Modules 12-17 - Mechanisms, Adverse effects and important considerations Flashcards
Statins:
Mechanism of action including overall therapeutic benefit
Main difference between the two statins.
Adverse effects
Inhibit HMG-CoA reductase.
Increases hepatic LDL receptors.
Decreases plasma LDL
1) increase HDL
2) Decrease LDL
3) Decrease TGs
Atorvastatin (Lipitor) vs. Rosuvastatin (Crestor)
Rosuvastatin is not greatly metabolized and caution must be exercised when prescribing to Asian patients
Adverse effects: Myopathy Hepatotoxicity Rhabdomyolysis (can lead to cardiac dysrhythmias) Teratogenic
Nicotinic Acid/Niacin Vitamin name? Mechanism of action Therapeutic benefit Adverse effects
Vitamin B3
Inhibits hepatic VLDL secretion –> less LDL in plasma as a result
Increased HDL + decreased LDL
Skin rash, Hepatotoxicity, hyperglycemia, Facial flushing, Increased levels of uric acid
Bile acid sequestrants
Mechanism of action
Adverse effects
Positively charged molecules that bind to bile acids (negatively charged) and prevent intestinal absorption of bile acids.
This causes a need for cholesterol for bile acid synthesis. Thus, there are increased hepatic LDL receptors, and less plasma LDL
Bloating, Constipation, Decreased absorption (thiazide diuretics, certain antibiotics, warfarin, digoxin)
Cholesterol absorption inhibitors
Combination pill
Mechanism of action
Adverse effects
Combination pill - statin + cholesterol absorption inhibitor - called vytorin [simvastatin + ezetimibe (Zetia)]
Binds to and inhibits intestinal cholesterol transporter, NPC1L1. This decreases cholesterol absorption –> decreased plasma LDL + increased hepatic cholesterol synthesis
No major adverse effects
Often used in combination with statins
Fibrates
Mechanism of action
Overall therapeutic benefit
Adverse effects
Activates PPAR-alpha:
1) Increased lipoprotein lipase synthesis
2) Decreased apolipoprotein CIII (lipoprotein lipase inhibitor)
3) Increased apolipoprotein a1, a2 (transport of lipids to the liver)
Decreased TGs and increased HDL
Increased risk of gallstones, myopathy, hepatotoxicity
Pathogenesis of atherosclerosis
Endothelial cell injury (smoking, hemodynamic factors, immune reaction, elevated blood lipids, HTN)
LDL cholesterol invades the sub-endothelial space
LDL becomes oxidized, and recruits monocytes
Monocytes become macrophages and engulf the oxidized LDL
Macrophages enlarge and become vacuolated = Foam cells
As foam cells accumulate, a fatty streak appears
As the fatty streak grows, platelet adhesion, smooth muscle migration and collagen synthesis occurs –> fibrous cap
Primary treatment of high LDL cholesterol/atherosclerosis.
Lifestyle modifications:
- Smoking reduction
- Exercise
- Weight control/diet
Loop Diuretics
Mechanism of Action
Adverse effects
Usual indication
Work at the ascending Loop of Henle to reduce Na+/Cl- reabsorption (with the unfortunate side effect of causing reduced potassium reabsorption)
This promotes sodium-chloride, and thus water excretion, decreasing BP (through a decrease in blood volume)
Adverse effects: Hypokalemia, Hyponatremia, Hypotension, Dehydration
Used in severe fluid overload cases - i.e. edema, severe renal failure, severe HTN (not responding to other diuretics)
Thiazide diuretics
Mechanism of action
Adverse effects\
Blocks Na+/Cl- reabsorption in the distal tubule –> decreased water reasborption –> decreased BP
Adverse effects: Hyponetremia, Hypokalemia, Dehydration
Potassium sparing diuretics/Aldosterone antagonists
Mechanism of action
Adverse effects
Important contraindication
Inhibit aldosterone receptors in the collecting duct –> decreased sodium reabsorption = decreased potassium excretion –> water excretion –> decreased BP
Adverse effects: hyperkalemia
DO NOT use with ACEIs or ARBs
Beta Blockers
Mechanism of Action - differentiate between 1st and 2nd generation
Adverse effects
Suffix
Block beta 1 receptors in the heart (Decreased CO and BP) and in the juxtaglomerular cells (decreased renin production = decreased PVR).
1st generation beta blockers also block beta 2 receptors in the lungs
Adverse effects: 2nd generation (selective): Bradycardia, rebound HTN, cardiac failure (rare), decreased CO 1st generation (non-selective) - additional AEs include bronchoconstriction and inhibition of glycogenolysis
“olol” - e.g. metaprolol
ACEIs
Mechanism of action
Adverse effects
Suffix
Inhibit ACE in the lungs –> reduction of angiotensin II production –> reduction of aldosterone (decreased Na+ reasborption), ADH (decreased water reabsorption) and decreased PVR (angiotensin II no longer binds to AT1 on smooth muscle)
Inhibition of bradykin breakdown (vasodilation)
Overall: decreased blood volume = decreased CO, and decreased PVR
Adverse effects:
-Angiotensin II: 1st dose hypotension, hyperkalemia (DO NOT USE WITH POTASSIUM SPARING DIURETICS)
Bradykinin: Persistent cough, angioedema
Suffix: “ipril” - e.g. Ramipril
ARBs Mechanism of action Therapeutic benefit Adverse effects suffix
Block the angiotensin II receptor (AT1) on smooth muscle (decreased PVR), and inhibit aldosterone synthesis (decreased Na+/H20 reabsorption)
Decreased blood volume (decreased CO) and decreased PVR
Adverse effects: Angioedema
(DO NOT USE WITH ALDOSTERONE ANTAGONISTS)
Suffix: “sartan” - e.g. eprosartan
DRIs
Mechanism of action
Adverse effects
Bind to and inhibit renin (rate limiting step in RAAS = affect whole pathway)
Adverse effects: Hyperkalemia, angioedema, diarrhea, persistent cough
Calcium Channel Blockers Difference between the two types Mechanism of action Adverse effects Suffix
Dihydropyridine - only blocks calcium channels in smooth muscle at therapeutic doses
Non-dihydropyridine - blocks both cardiac and smooth muscle calcium channels
Mechanism: Inhibition of calcium uptake reduces tone/contraction of smooth/cardiac muscle - decreasing PVR and CO
Suffix - “dipine”
Adverse effects:
-Dihydropyridine: headache, dizziness, skin rash, flushing, peripheral edema, reflex tachycardia
- Non-dihydropyridine” compromised cardiac function, dizziness, constipation, flushing, edema, headache
Centrally acting alpha 2 agonists
Mechanism of action
Adverse effects
Bind to and activate alpha 2 receptors in the brain stem –> decreased sympathetic outflow to smooth muscle and to the heart (decreased CO and PVR)
Adverse effects:
- drowsiness, dry mouth, rebound HTN
L-DOPA
Mechanism of action
Therapeutic benefit
Adverse effects
Inactive molecule that is actively transported across the BBB, then decarboxylated to become dopamine Increases available dopamine Often administered with carbidopa - inhibits peripheral metabolism Vitamin B6 (pyridoxine) speeds up the reaction (L-DOPA to dopamine)
Nausea, vomiting, Dyskinesia, cardiac dysrhythmia, orthostatic hypotension, psychosis
Dopamine agonist
Mechanism of action
Adverse effects
Directly activate post-synaptic dopamine receptors
Adverse effects: Hallucinations, Orthostatic hypotension, daytime drowsiness
Dopamine releasers
Mechanism of action
Adverse effects
Stimulate dopamine release from pre-synapatic nerve terminals
Block NMDA receptors (reduce dyskinesia side effect of L-DOPA - i.e. used in combination)
Block dopamine reuptake
Adverse effects: Nausea, vomitting, dizziness, Lethargy, Anticholinergic effects
Catecholamine-O-Methyltransferase inhibitor (COMT)
Mechanism of action
Adverse effects
Inhibits COMT, thus reducing methylation (and inhibition) of L-DOPA –> allows a greater drug fraction to reach the site of action
AEs: Hallucinations, vivid dreaming, nausea, orthostatic hypotension
MAOB inhibitor
Mechanism of action
Adverse effects
Inhibit Monoamine oxidase B and thus oxidative metabolism of L-DOPA and dopamine –> more conversion to dopamine in the brain + more dopamine available in nerve terminals to be released
AEs: Insomnia, orthostatic hypotension, dizziness
Anticholinergic drugs
Mechanism of action
Adverse effects
Block binding of Ach –> decreases urinary incontinence, salivation and diaphoresis
AEs: dry mouth, constipation, blurred vision, urinary retention, tachycardia
Cholinesterase inhibitors
Mechanism of action
Adverse effects
Inhibit cholinesterases and thus the metabolism of ACh –> more remains in the synaptic cleft
AEs: Diarrhea, Insomnia, Vomiting, nausea
NMDA receptor antagonists
Mechanism of action
Adverse effects
Block the NMDA receptor, decreasing calcium influx into the post-synaptic neuron –> prevents degradation of neurons
AEs: No Major Drug Adverse effects
Conventional Antipsychotics
Mechanism of action
Adverse effects
Block D2 (dopamine) receptors in the mesolimbic area of the brain Also block NE, histamine and ACh receptors
AEs: Anticholinergic effects, sedation, skin rash, fever, orthostatic hypotension, EPS
Atypical Antipsychotics
Mechanism of action
Adverse effects
Mainly block 5-HT1a and 5-HT2a receptors, and D2 receptors (minimally)
Adverse effects:
Type 2 diabetes risk, weight gain, sedation, orthostatic hypotension, anticholinergic effects
Phenytoin Mechanism of action Adverse effects What seizure types does it treat? Important considerations
Sodium channel blocker –> increases the length of the refractory state in neurons, prevent rapid firing of neurons
AEs: skin rash, sedation, gingival hyperplasia, teratogenic
Treats all seizure but absence
Non-linear kinetics; narrow therapeutic range
Voltage-dependent Ca2+ channel blocker
Mechanism of action
Adverse effects
Block voltage-gated Ca2+ channels –> prevent release of NT and action potential propagation
AEs: None
Glutamate antagonists
Mechanism of action
AEs
Block NMDA and AMPA receptors –> prevent CNS excitation
AEs: none
GABA potentiators
Stimulate GABA release Enhance GABA binding to its receptor Stimulate GABA reuptake Inhibit GABA metabolism All of which promote Cl- entry and hyperpolarization of neurons
AEs: none
TCAs
Mechanism of action
AEs
Inhibit the reuptake of NE and serotonin
AEs: Weight gain, cardiac toxicity, orthostatic hypotension, sedation, sexual dysfunction, reduced seizure threshold
SSRIs
Mechanism of action
AEs
Other important things to note
Inhibit reuptake of serotonin
AEs: Serotonin syndrome, weight gain, insomnia, sexual dysfunction
Lower propensity to give sides (compared to TCAs); primary treatment for depression
SNRIs
Mechanism of action
AEs
Important to note?
Inhibit the reuptake of serotonin and NE
AEs: Nausea, sexual dysfunction, diastolic HTN
Fast onset of action
MAOIs
Inhibit MAO-A and B –> decreased metabolism of serotonin, NE, dopamine
acts within the pre-synaptic nerve terminal to allow more of these NTs to be released
AEs: Agitation, anxiety, Insomnia, Orthostatic hypotension, HTN crisis
Lithium
Mechanism of action
AEs
What are the benefits of lithium?
Mechanism of action is unclear but thought to alter uptake and release of glutamate and block binding of serotonin
AEs - only present with diuretics (affect salt balance) - GI upset, Tremors, sedation, hypotension
Relieve manic/depressive symptoms
Do not worsen manic/depressive symptoms and do not affect rate of cycling
Prevent recurrence of manic/depressive symptoms
Benzodiazepines
Mechanism of action
AEs
Bind to a different site on the GABA receptor (i.e. not an agonist) and potentiate the effects of GABA –> Cl- uptake and CNS depression
AEs: CNS depression, Respiratory depression, anterograde amnesia, tolerance, withdrawal, teratogenic
Buspirone
Mechanism of action
AEs
Mechanism unclear - modulate serotonergic/dopaminergic neurotransmission
AEs: lightheadedness, dizziness, excitement
Insulin (general)
Mechanism of action
Adverse effects related to hypoglycemia
Promotes the uptake of glucose in the liver, and formation of glycogen
Promotes fatty acid synthesis and TG synthesis in adipose tissue
Promotes amino acid uptake and protein synthesis, as well as glycogen synthesis, in muscle cells
Rapid decrease: tachycardia, palpitations, sweating, nervousness
Gradual decrease: headache, confusion, drowsiness, fatigue
Severe decrease: coma, convulsions, death
Glucagon
Mechanism of action
Promotes glycogenolysis
Biuguanides
Mechanism of action
Adverse effects
Increase sensitivity to insulin and the number of insulin receptors
Decrease hepatic gluconeogenesis
Decrease intestinal glucose absorptoin
AEs:
Nausea, decreased appetite, decreased absorption of folate and vitamin B12, lactic acidsosis
Sulfonylureas
Mechanism of action
Adverse effects
Promote insulin secretion from the pancreas
Inhibit glycogenolysis
1st generation –> 2nd generation = 1000x more potent, less drug interactions
AEs: pancreatic burnout, hypoglycemia
Meglitinides
Mechanism of action
AEs
Promote insulin secretion
inhibit glycogenolysis
AEs: less chance of hypoglycemia or pancreatic burnout
Glitazones
Activate PPAR-gamma –> promotes transcription of genes controlling carbohydrate metabolism –> increased number of glucose transporters –> increased insulin sensitivity
Activates PPAR-alpha too –> decreased TGs and increased HDL
AEs
Edema, fluid retention, headache and myalgia
Alpha glucosidase inhibitors
Mechanism of action
Adverse effects
Inhibits enzyme important in digestion of complex carbs to simple carbs, thereby decreasing intestinal absorption of glucose
AEs: abdominal distention, cramps, flatulence, diarrhea, decreased absorption of iron
Gliptins
Mechanism of action
Adverse effects
Inhibit DPP-4 –> thus get increased release of incretin hormones (GLP-1 and GIP) after meals from the intestine which stimulate release of insulin and decrease glucagon release
AEs - none
Incretin mimetics
Mechanism of action
Adverse effects
Synthetic incretin analogs which promote insulin release and inhibit glucagon release
AEs - hypoglycemia, pancreatitis
Penicillin
Mechanism of action
Adverse effects
Indicate if broad/narrow; static or cidal
Binds to PBPs –> activates autolysins, which degrade the cell wall (peptidoglycan), and inhibits transpeptidases (which promote cross bridge formation)
AEs: allergy
Narrow spectrum (gram positive) and bactericidal
Exception is broad spectrum penicillin - can penetrate outer membrane of gram negatives
Cephalosporin Mechanism of action Adverse effects 1st gen --> 4th gen differences Indicate if broad/narrow; static or cidal
Inhibit transpeptidases, activate autolysins
1st–>4th - higher penetrance into CSF, more resistant to penicillinase (beta lactamase) and more effective against gram negative bacteria
Narrow –> broad (i.e. 4th generation is more broad than 1st)
Bactericidal
Vancomycin
Mechanism of action
Adverse effects
Indicate if static or cidal
Inhibits cell wall synthesis by binding to precursors of cell wall synthesis and blocking transglycosylation step
AEs: red person syndrome, ototoxicity
Bactericidal
Tetracyclines
Mechanism of action
Adverse effects
Indicate if broad/narrow; static or cidal
Bind to the 30S ribosomal subunit of bacteria and prevent addition of amino acids to the peptide chain
AEs: GI upset, photosensitivity, susceptibility to superinfection
Bacteriostatic, broad
Macrolide antibiotics
Mechanism of action
AEs
Indicate if broad/narrow; static or cidal
Bind to 50S ribosomal subunit and prevent addition of amino acids to the lengthening peptide chain
AEs: GI upset, QT interval prolongation
Bacteriostatic, broad
Oxazolidinones Mechanism of action AEs Indicate if broad/narrow; static or cidal Treatment indication
Bind to 50S ribosomal subunit and inhibit protein synthesis
AEs: reversible myelosuppresion
Bacteriostatic
Narrow (gram positive)
Used for MRSA or VRE only!
Aminoglycosides
Mechanism of action
AEs
Indicate if broad/narrow; static or cidal
Bind to 30s ribosomal subunit and inhibit protein synthesis
AEs: Irreversible ototoxicity, reversible nephrotoxicity
Narrow (gram negative), bactericidal
rapidly lethal to bacteria
Sulfonamides + Trimethoprim
Mechanism of action
AEs
Indicate if static or cidal
Block folic acid synthesis –> prevent DNA replication
AEs: photosensitivity, hypersensitivity (i.e. fever), Steven-Johnson Syndrome
Bactericidal when given in combination
Fluoroquinolones
Mechanism of action
AEs
Indicate if broad/narrow; static or cidal
Inhibit DNA gyrase and topoisomerase IV
AEs: GI upset (nausea, vomiting, diarrhea)
Broad, bactericidal
Isoniazid
Mechanism of action
AEs
Block the synthesis of mycolic acids
AEs: hepatotoxicity, peripheral neuropathy
used for treating TB
Alkylating agents - Cyclophosphamide
Mechanism of action
AEs
Indicate if cell cycle specific or not
Pro-drug activated by the liver - Forms cross bridges between guanine nucleotides, breaking DNA and inhibiting DNA replication
AEs - none
Cell cycle phase non specific
Platinum agents - cisplatin
Mechanism of action
AEs
Indicate if cell cycle specific or not
Forms cross bridges between guanine nucleotides, causing DNA mismatches/breaking and stopping DNA replication
AEs: ototoxicity, nausea, vomiting (emetogenic), nephrotoxicity
Cell cycle phase non-specific
Antimetabolites
Mechanism of action
AEs
Indicate if cell cycle specific or not
Inhibit enzymes or prevent DNA replication
Folic acid analogs - prevent folate conversion to folic acid
Purine/pyrimidine analogs - cause DNA replication arrest
AEs - none
Cell cycle phase specific - mostly S phase
Antitumour antibiotics - anthracycline
Mechanism of action
AEs
Intercalate DNA –> alter structure and inhibit DNA synthesis
AEs - severe bone marrow supression, cardiotoxicity
Mitotic inhibitors
Mechanisms of action
AEs
Vinca alkaloids - bind to tubulin and destabilize MT bundles, causing inapprorpiate chromosome segregation, and cell death (metaphase)
Taxanes - (late G2) bind to and stabilize MTs to prevent replication
AEs - none
Cell cycle phase specific (obviously)
Glucocorticoids
Mechanism of action
AEs
Toxic to lymphoid tissue; used as adjunct to other chemotherapy to reduce Nausea dn vomitting, pain and lack of appetite
AEs - adrenal insufficiency, osteoporosis, susceptibility to infection, electrolyte imbalance, GI ulceration, growth retardation
Prostate cancer treatments
Mechanisms
GnRH agonists - promote test release from testes, which negatively feedback to the prostate, decreasing GnRH synthesis and release, and thus androgen levels
Castration removes test synthesis from testes
Androgen receptor antagonists - block androgen binding in the prostate - decreased response (combined with either of the above)
Breast cancer treatment
Mechanisms of action
AEs
Tamoxifen - partial receptor agonist - minimally activates receptor and prevents endogenous estrogen from binding
Aromatase inhibitors - prevent conversion of androgens to estrogen (only effective in post-menopausal women since ovarian production of estradiol is not stopped)
Trastuzumab - monoclonal antibody which binds to HER2 and inhibits its replicative effects
AEs - Trastuzumab - cardiotoxicity
Tyrosine kinase inhibitors - imatinib/Gleevec
Mechanism of action
AEs
Bind to tyrosine kinases and inhibit cellular proliferation –> induce apoptosis
AEs: nausea, vomitting, muscle cramps, edema
