline
Endogenous catecholamine
Excitatory: A1 and B1
Inhibitory: A2 and B2
47
Describe 5-HT
Strong inhibitory action in most CNS areas
48
What are benzodiazepines
Widely used anxiolytics
Relatively safe and effective
See for: anxiety and insomnia
49
What receptors do benzodiazepines target
GABA receptors
50
Describe the mechanism of action for benzodiazepines
Binding of GABA = opening of ion channel allowing Cl- through the pore
Influx of Cl- causes hyperpolarisation decreasing neurotransmission
BZs increase frequency of channel opening
51
Describe barbiturates
Used to sedate patients or to induce and maintain sleep
Replaced by benzodiazepines
52
Why are barbiturates controlled substances
Induce tolerance and physical dependence
Associated with very severe withdrawal symptoms
53
What is the mechanism of action for barbiturates
Enhances GABAergic transmission
Prolongs to duration of pore channel opening
Decreases neuronal activity
54
Describe SSRIs
Group of antidepressants that inhibit serotonin reuptake
55
What are SNRIs
Antidepressants that inhibit NA and serotonin uptake
56
What are TCAs
Antidepressants that block NA and serotonin reuptake into the presynaptic neurone
57
What is the mechanism of action for TCAs
Inhibit neurotransmitter reuptake
Blocking of receptors
58
What are MAOIs
Antidepressants that ir/reversibly inactivate the MAO enzyme
Permits neurotransmitters to accumulate within the presynaptic neurone
59
What are the 2 types of depression
Unipolar
Bipolar
60
Describe unipolar depression
Depression with no evidence for genetic cause
Older at first occurrence in response to distressing circumstances
61
Describe bipolar depression
Depression and mania
Evidence for genetic cause
Biochemical disorder
Apathetic and inert
62
What is the monoamine hypothesis for depression
That it is a result of under activity of monoamines
Especially 5-HT
63
What is the evidence for the monoamine theory
Antidepressants such as TXA and MAOI facilities monoaminergic transmission
Urinalysis and CSF concs of MOPEG is reduced in depressed patients
64
What is the evidence against monoamine theory
Amphetamine and cocaine has no affect in depressed patients despite causing a release of NA and inhibits its re-uptake
65
What is a theory for the 2-3 week delay in effectiveness
Quick increase in [5-HT] which inhibits 5-HT firing
Autoreceptors become desensitised after exposure
66
What are the advantages of SSRIs over TCA and MAOI
Lack of anticholinergic and cardiovascular side effects
No weight gain
Low acute toxicity
No food reaction
67
What are the symptoms of schizophrenia
Hallucinations/delusions
Blurred emotions/ lack of feeling
Loss of motivation
Social withdrawal
68
Describe the dopamine hypothesis of schizophrenia for positive symptoms
Too much dopamine in the subcortical and limbic regions of the brain may cause positive schizophrenic symptoms
69
Describe the dopamine hypothesis of schizophrenia for negative symptoms
Negative symptoms are associated with less dopamine in the prefrontal cortex
70
What is a evidence for the dopamine theory of schizophrenia
Amphetamines that release of DA produce a syndrome that mimics the +tive symptoms of schizophrenia
Abnormally high DA content in post morgen amygdala
71
What is the serotonin hypothesis for schizophrenia
5-HT dysfunction is involved in the pathophysiology of the disease
72
What are the 3 types of phenothiazines derivatives
Aliphatics
Piperazines
Piperidines
73
What is the role of phenothiazines
First generation antipsychotic mediations
Used in the treatment of schizophrenia, bipolar disorders and other psychotic disorders
74
What os the mechanism of action for neuroleptics
Inhibit dopaminergic neurotransmission
Antipsychotic effects due to blockade of D2 receptors
75
What are the limitation of conventional antipsychotics
1/3 of patients fail to respons
Limited efficacy against negative and affective symptoms
High proportion of relapse
76
Name a few atypical antipsychotics
MARTA (multi acting receptor targeted agents)
SDA (serotonin-dopamine antagonists)
Selective D2/D3 antagonists
77
What is excitotoxicity
Release of excitatory neurotransmitters that can damage nerve cells e.g glutamate
78
How does excitotoxicity happen
When NMDA and AMPA receptors are over activated
Allows high level of Ca2+ to enter the cell
Activates proteases
Impaired mitochondrial function
Produces free radials
79
What diseased could excitotoxicity be involved in
Stroke
Parkinson’s Disease
Alzheimer’s Disease
80
What is a defence mechanism against excitotoxicity
Mitochondrial energy metabolism
ATP production sustains membrane potential an Ca2+ uptake by ER
81
What is oxidative stress
When products of oxidative phosphorylation create free radicals
They damage certain cellular components
82
How does a mutation in a gene cause Parkinson’s
Causes excessive production of A-synuclein that aggregates to form Lewy bodies
Clearance of the plaques is reduced as well
83
Describe the effect on the brain due to Parkinson’s
Degeneration of the basal ganglia and the substantia nigra
Reduced amount of DA
Correlated with a loss of cell bodies of dopaminergic neurons
84
What are the different treatments of Parkinson’s
Drugs that replace dopamine
Drugs that mimic the action of dopamine
MAO-B inhibitors
Drugs that release dopamine
Acetylcholine antagonists
85
What is the need for pain with short latency
Warn the organism that it is in danger so it will alter the situation
86
What is the need for pain with long latency
Immobilise the organism so that recover from injury can occur
87
What is nociception
The process whereby noxious peripheral stimulation are transmitted to the CNS
88
What are polymodal nociceptors
Main peripheral sense organs that respond to noxious stimuli
Majority are non-myelinated C fibres
Respond to thermal, mechanical and chemical stimuli
89
What happens when there has been an injury to tissue
Release of chemicals that sensitive or activate receptors
Neurone release substance P which stimulates mast cells and blood vessels
Histamines released from mast cells and bradykinin released from blood vessels add to pain stimulus
90
What is an opioid
Any substance which produces morphine-like effects that are antagonised by naloxone
Not necessarily similar to morphine
91
What is an opiate
Chemical compounds that are extracted from natural plant manner
Has a close structural similarity to morphine
92
What are endogenous opioids
Opioid peptides and their receptors
Involved in central and peripheral nervous systems
Involved in pain modulation, reward and response to stress
93
What are the 4 major opioid peptides
Leucine enkephalin
Methionine enkephalin
Dynorphins A
Dynorphins B
94
What are the 3 types of opioid receptor that mediate the main pharmacological effects of opiates
Mu
Delta
Kappa
95
How do the opioid receptors mediate the effects of opiates
GCPR that inhibit ardently cyclase = inhibit cAMP production
Bind to g-protein on ion channels to promote K+ channel opening = inhibitory effects
Bind to Ca2+ channel to inhibit ca2+ channel opening = reduces neurotransmitter release
96
What opioid receptor subtype accounts for the dysphoric effects
Sigma
97
What opioid receptor are most analgesic opioids agonists for
Mu
98
What does tolerance to opioids mean
An increase in the dose needed to reduce a given pharmacological effect
99
Describe tolerance in opioids
Develops rapidly
Extends to most effects
Tolerance to one opioid doesn’t necessarily mean tolerance to another
100
What are some important used of opioids
Relieve of mild to moderate pain
Relief of severe pain
Anxiety relief
Cough suppression
Euphoriant in terminal illness
101
What is morphine metabolised to
Morphine 6-glucuronide = pharmacologically active
102
What is drug dependence
When the administration of drug is sought compulsively
Continuous use despite the adverse psychological or physical effects produced
103
What supports the dopaminergic pathway involved in drug addiction
Higher frequency mutation A1 of the D2 receptor gene in alcoholics and drug abusers
104
How does nicotine cause dependence
Causes excitation of mesolimbic pathway and increased DA release in nucleus accumbens
105
What is the CNS effect of smoking
Activation of nicotinic Ach receptors = channel opening = neuronal excitation
106
What are the peripheral effects of nicotine
Effects on autonomic ganglia and peripheral sensory receptors in the heart and lungs
107
Describe the tolerance to nicotine
Rapid tolerance to the periphery caused by a desensitisation of nicotinic Ach receptors due to an increase in nicotinic Ach receptors in the brain
108
What are pharmacological approaches to treatment of nicotine dependence
Nicotine replacement therapy
Champix
Clonidine
109
How can alcohol cause neurological syndromes
On chronic basis
Due to thiamine deficiency
Alcoholics absorb their energy from alcohol and not their diets
110
How is drinking alcohol effective against atheroma formation
When consumed at sensible levels it increases plasma HDL
111
How can ethanol consumption protect against ischaemic heart disease
Inhibits platelet aggregation if drank in moderation
Possible due to inhibiting arachidnonic formation
112
How is ethanol metabolised in the blood stream
Ethanol -> acetaldehyde -> acetic acid
113
What is the tissue between the air sacs of the lungs called
Interstitium
114
Describe the structure of type 1 epithelial cells
Flat cells with broad cytoplasmic flaps
Have a perinuclear zone
Basement membrane fusing the alveolar epithelium to capillary endothelium
115
What is the function of type 1 epithelial cells
Site of gas exchange
116
What is the function of type 2 epithelial cells
Manufacture and release surfactant which reduces the surface tension
117
Which type of epithelial cell is capable of regeneration
Type 2
118
Why can type 1 cells not regenerate
No mitotic potential
119
What is the major cellular host defence mechanism in the alveolar space
Macrophage
120
How can alveolar macrophages leave the lungs cells
Must migrate to the nearest bronchiole
Exit via:
- the mucocilary escalator
- interstitium
- blood vessels or lymph
121
How does fibroblasts cause interstitial fibrosis
Fibroblasts not normal intestinal components
After disease, large amounts of collagen and elastin laid down
122
How do fibroblasts contribute towards interstitial fibrosis
Not normal interstitial components
After disease insult, large amounts of collagen and elastin laid down
123
How is a diagnosis of a pulmonary disease and disorders confirmed
Integration of pulmonary history and physical examination
Chest roentgenograms
Pulmonary function and blood gas laboratories
124
Describe lung function in restrictive lung disease
FEV1 and FVC decrease to same extent
FEV1 is still 70-80% of FVC
Absolute values are lower
125
Describe lung function in airflow obstruction
FEV1 decreases
FVC may be reduced but to a lesser extent
FEV1 is therefore <65%of predicted FVC
126
What is the purpose of bronchodilators
Oppose bronchoconstriction
Reduces resistance to air flow in respiratory tract
127
What are the 5 major groups of bronchodilators
Short acting anticholinergic
Long acting cholinergic
Short acting B2 agonists
Long acting B2 agonists
Theophyllines
128
What is the mechanism of action for bronchodilators
Competitive antagonist of muscarinic Ach receptors
Block vagal control of smooth muscle tone
Reduce reflex bronchoconstriction in response to irritants
129
How do anticholinergic effect goblet cells
Reduce mucus secretions
130
Why are anticholinergics not the first choice in asthma
Only reduce vagally mediated bronchoconstriction
No effect on inflammatory mediated bronchoconstriction
131
What are the side effects on anticholinergic bronchodilators
Dry mouth
Urinary retention
Constipation
132
What is the mechanism of action for B2 agonists
Reduce intracellular calcium to reduce bronchoconstriction
133
What is the difference between short acting and long acting B2 agonists
Short: acute symptoms and act within minutes, effects last 4-5 hours
Long: requires regular administration and effect achieved after several doses, effects last up to 12hrs
134
What are the side effects of B2 agonists as bronchodilators
Headache
Anxiety
Nausea
Tremor
Nervousness
Tachycardia
135
Why are B2 agonists bronchodilators typically administered by inhalation
Reduce chance of side effects due to non specificity:
Tachycardia, fine tremor, nervous tension and headache
136
What are examples of short and long acting B2 agonist bronchodilators
Short: salbutamol
Long: salmeterol
137
Describe the mechanism of action for Theophyllines
Inhibit phosphodiesterase = prevents cAMP breakdown
Promotes lowering of [intracellular Ca2+]
Prevents bronchoconstriction
138
What is the cons of theophyllines
It is an irritant so must be injected slowly
Dose required is between 10-20mg/L nut adverse effects can occur at this range - severity increases with conc
139
What are the side effects of theophyllines
Peripheral: nausea, vomiting and diarrhoea
CNS: headache insomnia and irritability
140
What is the purpose of anti-inflammatories when treating respiratory disorders
Suppress inflammation
Reduce mucus secretion, oedema and reactivity
141
How are glucocorticoid steroids beneficial in treating respiratory disorders
Reduce formation, release and action of inflammatory mediators
Inhibits virtually all aspects of the inflammatory cascade
142
Describe the mechanism of action for glucocorticoid steroids
Bind intracellular steroid receptors
Translocation of active receptor to nucleus = gene modulation
Downregulation of pro-inflammatory cytokines
Production of anti-inflammatory proteins
143
Why are glucocorticoid steroids the most important anti-asthma drug
Prevents exacerbations
Prevents remodelling i.e preserves lung function
144
Name an oral glucocorticoid steroid used in asthma treatment
Prednisolone
145
Why are oral steroids avoided where possible
Risk of increased appetite/weight gain
Mood changes
Adrenal suppression
Osteoporosis
146
Name an inhaled glucocorticoid steroid used in asthma treatment
Beclomethasone
147
What are the side effects to inhaled steroids
Hoarseness and oral candidiasis
Short term effect on growth
148
What histamine receptor is used in treating asthma
H1
Affects smooth muscle contraction
149
Why are 2nd generation H1 antagonists better than 1st generation
Non-sedating
Do not cross the blood brain barrier
Inhibit smooth muscle contraction in respiratory tract
Reduce bronchorestrictor response to allergens and exercise
150
Why can 1st gen H1 antagonists cause receptor depression
Bind to central and peripheral receptros
Can cross the blood brain barrier
Therefore dose must be limited
151
Why do H1 antagonists produce anti-cholinergic effects
Potent muscarinic receptor antagonists
152
What are the typical anticholinergic side effects
Dry skin, constipation, tachycardia and urinary retention
153
What are the different mucoactive medications
Expectorants
Mucoregulators
Mucolytics
Mucokinetics
154
What are expectorants
Hypertonic saline that increase secretion volume and/or hydration of mucus
155
What are mucoregulators
Anticholinergic agents that decrease secretion volume
156
What are Mucolytics
N-acetylcysteine that break disulphide bonds linking mucin polymers
157
What are mucokinetics
Bronchodilators that improve cough clearance by increasing expiratory flow
158
What is a cough
Forced expiratory blast stimulated by the sensory nerves in the lining of the respiratory system
159
Describe the mechanism of a cough
Vocal cords close
Abdominals contract and intercostals brace
Generate positive pressure in thorax
Vocal chords open
Shear force clears airway
160
What is sputum
The coughed up mixture of saliva and mucus
161
Describe antitussives
Suppress cough w questionable efficacy
162
Give an example of a non-narcotic antitussive
Dextromethorpan
Limited evidence for effectiveness
163
Give an example of an effective antitussive
Codeine
Has intolerable side effects such as gastrointestinal discomfort and sedation
164
What are the 2 types of glands
Exocrine and endocrine
165
What is the master endocrine gland
Pituitary
166
What is the supreme commander gland
Hypothalamus
167
Describe the anatomy of the pituitary gland
Has 2 distinct lobes: posterior and anterior
168
What is the role of the posterior lobe in the pituitary gland
Stores and secretes hormones synthesised in hypothalamus
169
What is the role of the anterior lobe in the pituitary gland
Synthesise and secretes homes in response to hypothalamic regulation
170
Describe the structure of the posterior pituitary gland
Consists mainly of axons extending from the supraoptic and paraventricular nuclei of the hypothalamus
171
What is the role of the axons in the posterior pituitary gland
Release antidiuretic hormone and oxytocin into the capillaries of the hypophyseal circulation
172
How are the hormones in the posterior pituitary gland stored
Neurosecretory vesicles
173
Where is ADH synthesised
The supraoptic and paraventricular nuclei in the hypothalamus
174
Where is ADH transported to once synthesised in the hypothalamus
Posterior pituitary gland via the neurohypophysial capillaries
175
What factors control the release of ADH
Most influential: osmotic pressure and volume status
176
Describe the mechanism of action of ADH
ADH bins to V2 receptors on the basolateral of principal cells
Promotes conversion of ATP -> cAMP via adenylate cyclase
Activates protein kinase A
Promotes fusion of aquaporin 2 into the apical luminal membrane
177
What is the result of the aquaporin 2 fusing with the membrane
Enhances water permeability in distal convoluted and collecting duct resulting in concentrated urine
178
What part of the nephron is impermeable to H2O
Ascending limb loop of Henle, DCT and collecting duct
179
What is the purpose of anti diuretic hormone
Promotes membrane fusion on AQP2 concentrating urine
180
Name an ADH hormone level stimulants
Opioids, anti-depressants, nicotine and MDMA
181
Name an ADH hormone level depressant
Alcohol
182
Describe the symptoms of ‘Syndrome of inappropriate ADH secretion’ (SIADH)
Excessive ADH secretion
High urine osmolality
Increased total body water
Hyponatremia
Hypoosmotic blood plasma
Hypervolemia
183
What are a few causes of SIADH
Post-operative metabolic response to trauma and stress
Head trauma
Ectopic ADH production e.g tumours
Drugs
184
What is the treatment for SIADH
ADH V2 antagonist
Tolvaptan
185
Describe the symptoms of diabetes insipidus (DI)
Non functional ADH system
Excessive loss of water
Polyuria and polydipsia
Hypernatremia and hypotension
186
Describe neurogenic DI
Failure of ADH secretion
Lesion of hypothalamus or pituitary
187
Name a treatment for neurogenic DI
Synthetic ADH
Desmopressin
188
Describe nephrogenic DI
Failure of principal cells to respond to ADH
V2 receptor mutation
189
Name a treatment for nephrogenic DI
Restricted Na+ diet
190
Where are the receptors for oxytocin located
Amygdala, nucleus accumbens and ventral pallidum
191
How is autism and oxytocin potentially related
Lowered plasma oxytocin in children with ASD
Administration of oxytocin could potentially change brain patterns
192
What hormones does the anterior pituitary release
Thyroid stimulation
Adrenocorticotrophic
Follicle stimulating
Lutenising
Growth
Prolactin
193
Which hormones released by the anterior pituitary are direct acting
Growth and prolactin
194
How is the synthesis of the homes released by the anterior pituitary controlled
Hypothalamic releasing factors
195
How is T3 and T4 is released from the thyroid gland
Hypothalamus releases TSH releasing hormone
Stimulates the pituitary glands to release thyroid stimulating hormones
Stimulates the thyroid gland to release T3 and T4
196
What is the role of the thyroid gland
Makes T3 and T4 as well as calcitonin
197
What is the role of the colloid
Synthesise thyroglobulin
198
What is role of thyroglobulin
Precursor to thyroid hormone production
199
How is T3 and T4 produced
Thyroglobulin + iodide
Iodide comes from the bloodstream
200
How is the production of T3 and T4 regulated
TSH that is released feeds back to the pituitary stop making more
Negative feedback
201
Describe thyroxine (T4)
the most abundant hormone produced
202
Describe triiodothyronine (T3)
The most biologically active hormone
203
Describe the iodisation process
Incorporating iodine into tyrosine residues in thyroglobulin
Produces T1 and T2
204
Describe the coupling process
Tyrosine residues bind
T1+T2 = T3
T2+T2 = T4
205
What enzyme manages T3 and T4 levels
Thyroperoxidases
206
Where does T4 and T3 bind to on their receptor
Ligand binding domain
207
How does the DNA binding domain bind to DNA and begin transcription
Uses zinc fingers to bind DNA
Recruits RNA polymerase to transcribe new mRNA
208
How is the hinge region helpful
Helps orientate DNA so that ligand binding domain isn’t in the way
Protects DNA binding domain and the nuclear localisation sequence in the N terminal while in the cytoplasm
209
What is the sequence in the promoter region for thyroid hormones
Thyroid response element (TRE)
210
What is Hashemites disease
Autoimmune response that destroys thyroid cells
211
What is the treatment for Hashemites
Typically the administration of synthetic thyroid hormone
Don’t promote the body to make more - synthetic analogue instead
212
What thyroid hormone is use to treat Hashemites
First line: synthetic T4
Patients with significant basal metabolic stress are replaced w a synthetic analogue
213
Describe thryotoxicosis
Overactive thyroid
Higher metabolism rate
Increase in temperature
Tachycardia
214
What is Graves’ disease
Autoimmune disease which promotes thyroid secretion
215
What causes toxic modular goitre
Benign tumour or adenoma
216
What are the 3 types of changes associated with a toxic modular goitre
Hypoplastic change
Dysplasia change
Metastatic change
217
What is a hypoplastic change
When cellular function is maintain but an increased number of cells
218
What is a dysplasia change
Function of the cell changes
219
What is a metaplastic change
Swap the function for another function within that hormone gland
220
What is the first line treatment for hyperthyroidism
Thiourelynes
Block TPO so can’t make T1 and T2
221
What is another treatment for hyperthyroidism
Excess iodine which blocks the catalytic functions of TPO
Can be radioactive which destroys thyroid tissues
222
Describe the mechanism of steroid hormone receptor signalling
Steroids diffuse into cell
Bind to intracellular receptors -> translocate to nucleus
Activated receptors bind to response elements in DNA
Modulate txn of specific genes
.mRNA is translated to protein
Protein exerts its effects on the cell
223
Which part of the adrenal gland produced aldosterone/mineralcorticoids
Zona glomerulosa
224
Which part of the adrenal gland produces cortisol/glucocorticoids
Zona fasiculata
225
Which part of the adrenal gland produces androgens
Zona reticularis
226
Which part of the adrenal gland produces nor/adrenaline
Medulla
227
What is the effect of aldosterone on the distal tubule
Increases Na+ reabsorption into the blood
Increases K+ secretion into the urine
228
What receptors does aldosterone act upon
Mineralcorticoid receptors specific to kidney
229
How is aldosterone regulated directly
Stimulated by low plasma Na+ or high K+
Action on the Zona glomerulosa cells
230
How is aldosterone regulated indirectly
Stimulated by angiotensin II
231
How does angiotensin II stimulate water and salt retention
Increases aldosterone secretion from adrenal gland cortex
Increases ADH secretion from posterior pituitary gland
Increases H2O absorption from collecting duct
232
Name a primary cause of hyperaldosteronism
Conn’s syndrome
Adrenal hyperplasia/tumour of z.glomerulosa
233
Name a secondary case of hyperaldosterism
Chronic low blood pressure
Congestive heart failure = high renin - excess aldosterone
234
What are some symptoms of hypoaldosterism
Hypernatremia: thirst and oedema
Hypertension: headache, confusion and fatigue
Hypokalemia: arrhythmias, constipation and weakness
235
How is hyperaldosterism treated
MR antagonists: spironolactone
236
What is a primary cause of hypoaldosterism
Addisons disease
Autoimmune disorder causing the destruction of z.glomerulosa cells
237
What is a secondary cause of hypoaldosterism
Renin deficiency
Genetic predisposition
238
What are some of the symptoms of hypoaldosterism
Hyponatremia: confusion, fatigue, seizure and coma
Hypotension: dizziness and vascular collapse
Hyperkalemia: arrhythmias, constipation and weakness
239
How is hypoaldosterism treated
MR agonist: fludrocortisone
240
Why is aldosterone itself not used in treating hypoaldosterism
Has a short half life
241
What receptors does cortisol act upon
Glucocorticoid receptors
242
What effects does cortisol have on the liver
Increases gluconeogenesis and prevents glycogenisis
243
What effect does cortisol have on skeletal muscle
Increase in protein degradation
Increases amino acids for gluconeogenesis
244
What effect does cortisol have on adipose tissues
Increased lipolysis
Increased free fatty acids and glycerols for gluconeogenesis
245
What is the effect of cortisol on the bone
Matrix protein breakdown
Increases amino acids for gluconeogenesis
246
What is the effect of cortisol on the pancreas
Inhibits insulin release
Hyperglycaemia
247
What is cortisol effect on metabolism in general
Mobilisation of energy stores in times of stress
248
What are the therapeutic exploitations of glucocorticoids
Effective anti-inflammatories and immunosuppressive agents
249
Describe how cortisol boosts anti-inflammatory effects
Induces lipocortin which inhibits phospholipase A2
Decreases inflammatory mediators e.g prostaglandins
Decreases histamine release and proliferation/ repair of tissues
Decreases in thromboxane i.e increase in bruising
250
Describe how cortisol has immunosuppressive effects
GR complexes bind directly to p65 subunit of NF-kB preventing activation of inflammatory genes
GR promotes IkBa synthesis - prevents p50/65 nuclear translocation
Prevents NFkB activation of anti inflammatory genes
Suppresses immune cell activation/replication
251
What are the symptoms of Cushing syndrome
Lipolysis and fat redisposition - shoulder fat and moon face
Muscle protein degradation - weakness and skin transparency
Bone protein degradation - osteoporosis
Gluconeogenesis - diabetes mellitus
252
What is the primary cause of Cushing’s syndrome
Adrenal hyperplasia or tumour of z.fasciculata
253
What is a secondary cause for Cushings Syndrome
Chromic glucocorticoid therapy
254
What os a treatment for Cushing’s syndrome
11B-hydroxylase antagonist e.g metyrapone
Decreases the amount of cortisol available for secretion
255
How is cortisol regulated
HPA axis e.g stress circadian rhythm and feedback
256
Describe Type 1 diabetes
Insulin deficiency disorder
Autoimmune pathogenesis
Requires insulin therapy
257
Describe type 2 diabetes
Insulin insensitivity and inadequate compensatory insulin secretion
Metabolic pathogenesis i.e over eating
May progress to be insulin requiring
258
Describe biguanides
E.g Metformin
Inhibit liver gluconeogenesis - decreases glucose entry into the blood
Can cause GI upset e.g diarrhoea and lactic acidosis
259
Describe sulfonylureas
E.g gliclazide
Increases insulin supply
Bind to SU receptor to open K+ channels and depolarise islet B-cells to increase insulin secretion
Causes hypoglycaemia and modest weight gain
260
Describe PPAR-ay agonists
E.g pioglitazone
Improve insulin sensitivity
Enhances peripheral lipogenesis and decreases lipolysis = decrease in plasma fatty acid levels
Causes fluid retention and cardiac failure
Weight gain and peripheral fractures
261
Describe DPP-4 inhibitors
E.g sitagliptin
Increase insulin supply
Inhibits the degradation of natural GLP-1
Well tolerated
262
Describe GLP-1 receptor agonists
Increase insulin supply
Stimulates insulin secretion
Inhibits glucagon secretion
Inhibits eating
Causes CV events in high CV risk people
Nausea and vomiting
263
Describe SGLT2 inhibitors
Increase glucose loss from blood
Inhibit renal tubular resorption channel for glucose - causes urinary glucose loss
Urogenital infections and toe amputations
Reduce heart failure + protect kidneys
264
What therapies are used for type 2 diabetes
Glucose lowering therapies
265
What therapies are used for type 1 diabetes
Insulin therapy
266
What are the 3 types of available insulin
Meal time insulin
Basal insulin
Insulin mixes
267
Describe meal time insulin
Unmodidfed human insulin
Rapid acting insulin analogue
268
Describe basal insulin
NPH insulin - protea mine complex suspension
Long acting insulin analogues
269
Describe insulin mixes
Soluble + NPH insulin
Rapid acting and long acting analogues
270
What is the possible insulin regime for type 2 diabetes
1 daily insulin:
NPH insulin i.e long acing insulin analogues
271
What technical issues does insulin therapy have
Need to deliver SC
High variability between absorption profiles
Insulin given prospectively not regulated min by min
272
What personal issues are there with insulin therpay
Nuisance of delivery systems i.e repetitive and a reminder of the condition
Consequences of erratic insulin profiles i.e unwanted eating habits and hypoglycaemia
Better glucose control gives weight gain
273
What are the typical routes of administration for anti fungal agents
Topical for superficial infections
Systemic for both types on infections
274
Name 2 ergosterol inhibitors
Azores and polyenes
275
How do azoles work
Block 14-a demethylase cytochrome
Results in a lack of ergosterol in fungal membranes
Effects membrane associated functions in fungus
276
How do polyenes work
Bind to sterols in membrane forming an ion channelS
Gi her affinity for fungi sterols than mammalian sterols
277
Name an intracellular inhibitor
Mitotic inhibitors
278
How to mitotic inhibitors work
Inhibits cells division by interfering w spindle formation
279
What are the 3 main agents of echinocadins
Caspofungin
Anidulafungin
Micafungin
280
Describe how echinocadins work
Non competitive inhibitors of 1,3-b- and 1,6-b-D glucan synthase
Important in the synthesis of an essential component of fungal cell wall
Changes in conc lead to osmotic instability and cell lysis
281
Why do echinocadins not affect human cells
Human cells do not contain 1,3-b-glucan
282
How well do fungal develop resistance against polyenes and azoles
Polyenes: very rare
Azoles: common and major clinical concern
Other: rarely
283
What are the 2 sites of parasitic infection
Lumen of alimentary canal
Tissue of host
284
Why is it easier to treat GI tract parasitic infections
Worms are localised in a limited compartment
285
What agents are used in the treatment of worms
Interfere with metabolism
Cause paralysis rather than inhibitors of DNA synthesis
286
What are the 3 classes of drugs used to treat worms
Mebendazole
Praziquantal
Piperazine
287
How does mebendazole work to treat worms
Target microtubules of worm binding to b-tubulin
Prevents polymerisation
Prevents glucose uptake by worm
288
What type of worm infections does mebendazole treat
Variety of worms
Mainly roundworm and threadworm
289
How does praziquantal work to treat worm infections
Causes increased muscular activity in worms
Followed by contraction and spastic paralysis
290
What does high doses of praziquantal do to worms
Damage the tegument of the worm as well
Effects due to increased Ca2+ permeability
291
What types of worm infections does praziquantal treat
Schistosomes and tapeworms
292
What could cause the adverse affects from praziquantal
Toxic products from dead worms rather than drugs
293
How does piperazine work to treat worm infections
Reversible inhibits neuromuscular GABA transmission
Paralysed worm expelled alive by informal intestinal peristaltic activity
294
What type of worm infections does piperazine treat
Common roundworm and threadworm
295
Describe a virus replication cycle
Attachment to host cell
Un-coating of virus
Control of DNA, RNA and/or protein production
Production of viral subunits
Assembly of virions
Release of virions
296
What is viral latency
Recurrence of infection
297
What are a few reasons for viral latency
Non replicating cells
Joint replication processes
Limited immune detection
298
Describe how antiviral resistance occurs
Rapid retaliation rates w a high rate of spontaneous mutation
Prevent binding of drug to active sites of key enzymes
299
What are a few examples of herpesvirus
Simplex = cold sores
Varicella zoster = chicken pox
Epstein Barr = glandular fever
300
When does the herpesvirus become latent
When it infects the sensory ganglia
301
What is aciclovir
A synthetic guanosine analogue
302
What type of herpesvirus is aciclovir most effective against
Simplex - high specificity
Varicella zoster - less susceptible
Cytomegalovirus - small and reproducible
EBV - slightly sensitive
303
How does aciclovir become metabolic active
Utilises simplex virus specific thymidine kinase
304
Describe aciclovir antiviral action
It’s a DNA chain terminator
Inhibitor of viral DNA polymerase
305
How is the HIV virus transmitted
Congenitally, parenterally and by sexual contact
306
What are the 2 forms of HIV
HIV-1: responsible for human AIDS
HIV-2: less virulent forms of immune suppression
307
Describe the primary HIV infection
Asymptomatic
10-15% develop febrile illness
Acute retro viral syndrome
308
Describe clinical stage I of HIV infection
Asymptomatic phase
Some develop PGL
309
Describe clinical stage II of HIV infection
Progression to severe infections
Increase in opportunistic infections
Weight loss
310
Describe clinical stage III of HIV infection
Increased weight loss
Oral candidiasis and other infections
311
Describe clinical stage IV of HIV infection
HIV wasting syndrome
HIV encephalopathy
AIDS related complex (ARC)
312
What are the target cells for HIV
Cytotoxic/helper T lymphocytes CD8+ and CD4+
313
What receptor does HIV attach to
CD4 and CCR5 or CXCR4
314
Describe Enfuvirtide in treating HIV
Fusion inhibitors - inhibits fusion of cellular and viral membranes
Most effective as combination therapy
Emergence in resistance in outer envelope glycoprotein gp41
315
Describe maraviroc in treating HIV infections
CCR5 inhibitor - binds to CCR5 on CD4 cells preventing interaction of HIV-1 gp120
= no access into the cell
316
What are the downfalls of Maraviroc
Does not prevent HIV-1 entry into CXCR4-tropic or dual tropic cells
Should be used on treatment history and tropism assay results
317
Describe NRTI’s in treating HIV
Portent inhibitor of HIV replication
Active when phosphorylated intracellularly to its triphosphate
Inhibits viral reverse transcriptase
318
What are the downfalls in using NRTIS in treating HIV
Inhibits mammalian y and b DNA polymerases increasing risk of toxicity in man
Life long therapy
319
What are the indications and adverse effects to NRTIs
Indicated: patients w advanced HIV infection
Adverse effects: headache, nausea, anaemia, leukopenia and neutropenia
320
What is the problem w NRTIs
Big problem with monotherapy - resistance
Combination therapy more effective
321
What are NNRTIs
Structurally distinct from NRTIs
Bind to reverse transcriptase causing enzyme denaturation
322
Describe how Ritonovir works in HIV treatment
Protease inhibitors that target virus specifc protease enzyme that’s required for post translation processing
323
What are the downfalls for using protease inhibitors in HIV treatment
Drug-drug interaction problems
Resistance issues
324
What is the preferred drug treatment for HIV
Highly active anti-retro viral therapy (HAART)
NRTI (x2) + NNRTI (x1) or PI (x1/2)
325
Describe raltegravir as a HIV treatment
Integrase inhibitors
Inhibits integration of transcribed viral DNA into host cell chromosomes
326
When are integrase inhibitors used
As combination therapy for:
- patients w resistant strains of HIV
- patients w ongoing viral replication whilst receiving A.Vs
327
Describe inflammation
Protective response of vascularised tissues that brings the host defence in order to eliminate the offending agents
328
What are the 5R’s of the inflammatory response
Recognition of the offending agent
Recruitment of leukocytes
Removal of offending substance
Regulation of response
Repair of the damaged tissue
329
What are the 2 types of inflammation
Acute and chronic
330
Describe acute inflammation
Rapid onset
Short duration
Mainly neutrophils
Prominent characteristic response
331
What are the cardinal signs of acute inflammation
Redness
Heat
Swelling
Pain
Loss of function
332
What are the 3 major components of acute inflammation
1- dilation of small vessels
2- increased vascular permeability of the microvasculature
3- emigration of leukocytes
333
Describe chronic inflammation
Slow onset
Long duration
Monocytes/macrophages/lymphocytes
Less characteristic response
334
Define selective toxicity
The drug is harmful to the infective agent but not to the host
335
Define antibiotic
A medicine that inhibits the growth or destroys bacteria
336
Define the 2 types of antibiotics
Bacteriostatic: inhibit multiplication
Bactericidal: kill bacteria
337
What is the mechanism of action of penicillin
Beta-lac tam ring bind to DD-transpeptidase
Inhibits crosslinking
Prevent cell wall formation
338
What penicillins are used to treat only gram positive infections
Natural penicillins
339
What penicillins are used to treat only gram negative infections
Reverse spectrum penicillins
340
What penicillins are used to treat both gram positive and negative infections
Broad spectrum penicillin
Extend penicillins
341
What penicillins are used to treat only B-lactamase resistance infections
B-lactamase resistant penicillins
342
Describe cephalosporins
Beta-lactam broad spectrum antibiotics
Used to treat septicaemia, pneumonia and meningitis
343
What are the adverse effects of cephalosporins
Can cause nephrotoxicity and diarrhoea
344
Describe carbapenems
Broad spectrum antibiotics
Contain B-lactam ring
Treat lower respiratory tract infections and sepsis
345
Describe monobactams
Active against gram-negatives
B-lactam is peripheral not central
346
What are the major estrogens produced by the body
Estradiol, estrone and estriol
347
What does oestrogen drive
Follicular development
348
Describe how oestrogen and progesterone are released from the ovary
GnRH released into bloodstream and travels to anterior pituitary gland
Anterior pituitary releases FSH and LH
FSH and LH bin receptors on target cells in ovary and release oestrogen and progesterone
349
What does FSH stimulate the release of
Oestrogen
350
How are the levels of progesterone and oestrogen regulated
Negative feedback to the hypothalamic-pituitary-ovarian axis
Oestrogen inhibits FSH
Progesterone inhibits GnRH, FSH and LH
351
Describe the ovarian cycle
FSH is increasing due to low ovarian production
FSH aids follicular development
Follicles produce oestrogen
Positive feedback indicating the LH surge
LH surge induces ovulation
Remainder of ovualtory follicles are luteneised
Secretes progesterone and oestrogen
352
What happens after ovulation if theres no fertilisation
Corpus luteum regression
Progesterone and oestrogen levels drop
Endometrium can’t be maintained
Releases GRH, FSH and LH again
353
What happens after ovulation if there is fertilisation
Ovum secretes human chorionic gonadotropin (HCG)
Stimulates luteum to continue secreting progesterone
Maintains endometrium and pregnancy
Inhibits further secretion of GRH, FSH and LH
354
What is targeted by ER and PR agonists in contraceptives
GnRH, FSH and LH
Prevents development of ovarian follicles
Blocks ovulation by blocking FSH peak
Makes cervical mucus less suitable for sperm passage
355
What is targeted by PR antagonists in contraceptives
Inhibits LH
Thickens the mucus
Blocks ovualtion i.e LH surge
FSH peak can still occur
356
What are the side effects of sex hormone agonists
Anabolic effects - weight gain and water retention
Skin changes and mild nausea
Venous thromboembolic disease
Myocardial infarction and stroke depression
357
How are hormone antagonists used to treat cancer
Some tumours arise in hormone sensitive tissues and can be hormone dependent
Their growth may be inhibited by ER, PR and AR antagonist - agents that inhibit the synthesis of ER, PR or TR
358
How does tamoxifen work in treating cancer
Competitive inhibitor of ER and binds forming a dimer
Translocation to nucleus where it binds to DNA
Forms unstable complex and can’t recruit RNA polymerase
