Systemic pharmacology Flashcards
What is Haemostasis?
The arrest of blood loss from damaged blood vessels
How is haemostasis obtained endogenously?
A haemostatic plug is fomed involving adhesion and activation of platelets andd activation of clotting factors
What is thrombosis?
A pathological condition related to the formation of a haemostatic plug associated with arterial disease or stasis of the blood in the veins/atria of the heart
What is an embolus?
Portion of a thrombus that breaks away into the circulation
Where does an embolus from the veins commonly lodge?
In the lungs
Where does an embolus from the left heart commonly lodge?
Brain
What aspect related to blood flow is normally targeted in disease?
Therapy to promote haemostasis is rarely employed
Therapy of thromboembolic disease are extensively used due to the prevalence in the developing world.
Examples of drugs used to treat thromboembolic disease
Anticoagulants
Antiplatelets
Fibronolytic drugs
Example of procoagulant drug
Vitamin K
How does vitamin K increase coagulation?
Activates coagulation factors through y-carboxylation of glutamic acid residues
Coagulation factors targeted: II, VII, IX, X
What do anticoagulants target?
The activation of clotting factors
What do antiplatelets target?
Platelet adhesion, activation and aggregation
What do fibrinolytic agents target?
Activate plasminogen to the active enzyme plasmin
Plasmin degrades fibrin
What are the two forms of administering anticoagulants?
Injection - heparin
Oral - warfarin
Explain the mechanism of action of heparin
Accelerates the action of antithrombin II
Inactivates pro-coagulant factors
What form of heparin is more frequently administered
Low-molecular weight heparins
Due to their longer half-life
Advantages of injectable anticoagulants
Acts immediately upon intravenous administration
Acts after 1 hour following subcutaneous administration
Disadvantages of anticoagulants
Bleeding
Thrombocytopenia
Explain the mechanism of action of warfarin
Inhibits the reduction of vitamin K
Vitamin K is necessary to activate coagulation factors
How long does it take for the effects of warfarin to take place
Days
Examples of antiplatelet drugs
Aspirin
Clopidrogel
Dipyrimadole
GPIIb
Explain the mechanism of action of aspirin
Irreversibly inhibits cyclooxygenase
COX is an enzyme which forms TXA2 in platelets and PGI2 in endothelium
Why must the dose of aspirin be carefully controlled?
In platelets, COX successfully blocks TXA2 formation, promoting anticoagulation
In endothelial cells, PGI2 is useful in preventing coagulation as well
Therefore, a dose must be given which inhibits TXA2 formation in platelets whilst allowing endothelial cells to produce PGI2
What type of binding does aspirin make with platelets?
Irreversible
When does the effect of aspirin on TXA2 end?
Due to irreversible binding, the platelet cannot make more TXA2 once aspirin has carried out its effect
So platelet TXA2 is only restored when they are replaced
Explain the mechanism of action of Clopidogrel
Inhibits ADP-induced aggregation in platelet cells
How are fibrinolytic drugs administered?
Intravenously
Which anticoagulant drug is used for long-term therapy?
Warfarin
Heparin and LMWH - short term administration
When are drugs inhibiting thromoemboli given?
Myocardial infarction
Unstable angina
Coronary surgery
What are the main disorders of the respiratory system?
Asthma
Chronic obstructive pulmonary disease
Which NT-receptor interactions commonly cause constriction of the airway smooth muscle?
Upper airways = ACh acting on M3 receptors
Lower airways = NANC
How can lower airway smooth muscle be relaxed?
Inhibitory NANC transmitters
Innervation of blood vessel smooth muscle
Sympathetic innervation only
Relaxed mainly by circulating adrenaline
What stimulates mucus secretions from glands?
Parasympathetic system
Inflammatory mediators
Chemical and physical stimuli
What inhibits mucus secretions from glands?
Sympathetic system
Underlying physiological mechanisms of asthma
Reversible airway obstruction caused by inflammatory reactions
Causes bronchoconstriction and mucus secretion
Occurs in response to stimuli that are not noxious
Symptoms of an asthma patient
Difficulty breathing out
Wheezing
Coughing
Risk factors for development of asthma
Genes
Allergens
Viral infections
Pollutants
What are the two phases of asthma?
Immediate - release of spasmogens (histamine) and chemotaxins
Delayed - influx and activation of inflammatory cells which release further mediators
What reverses the immediate phase of an asthma attack?
B2-adrenoreceptor agonists
Xanthines
What reverses the delayed phase of an asthma attack?
Glucocorticoids
What is the aim of the drugs targeting the immediate phase of asthma attacks?
Reduce the bronchoconstriction
What is the aim of the drugs targeting the delayed phase of asthma attacks?
Reduce the bronchoconstriction an
Reducing the bronchial inflammation
Reducing the mucus concentration/secretion
Precipitating factors of an asthma attack
Allergens
Respiratory viral infections
Air pollutants
Exercise
Two types of drugs used in the treatment of asthma
Bronchodilators
Anti-inflammatory agents
Difference between first-and second-line drugs
First-line drugs are the most recommended drug
Second-line drugs are good alternatives
Examples of first-line bronchodilators
B2-adrenoceptor agonists
Examples of second-line bronchodilators
Xanthine compounds
Muscarinic receptor antagonists
Cysteinyl leukotriene receptor antagonists
Describe the mechanism of action of B2-adrenoceptor agonists
Physiological antagonist to spasmogenic mediators
Can be short-acting (emergency) or long-acting (preventative)
Examples of B- adrenoceptor agonist drugs
Salbutamol
Salmeterol
Describe the mechanism of action of xanthine compounds
Inhibits PDE (breaks down cAMP into AMP)
Increases cAMP and cGMP concentrations
Leads to smooth muscle relaxation
Why is xanthine a second line drug in the treatment of asthma?
Narrow therapeutic index
How do muscarinic receptor antagonists work?
Binds to muscarinic receptor subtypes and decreases acetylcholine mediated spasm
Reduces mucus secretion
Increases ciliary clearance of bronchial secretion
Example of a cysteinyl leukotriene receptor antagonist
Montelukast
Blocks leukotrienes from binding to their receptor
Inhibits the inflammatory effect of leukotrienes
Common anti-inflammatory agents given to asthma patients
Glucocorticoids
Cromoglycate
What phase of an asthma attack do glucocorticoids target?
The inflammatory component of the delayed phase
Explain the mechanism of action of glucocorticoids
Reduce activation of inflammatory cells
Reduce the release of cytokines
Through blocking the transcription of inflammatory mediators
Explain the mechanism of action of sodium cromoglycate
Known to block mediator release from mast cells
Reducing IgE release
But unknown effect in asthma phase
Given prophylactically by inhalation of an aerosol or powder
What is COPD?
Common condition caused by chronic inflammation of the airways
Gives rise to cough
At first intermittent, then chronic
What is the treatment of COPD?
Palliative
Muscarinic receptor antagonists
What is a cough normally caused by?
Irritation in the bronchi and bronchioles
To which subjects are antitussive drugs like codeine not recommended?
Asthma patients
Chronic bronchitis - can cause sputum retention
What are the main functions of the kindey?
Excretion of waste products
Salt and water regulation
Maintain an acid-base balance
What is the main active transport mechanism in the kidney tubule?
Na+/K+ ATPase
Describe the process that occurs within the kidney during filtration
- In the renal corpuscule (glomerulus + Bowman’s capsule) ultrafiltration causes a solution without cells, proteins and large molecules to enter the Bowman’s Space
- The ultrafiltrate passes down to the PCT, loop of Henle and DCT, where reabsorption takes place
- During reabsorption, solutes and water are removed from the tubular fluid and transported into the blood
- Most water is reabsorbed in the collecting tube
What is reabsorbed in the PCT?
50% salt and 50% water
What is reabsorbed in the PST?
20 % salt and 20% water
What is reabsorbed in the descending loop of Henle?
5% water
What is reabsorbed in the thick ascending loop of Henle?
20% sodium
What is reabsorbed in the DCT?
5% sodium
What is reabsorbed in the collecting duct?
4% salt
19% water
What is the reabsorption like in the collecting duct?
Highly regulated
What is the main factor providing the osmotic gradient for AHD-mediated water reabsorption?
The hypertonicity of the interstitium produced by the reabsorption of salt in the thick ascending loop
How do diuretics work?
Block channels reabsorbing ions like sodium
Increasing the sodium concentration in the tubules
And therefore increasing the water excretion
Water loss is secondary to salt loss
Pharmacological actions of diuretics
Increase the flow of urine
Loss of K+ and H+,
Decreased excretion of uric acid (high concentration of acid in tubule)
Moderate vasodilator effects
Differences in pharmacological action between loop and thiazide diuretics
Loop diuretics - Increased excretion of Ca2+ and Mg2+
Thaizide duiretics - decreased excretion of Ca2+ and increased excretion of Mg2+
Unwanted effects of diuretics
Hypokalaemia due to K+ loss
Metabolic alkalosis due to H+ loss
Increased plasma uric acid
Examples of loop diuretics
Furosemide
Bendolumethiazide
What are potassium-sparing diuretics?
Act in the collecting tubules
Block the ENAC channels, and therefore indirectly the ROMK channels
Less potassium is secreted into the urine, and more is pumped back into the blood
Mechanisms of action include:
- Inhibiting aldosterone’s Na+-retaining, K+-excreting effect (reduce gene expression of eNAC)
- Inhibiting Na+ reabsoprtion and reducing K+ excretion
Unwanted effects of potassium-sparing diuretics
Hyperkalaemia
Acidosis
Mechanism of action of osmotic diuretics
Inert compounds pass into the tubules in the glomerulus, increasing the osmotic pressure of the filtrate
Overall effect = increase water excretion
Which part of the nephron do osmotic duiretics primarily work on?
Proximal tubule
What are the principle unwanted effects of osmotic diuretics?
Temporary expansion of the extracellular fluid compartment
Hyponatraemia
What are the main physiological aspects of the GI tract?
Gastric acid secretion
Motility of the bowel
Excretion of the bowel contents
What are the main pathophysiological aspects of the GI tract?
Peptic ulcers
Vomiting
Disturbances of excretion
Gallstones
What leads to peptic ulcer formation?
Alteration of the balance between mucosal-damaging processes and mucosal-protective mechanisms
Important factors which increase mucosal damage
H. Pylori
Non-steroidal inflammatory drugs
3 main ways to treat peptic ulcers
Reduce acid secretion
H. pylori infection treatment
Protecting the gastric mucosa
Pharmacological methods of reducing acid secretion
Histamine antagonists or proton pump inhibitors
Selective muscarinic antagonists
Antacids
PGE2 analogues
Why are histamine antagonists and proton pump inhibitors effective at treating peptic ulcers?
Histamine binds to H2 receptors on parietal cells, inducing gastric acid secretion through activating the respective ion pumps
Proton pumps are essential for the movement of H+ out of the parietal cells using K+/H+ antiporter, so it can combine with Cl- and form gastric acid
Treatment of H. pylori infection
Combination of proton pump inhibitor/ H2 antagonist with 2 antibiotics
Amoxicillin and metronidazole
Pharmacological approach to protecting the gastric mucosa
Give compounds like Sucralfate which form complex gels on the mucosa and have a protective effect
Unwanted effects of H2 antagonists
Potentiate the actions of many drugs
Unwanted effects of drugs protecting the gastric mucosa
Reduce absorption of other drugs
What stimulates acid secretion in the stomach?
Histamine receptors acting through Gs receptors
Acetylcholine acting on muscarinic receptors
Gastrin acting on gastrin receptors
What are the two ways in which ACh and gastrin cause gastric acid secretion?
Directly through increasing the calcium concentration in parietal cells
Indirectly via the stimulation of histamine release by mast cells
Which pathway inhibits HCl secretion?
Prostaglandin receptor
Underlying physiology of vomiting
Complex response
Involves the coordinated activity of the involuntary muscles of the GI tract and the somatic respiratory and abdominal muscles
Which part of the brain control vomiting?
Two centers in the medulla:
- the vomiting center
- the chemoreceptor trigger zone (CTZ)
What stimuli activate the CTZ?
Disorientating motion
Toxins/drugs
Stimuli from pharynx/stomach
What stimuli activate the vomiting center?
Repulsive experiences
Stimuli from pharynx/stomach
What is the importance of the vestibular nuclei?
Relay the stimulus of disorientation to the CTZ
Anti-emetics targeting the vestibular nuclei
H1 antagonists
Muscarinic antagonists
Anti-emetics directly targetting the CTZ
D2 antagonists
5HT3 antagonists
Cannabinoids
Anti-emetics targeting the local gut stimuli
H1 antagonists
Muscarinic antagonists
What is the role of Neurokinin?
Control chemotherapy emesis
What is the difficulty of oral administration of emetics?
Vomiting of the drugs reduces their efficacy
What are the unwanted effects of anti-emetics?
Anti-histamines = drowsiness
Anti-muscarinics = dry mouth, blurry vision
D2 antagonists = extrapyramidal effects on movement, increased release of prolactin
GI imbalances
Clinical uses of antiemetic drugs
5HT3 antagonists = chemotherapy
Muscarinic antagonists = motion sickness
Cannabinoids = emesis caused by cytotoxic drugs
What, apart from emesis and peptic ulcers, are other common GI conditions?
Diarrhoea
Constipation
Gallstone
Treatment for diarrhoea
If caused by infections = antibiotics
Replacement of fluid and electrolytes
Opiates and muscarinic antagonists = reduce motility
Treatment for constipation
Bulk laxatives = not digested, stimulate peristalsis through increasing the mass of material in the gut lumen
Osmotic purgatives = retain water and increase peristalsis
Stimulate purgatives = increase mucosal secretion and stimulate enteric nerves
Treatment for gallstones
Non-calcified cholesterol gallstones can be dissolved by bile acid
What are the two main thyroid hormones?
T3
T4
Compare T3 and T4
T3 has a faster turnover rate
T3 is found intracellularly, T4 is found in the circulation
T3 is found in target organs, T4 is bound to thyroxine-binding globulin
Functions of thyroid hormone
Important for
- growth and development
- energy metabolism
What is the functional unit of the thyroid?
The follicle
Contains a single layer of epithelial cells around the follicle unit
Containing a thick colloid composed of thyroglobulin
What is the action of TH in metabolism?
Increases basal metabolic rate through increasing oxygen consumption and increasing heat production
Modulates glucocorticoids, catecholamines, insulin and glucagon
= increasing metabolism
What is the action of TH in growth and development?
Potentiates growth hormones
Essential for maturation of the CNS and skeletal development
Describe the cellular action of TH
T4 converts to T3 which binds to receptors on DNA
When unbound, these receptors repress basal transcription
T3 activates transcription, resulting in mRNA and protein synthesis
Describe the release of TH
Stimulus (cold, trauma, stress) stimulates the hypothalamus to release thyrotrophin-releasing hormone
TRH activates the anterior pituitary to release thyrotrophin
Thyrotrophin acts on the thyroid to release T4 and T3
T4 and T3 inhibit the anterior pituitary through negative feedback, to prevent the release of T3 and T4
Symptoms of hyperthyroidism
Loss of weight
Increase in temperature
Sweating
Nervousness
Tremor
Tachycardia
Two common types of hyperthyroidism
Diffuse toxic goitre (Grave’s disease)
Toxic nodular goitre
Characteristic signs of Grave’s disease
Exophthalmos
Increased sensitivity to catecholamines
What is toxic nodular goitre?
A benign tumour
Types of hypothyroidism
Myxoedema
Cretinism
Hashimoto’s thyroiditis
Radioiodine therapy induced hypothyroidism
Signs of Myxoedema
Low metabolic rate
Slow speech
Mental impairment
What is cretinism?
Hypthyroidism in childhood
Manifestations include retardation in growth and mental deficiency
Features of simple non-toxic goitre
Hypothyroidism caused by deficiencies in iodine
Leads to a rise in thyrotrophic hormone
Increases the size of the gland
Hypothyroidism can occur
What are the main drugs used to treat hyperthyroidism?
Thioureylenes
Radioiodine
Iodine
Other miscellaneous drugs
Mechanism of action og Thioureylenes
Decrease the thyroid hormone output
Inhibit T4 to T3 breakdown or inhibit the oxidation of iodine
How long do Thioureylenes take to work?
Weeks
Due to the iodine stores
Unwanted effects of Thioureylenes
Rashes
Granulocytopenia
Headache
Nausea
Jaundice
Mechanism of action of Radioiodine
Taken up by the thyroid gland similarly to iodide ions
Incorporated into the thyroid
The b-rays the iodine emits causes destruction of the nearby thyroid cells
Unwanted effect of Radioiodine
Causes hypothyroidism
Will need replacement therapy with synthetic T4
Mechanism of action of iodine
Temporarily reduces TH secretion
How can other miscellaneous drugs be used to treat hyperthyroidism?
B-adrenoceptor antagonists decreases signs and symptoms like tachycardia, dysrhythmias, tremor and agitation
What drugs are used to treat hypothyroidism?
Levothyroixine
Liothyronine
Have same actions as the natural hormones
What are unwanted effects of Levothyroixine and Liothyronine?
Increase heart rate and output
Dysrhythmias
