Assignment 2
PART A - (Total 15 marks)
Cephalexin and Gentamicin
The mechanism of action of amoxicillin is focused on the prevention of the synthesis of the bacteria’s cell wall through the binding and inhibiting of the cell wall transpeptidases (Katzung, Masters, and Trevor, 2012). Specifically, it attaches to the penicillin-binding protein 1A found in the cell wall of bacteria. Then, the agent disintegrates the lactam ring to allow the acylation of the penicillin-sensitive transpeptidase C-terminal domain. The formation of the cross-link of the linear peptidoglycan strands is prevented by the inactivation of transpeptidases. Since the third and last stage of the synthesis of the bacteria’s cell wall has been prevented, cell lysis occur which is usually mediated by autolytic enzymes found on the bacteria’s cell wall (Drawz & Bonomo, 2010).
Similar to penicillins, cephalexin acts by preventing the synthesis of the bacteria’s cell wall through the attachment and inhibition of cell wall transpeptidases (Katzung, Masters, and Trevor, 2012). Specifically, it binds to the binding proteins located in the bacteria’s cell wall which can lead to the inhibition of the third and last stage of the synthesis of the bacterial cell wall. Then, cell lysis occur through the help of autolytic enzymes. Additionally, it was observed that cephalexin has the ability to interfere with an autolysin inhibitor (Faarup, 1975).
Trimethoprim is an antibacterial agent which is known to be an inhibitor of dihydrofolic acid reductase. The mentioned reductase is responsible for the conversion of dihydrofolic acid to tetrahydrofolic acid which is a step closer to the synthesis of purines to DNA (Katzung, Masters, and Trevor, 2012). The affinity of the trimethoprim for the dihydrofolate reductase of the bacteria is several times higher than the affinity for human dihydrofolate reductase (Brumfitt & Hamilton-Miller, 1993).
Gentamicin irreversibly attaches to the 30S-subunit proteins and 16S rRNA of the bacteria. Binding to these sites can interfere with the decoding site which is located in nucleotide 1400 in the 16S rRNA of the 30S sub-unit. The region involved in the binding process is the one which interacts with the anticodon of tRNA thus, resulting to the misreading of the mRNA. As a result, the polysomes are broken up into non-functional monosomes (Scherr, 1975).
Drugs act as haptens and covalently bind to serum or cell-bound proteins. The drug becomes immunogenic resulting to the stimulation of the antidrug antibody production. Haptens also have the ability to directly attach to the MHC II molecule which allows direct activation of T-cells. Penicillin is an example of a prohapten which becomes hapten after metabolism. The main degradation product of penicillin is benzylpenicilloic acid which has been observed to form benzylpenicilloyl by combining with other tissue proteins. Benzylpenicilloyl is considered as a major antigenic determinant (Delves, 2014).
Given the fact that Mr BT is allergic to penicillins, is cephalexin therapy contraindicated here? (3 marks)
Cephalexin therapy is contraindicated especially if the penicillin allergy is severe. Since cephalexin, a cephalosporin, is relatively similar to penicillins, there is a high possibility that a cross-reactivity will occur (AUSG, 2005).
PART B: (Total 30 marks)
Describe the mechanism of action of the corticosteroids and indicate the adverse effects that require monitoring during treatment with these drugs. (6 marks)
Corticosteroids are commonly mediated by different glucocorticoid receptors which allow interaction with the promoters of certain target genes. Without the presence of hormonal ligands, the glucocorticoid receptors exist as cytoplasmic in the heat-shock proteins. Some of the important molecules of these receptors are two molecules hsp90. The free hormones are able to enter the cell and bind to the receptor. The binding results to conformational changes which allow the dissociation of the heat-shock proteins. The complex formed by the ligand and the receptor interacts with the DNA and nuclear proteins. Then, the same complex binds to the glucocorticoid receptor elements found in the responsive genes’ promoters. Additionally, the ligand-bound receptor also allows formation of complexes and influences the functions of other transcription factors (Katzung, Masters, and Trevor, 2012).
During treatment, one of the major adverse effect of corticosteroids that need monitoring is immunosuppression. The reduced function of the immune system needs close monitoring because the patient has a high risk of acquiring serious infections. Another adverse reaction is the delayed wound healing during treatment. Since the immune system is suppressed, the inflammation processes of the body are also affected thus, leading to a delay in the healing of the patient’s wound (Ritter, et al., 2008).
a. Dexamethasone - (Steroids and steroid derivatives) Hydroxysteroids
b. vincristine – (Alkaloids and derivatives) Vinca Alkaloid
c. L-asparaginase – (Carboxylic acids and derivatives) Peptides
d. daunorubicin – (Phenylpropanoids and polyketides) Anthracyclines
e. methotrexate – (Pteridines and derivatives) Folic Acids
f. cytarabine – (Pyrimidine nucleosides) Pyrimidine Nucleosides
g. filgrastim – (Carboxylic Acids and derivatives) Peptides
(Ritter, et al., 2008).
Describe the mechanism of action of each of the drug groups identified in question
Antibiotic Type Cytotoxic Agent (5 marks)
a. Hydroxysteroids- Unbound hydroxysteroids binds with glucocorticoid receptors found in the cytoplasm by crossing the cell membrane. A modification of transcription and protein synthesis occurs due to the binding of the complex with the DNA elements. Modification of transcription and synthesis of proteins lead to the leukocyte infiltration inhibition at the site of inflammation, humoral immune response suppression, and edema or scar tissue reduction (Ritter, et al., 2008).
b. Vinca Alkaloid - Their antitumor activity is brought about by its ability to inhibit mitosis at metaphase by interacting with tubulin. Additionally, Vinca Alkaloids may also interfere with the metabolism of amino acid, cyclic AMP, and glutathione, activity of calmodulin-dependent Ca2+ transport ATPase, cellular respiration, and even biosynthesis of nucleic acid and lipid (Katzung, Masters, and Trevor, 2012).
c. Peptides – Peptides are responsible for the conversion of amino acids. As an example, asparaginase is responsible for the conversion of asparagine to aspartic acid and ammonia. Aside from these, peptides also facilitate production of substances needed for general cellular metabolism (Katzung, Masters, and Trevor, 2012).
d. Anthracyclines – They have antimitotic and cytotoxic activity. One of the proposed mechanism of anthracyclines is the formation of complex with DNA through intercalating between base pairs. The formation and stability of the complex lead to the inhibition of the activity of topoisomerase II which results in the prevention of the ligation-religation reaction of the topoisomerase II (Ritter, et al., 2008).
e. Folic Acid – The anti-tumor activity of cytotoxic agents belonging to the family of folic acids is the result of their ability to inhibit folic acid reductase. This inhibition leads to DNA synthesis and cellular replication inhibition (Klareskog, et al., 2004).
f. Pyrimidine nucleosides – Responsible for the direct damage in the DNA. It exhibits specificity of cell phase such as cell killing of cells undergoing DNA synthesis and blocking of the progression of the DNA synthesis of cells from the G1-phase to S-phase. It has been observed that these actions are a result of the inhibition of DNA polymerase (Ritter, et al., 2008).
What are the common immediate and delayed adverse reactions associated with cytotoxic drugs? (4 marks)
Immediate adverse reactions – Some reactions include urticarial, angioedema, bronchospasm, pruritus, vomiting, nausea, anaphylaxis, and diarrhea (Riedl & Casillas, 2003)
Delayed adverse reactions – Some reactions include allergic contact dermatitis and maculopapular drug rash (Riedl & Casillas, 2003)
Describe the clinical management of a client with increased susceptibility to infection. (5 marks)
The clinical management of an immunocompromised patient is focused on the management of the deficiencies experienced by the patient. In cases where hypogammaglobulinemia exist, the condition is treated with immunoglobulin replacement and are monitored by primary care physicians. On the other hand, secondary immunodeficiency care is more focused on providing careful monitoring in case infectious episodes may occur. Granulocyte transfusions may also be considered especially when it comes to anticipated transient neutropenia (Steele, 2012).
Doxycycline belongs to the group of tetracycline and it is considered to be a bacteriostatic agent. The lipophilic characteristic of doxycycline allow it to pass through the bacteria’s lipid bilayer and reversibly bind to the 30S and 50S ribosomal subunits. The binding prevents the aminoacyl tRNA from binding to the mRNA. This results to the inhibition of the bacterial protein synthesis (Ritter, et al., 2008).
Define the term ‘antimicrobial drug spectrum of activity’. What is the spectrum of activity of doxycycline? Why choose a drug with this spectrum of activity? (2 marks)
Antimicrobial drug spectrum of activity refers to the range of activity of drugs as an antibiotic. Drugs which are effective against gram positive and gram negative bacteria is considered as a broad-spectrum antibiotic. The spectrum of activity of doxycycline is broad. It is beneficial to use a drug with this spectrum of activity because it can kill both gram positive and gram negative bacteria (Scholar & Pratt, 2000).
PART C - (Total 35 marks)
What is the rationale for the use of fibrinolytic drugs in acute myocardial infarction (AMI)? Are there any constraints regarding the timing of administration of these drugs in AMI? (4 marks)
Fibrinolytic drugs are used during acute myocardial infarction because of its ability to dissolve blood clots through the activation of plasminogen. The timing of administration is important because every delay in the administration if these drugs lead to the reduced effect of therapy and increased mortality. Ideally, fibrinolytic drugs should be given within the first 2 hours (Aylward, 1996).
Compare and contrast the mechanisms of action of the fibrinolytic drugs streptokinase and aspirin. (3 marks)
Streptokinase is a fibrinolytic drug which combines with the proactivator plasminogen to activate the plasmin. Plasmin is responsible for the dissolution of the thrombi and thromboemboli. On the other hand, aspirin acts as an antithrombic agent which causes inhibition of the aggregation, shape change, and degranulation of the platelets thus, leading to prolonged bleeding time. Aspirin is responsible for the inhibition of thromboxane A2 synthesis through the irreversible acetylation of cyclooxygenase (Katzung, Masters, and Trevor, 2012).
What adverse reactions should be monitored during and after fibrinolytic drug therapy? (3 marks)
The adverse reactions that should be monitored include bleeding complications which can be associated with the fibrogenolysis and lysis of hemostatic plugs. Most of the time, the bleeding is monitored in the catheterization site. Aside from these, gastrointestinal and cerebral hemorrhages may also occur (Klabunde, 2007).
Describe the mechanism of action of the antidysrhythmic agent amiodarone.
Amiodarone acts by prolonging the duration and refractory period of the myocardial cell-action potential and by acting as a noncompetitive a- and b-adrenergic inhibitor. Based on the Vaughan Williams antiarrhythmic drug class, amiodarone belongs to Class III (Klabunde, 2010).
Compare and contrast the actions of heparin and streptokinase (3 marks)
Heparin acts by reversibly binding to antithrombin III which inactivates factors IIa and Xa. The complex formed by the binding of heparin to antithrombin III can also inactivate other factors such as factors IX, XI, XII, and plasmin. Heparin mainly acts by the acceleration of the neutralization rate of activated coagulation factors. Heparin is not considered as a thrombolytic or fibrinolytic because it is only responsible for the prevention of the progression of existing clots. On the other hand, streptokinase acts by binding with plasminogen which activates plasmin. Plasmin is responsible for the degradation of the fibrin clots, fibrinogen, and other plasma proteins (Katzung, Masters, and Trevor, 2012).
Heart failure occurs when the heart is no longer capable to provide the required cardiac output needed by the body. The reduction of the cardiac output leads to myocardial injury which will also result to a cascade of events. Derangements of the hemodynamic and neurohormonal processes are some of these events which lead to the provocation of the activation of different neuroendocrine systems. Increase in the secretion of epinephrine and norepinephrine causes vasoconstriction which allows increase in the afterload of calcium. The increased entry of calcium in the myocytes impairs the myocardial relaxation and strengthens the contractility of the myocardium. Overload of calcium can lead to the occurrence of arrhythmias which can eventually result to death. Increase in the afterload of calcium can lead to the impairment of the myocardial lusitropy thus contributing to the further decrease of cardiac output. Increase energy expenditure of the heart leads to cell death thus, contributing to the reduction of cardiac output and heart failure (Dumitru, Baker, & Ooi, (2016).
Describe the mechanism of action of ACE inhibitors and indicate why they are a drug of choice in heart failure (4 marks)
ACE inhibitors function to prevent the formation of angiotensin II by competing with the activity of ACE. Angiotensin II is an octapeptide which functions as a vasoconstrictor, aldosterone release promoter, and sympathetic activity facilitator. The inhibition of ACE results in reduced blood pressure due to vasodilation. There are drugs of choice for heart failure because there are different drugs specific for a particular symptom (American Heart Association, 2015).
Pulmonary oedema is caused by alterations in fluid distribution between pulmonary blood vessels and the lung tissue. Using fluid dynamics and changes in fluid pressure, explain the link between heart failure and pulmonary oedema. (3 marks)
Pulmonary edema results when the heart is unable to pump blood efficiently, thus, leading to the backflow of blood to the veins. Increased pressure in the veins due to the backflow of blood will push the fluid towards the air spaces of the lungs. The fluid affects the normal movement of oxygen in the lungs resulting to shortness of breath (Massie, 2011)
Compare and contrast the actions of the loop and thiazide diuretics (4 marks)
Loop diuretic - binds to the carrier protein to reduce NaCl reabsorption which decrease hypertonicity of the interstitium and reduces water reabsorption (Wittner, et al., 1991).
Thiazide diuretic – inhibits the reabsorption of sodium and chloride in the kidney’s distal tubule. This results to increased excretion of sodium and water (Collard and Johnson, 2001)
At what stages do the diuretics and the peripheral vasodilators interrupt the pathophysiology of heart failure? (3 marks)
Diuretics- Stage C and D
Peripheral Vasodilators- Stage A, B, C, and D
(Beckerman, 2015)
PART D - (Total 10 marks)
Compare and contrast the general characteristics of the following drug groups:
the TCAs and the SSRIs
TCA blocks the uptake of serotonin and norepinephrine which help the brain send and receive signals while SSRIs only inhibit reabsorption of serotonin.
the non-selective MAOIs and the RIMAs
Non-selective MAOIs prevents removal of norepinephrine, serotonin, and dopamine by irreversibly binding to monoamine oxidase while RIMA acts similarly with MAOIs. The only difference is the reversibility and selectivity of RIMA. RIMA reversibly bunds with the enzyme, thus, allowing it to detach.
the TCAs and the tetracyclic antidepressants
TCA increase levels of serotonin and norepinephrine while blocking the action of acetylcholine. On the other hand, tetracyclic antidepressants contain four cyclic rings and inhibit reabsorption of serotonin and noradrenaline in the brain.
the TCAs and the non-selective MAOIs
TCA is a cyclic antidepressant that block the reabsorption of serotonin and norepinephrine while MAOS is an inhibitor which targets monoamine oxidase to prevent the removal of norepinephrine, serotonin, and dopamine.
the SSRIs and the SNRIs
SSRI is a selective drug which blocks the reabsorption of serotonin while SNRI is called dual-action antidepressant because it blocks the reabsorption of both serotonin and norepinephrine.
(Katzung, Masters, and Trevor, 2012)
END OF ASSIGNMENT TWO
References
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