Auc_Pharm_Block4

Front 1

Levothyroxine

Back 1

-Hypothryoid drug

-T4 drug that gets deiodinized to Liothyronine (T3), the active form

-Activated nuclear receptors, leading to gene expression with RNA formation and protein synthesis

-Max effect seen after 6-8 WEEKS of therapy

-Drug of choice for thyroid hormone replacement therapy

-Stable and low cost

-Long t1/2 (7days)

Front 2

What are the drugs used for hypothyroidism?

Back 2

-Levothyroxine (T4): hypothrydoism, lowers TSH

-Liothyronine (T3): Used for MYXEDEMA COMA & PRE-COMA (injection) 'hypothyroidism' bc it is more potent and since the person is comatose, their MBR is decreased, drug will last longer. Concomitant artificial rewarming contraindicated.

-Dessicated thyroid (pork): Not FDA-approved, lowers TSH

Front 3

What are some adverse effects of supplying thyroid hormone?

Back 3

-Overdose leads to thyrotoxicosis

-Angina or MI usually in older patients

Front 4

Liothyronine (T3)

Back 4

-Drug used for hypothryoidism

-Best used for short-term suppression of TSH

-Higher cost, relatively shorter t1/2 (24hours)

-Can lead to cardiotoxicity

Front 5

What are the drugs that belong to the thiamide class?

Back 5

-All anti-thryoid drugs

-Methimazole (MMI), Propylthiouracil (PTU, preferred drug in pregnancy and thyrotoxicosis) & Carbimazole (not available in USA)

-Block de novo thyroid hormone synthesis within 1-2 hours after administration

-Have no effect on release of preformed hormone from the thyroid gland

Front 6

What are the 3 classes of drugs we use to treat hyperthyroidism?

Back 6

Thioamides (Mehimazole (MMI), Propylthiouracil (PTU), and Carbimazole)

Iodides (KI, NaI)

Radioactive Iodine (131 I)

Front 7

Propylthiouracil (PTU)

Back 7

Preferred in 1st trimester of pregnancy and thyroid crisis (high doses)

-Prevents hormone synthesis by inhibiting thyroid peroxidase-catalyzed reactions and blocking iodine organification

-Blocks coupling of iodotyrosines

-Inhibits peripheral deiodination (deiodinase D1) of T4 to T3

Front 8

Methimazole (MMI)

Back 8

-Preferred drug for hyperthyroidism, once daily oral dosing

-10X more potent than PTU, similar mechanism of action as PTU but DOES NOT EFFECTIVELY BLOCK DEIODINASE D1 (does not decr. synthesis)

-Decreases the degree of hyperthyroidism in prep for subtotal thyroidectomy or radioactive iodine therapy

-Used when thyroidectomy is contraindicated

Front 9

What are the pharmacokinetics of PTU and MMI?

Back 9

Slow onset of observable effects, 3-4 weeks before stores of T4 are depleted

Front 10

What are the side effects of PTU and MMI?

Back 10

-Pruritic maculopapular rash (common);edema

-Hepatitis (PTU-black box warning)

-Agranulocytosis (rare, but serious), usually reversible upon drug withdrawal

-Incr. chances of thyroid hyperplasia with long-term use

Front 11

Iodides (NaI, KI): Pharmacological action and clinical use

Back 11

-Inhibits synthesis and release of T3 and T4

-Decrease size and vascularity of thyroid gland

-Clinical use: before thyroid surgery, decr. vascularity of gland

-Treatment of hyperthyroidism --> thyroid storm (short term) --> improvement quite rapid (2-5 days)

Front 12

What was used to prevent thyroid gland destruction by radioactive iodine in nuclear war/accident?

Back 12

Iodides (NaI, KI)

Front 13

Adverse reactions to Iodides?

Back 13

-Acneiform rash

-Swollen salivary glands, mucous membrane ulcerations

-Chronic use in pregnancy can cause fetal goiter

Front 14

Radioactive Iodine (131 I) mechanism of action

Back 14

-Administered as a single dose, orally

-Produces ionizing radiation that damages thyroid gland (131 I is concentrated in thyroid cells)

-Therapeutic effect depends on emission of beta rays w/ a short penetration range of 0.4-2mm and an effective half-life of 5 days

-beta rays destroys the thyroid gland with little damage to surrounding tissue

-Used to treat thyrotoxicosis

Front 15

Radioactive Iodine: indications

Back 15

-Radioactive iodide uptake test to evaluate thyroid function

-Thyrotoxicosis: multinodular hyperthyroidism and toxic adenomas

-Therapeutic effects take about 1-3 months

Front 16

Symptom management of hyperthyroid effects with beta blockers and calcium channel blockers

Back 16

Front 17

Where do you find the specific Glucose transporters?

Back 17

Front 18

Which GLUT transporter do you find on beta cells of the pancreas?

Back 18

GLUT2

Front 19

Which GLUT transporters do you find in almost all tissues?

Back 19

GLUT1: Regulate basal uptake of glucose; transport across the BBB

-Found in all tissues, esp. red cells and brain

-Necessary to sustain tissues at low energy

Front 20

Which glucose transporters are insulin-mediated for uptake into muscle and adipose tissue?

Back 20

GLUT4

Front 21

Pharmacokinetics of insulin

Back 21

-Half life is 5 minutes

-Degraded by Hepatic glutathione insulin dehydrogenase ***(805) and kidneys

Front 22

What are adverse effects of insulin?

Back 22

-Hypoglycemia (too much insulin): hunger, sweating, tachycardia, confusion, coma, ad convulsions can occur

-Hypersensitivity with local reactions may occur; anaphylaxis is rare (glycosylation is protection against the immune system)

-Lipodystrophy may occur at site of injection

Front 23

What are the short-acting regular insulin used?

Back 23

Insulin R --> Humulin R

-Given BEFORE they eat (around 30 minutes before, lasts 5-8 hours)

Front 24

What are the rapid acting insulin analogs?

Back 24

Aspart, lispro, Glulisine

-Given if eating <30 minutes, has an onset of 5-15 minutes and lasts 3-4 hours

-It is rapidly metabolized and excreted

Front 25

Are the the intermediate acting insulins?

Back 25

NPH or Lente insulin

-Onset is 60-180 minutes (1-3 hours) and lasts about 16-24 hours

Can also give a mixture of NPH and regular insulin which has an onset of ~30 minutes and lasts 16-24 hours

Front 26

What is the long-acting insulin?

Back 26

Ultralente insulin (basal, no peak)

-Onset is 240 to 360 minutes (4-6 hours) and lasts 24-48 hours

Front 27

What are the basal insulins?

Back 27

Glargine and Detemir

-Onset is 60 to 120 minutes (1-2 hours), lasts around 24 hours with NO PEAK

Front 28

Insulin types and duration of action

Back 28

Note: Regular insulin has a slower onset, decr. peak and increased area under the curve (hence, greater length of effect)

-Insuulin detemir and insulin glargine have no real peak

Front 29

Insulin and Synthetic Analogues

Back 29

Front 30

Oral Hypoglycemic agents for DM2

Back 30

-Insulin secretagogues (insulinotropics): sulfonylureas, meglitinides, DPP-IV

-Insulin sensitizers: biguanides (metformin), Thiazolidinediones

-Drugs that slows the absorption of starches: A-glucosidase inhibitors (Acarbose)

Front 31

Insulin secretagogues (insulinotropics)

Back 31

-Act directly or indirectly to stimulate pancreas to produce more insulin

-Useful for patients with DM2 who cannot be managed on diet alone

Front 32

Insulin sensitizers

Back 32

Decrease blood glucose without increased insulin release

-i.e. improve target cell response to insulin

-Biguanides (decr. hepatic glucose production)

-Thiazolidinediones (bind PPAR in muscle)

Front 33

Sulfonylureas mechanism of action

Back 33

Stimulates the release of insulin from pancreatic beta cells by binding to SUR and blocking the ATP-dependent K+ channels. Reduces K+ efflux leading to beta cell depolarization, calcium influx and secretion of insulin

-May also incr. the Sn of peripheral tissues (muscle and fat) to insulin

-Sulfonamide antibiotics can cause hypoglycemia

**Person must have functional beta cells

Front 34

1st and 2nd generation sulfonylureas

Back 34

1st generation: Tolbutamide, Tolazamide, Acetohexamide

2nd generation: Glyburide, Glimepiride, Glipizide, Gliclazide

Front 35

Tolbutamide

Back 35

-1st gen. sulfonylurea

-Dose duration 6-10 hrs

-Inactived by LIVER through oxidation to carboxytolbutamide, excreted by the kidney

-*** May give FP test for proteinuria

Front 36

Acetohexamide

Back 36

-1st gen. sulfonylurea

-Dose duration 10-20 hrs

-Metabolites formed by hydroxylation in liver (L-hydroxyhexamide is most active)

Front 37

Tolazamide

Back 37

-1st gen. sulfonylurea

-Metabolized by the liver to 6 compounds, 3 of which have hypoglycaemic activity and are excreted by the kidney

Front 38

Glyburide and Glipizide

Back 38

-2nd gen. sulfonylurea

-Dose duration 12-24 hours

-These compounds are metabolized by the liver, partially excreted into bile, and the remainder excreted by the kidney

Front 39

Which drugs have opposite effects to sulfonylureas?

Back 39

Diazoxide and Milodoxil - Open K+ channels

Front 40

Which drugs antagonize sulfonylurea actions?

Back 40

Thiazide diuretics, estrogens, or any agents that inhibit insulin release or antagonize peripheral action

Front 41

Which drugs potentiate the hypoglycaemic effect caused by sulfonylureas?

Back 41

-Sulfonamides

-Beta-blockers

-Alcohol

-MAO inhbitors

-Phenylbutazone

-Bishydroxycoumarin

-All lower blood sugar, enhance effects

Front 42

What do we use to treat gestational diabetes?

Back 42

Regular insulin

Front 43

Side effects of Tolbutamide?

Back 43

-Minimal anti-diuretic effect (the other agents have mild diuretic effects)

-Reported incr. in cardiovascular mortality** (skin disorders, hypothyroid)

Front 44

Which insulinotropic is a non-sulfonylurea oral hypoglycaemic agent?

Back 44

Meglitinides

Front 45

What kind of drug is Repaglinide?

Back 45

Insulinotropic: stimulates insulin secretion by pancreatic beta cells

-Fast acting, short duration and may be administered before meals from 30 min. right up to meal time (sulfonylureas take 30 min.)

-Same mechanism as sulfonylureas

Side effects: generally minimal (hyperglycaemia, and hypoglycaemia)

-Recently contra-indicated in patients taking GEMFIBROZIL due to risk of severe/prolonged hypoglycemia

-Can also occur with clarithromycin, itraconazole, ketoconazole, MAOis

-Due to CYP2C8 and CYP3A4 interactions

Front 46

Metformin

Back 46

Biguanide

-Indicated for use in DM2

-Several proposed mechanism of action: incr liver, muscle and fat cell sensitivity to insulin, incr. peripheral glucose uptake and utilization, incr. muscle glycogen synthesis, decr. hepatic glucose output

-Particularly useful in ppl with REFRACTORY OBESITY

-Dec. a number of cardiac RFs

(Phenformin: association with lactic acidosis & no longer available)

Front 47

Side effects of metformin

Back 47

-Common: GI disturbances (nausea, diarrhea, flatulence)

-LACTIC ACIDOSIS (rare): where clearance is reduced, i.e. renal or hepatic impairment

-No sig risk of hypoglycaemia (does not stimulate insulin secretion)

-Avoid in patients with alcohol base, severe hepatic impairment, and severe CHF

-Co-administered with sulfonylurea (decr. HB1Ac values by 1-2%)

Front 48

What are the 2 thiazolidinediones?

Back 48

Rosiglitazone and pioglitazone ("glitazones" are the 1st drugs developed to target insulin resistance)

Front 49

Rosiglitazone and Pioglitazone mechanism of action

Back 49

Affect FA metabolism by binding to PPAR

-Ligand-activated TFs (rosiglitazone - GLUT4)

-Decr. blood glucose levels by improving target cell response to insulin

Rosiglitazone: alters the FA metabolism so that they do not compete with glucose for oxidative metabolism

-Leads to incr. sensitivity of TISSUES to insulin by recruiting GLUT4 to the cell surface (incr. uptake and suppressed hepatic glucose output)

Front 50

Therapeutic uses of Thiazolidinediones

Back 50

-DM2 treatment with inadequate control of hyperglycemia

-NOT USED FOR DM1

-Use of Troglitazone in UK and USA was stopped due to potential hepatotoxicity

Front 51

What is required for prescribing Rosiglitazone and Pioglitazone?

Back 51

Has strong warnings and requires hepatic function tests before initiating therapy and continuing every 2-6 months

Front 52

What are the incretin hormones?

Back 52

GLP1(glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide)

-Major incretin peptides that affect glucose metabolism

Front 53

What is a major advantage of GLP1?

Back 53

Restores beta cell function and promotes beta cell differentiation

-Also increases insulin biosynthesis

Front 54

What are the GLP-1 analogs?

Back 54

Exenatide (synthetic) and exendin-4

Front 55

Exendin-4

Back 55

GLP1 analog

-39AA peptide in the salivary secretions of Gila monster, PROTEASE RESISTANT

-Incr. glucose dependent insulin secretion

-Decr. elevated glucagon secretion and slows gastric emptying

-Improve glycemic control by decr. fasting and postprandial glucose concentrations in DM2

Front 56

Side effects of Exenatide or Exendin4

Back 56

Can be administered twice daily, alone or with metformin, a sulfonylurea, or both --> significantly decreases HbA1c

-Can cause GI disturbances: nausea, vomiting, diarrhea

-Can also cause hypoglycaemia, when taken in conjunction with a sulfonylurea

Front 57

Liraglutide

Back 57

Injectable, long-acting synthetic GLP-1 analog with 97% homology to GLP-1

-Has a prolonged half life, once daily dosing

-Acts by binding to the GLP1 receptor and increasing insulin secretion and decr. glucagon release

-Results in reduced HbA1c (from 0.8 to 1.5%) and weight loss (nominal to 3.2kg)

Front 58

DDP4 inhibitors

Back 58

Sitagliptin

-Blocks DDP4, a cell surface peptidase that cleaves a wide range of proteins and peptides

-Incr. endogenous GLP1 and GIP --> Incr. insulin and decr. glucagon secretion --> better glycemic control

-Adjunct to monotherapy to diet and exercise

-May be used in combo with metformin or a Thiazolidinedione (TZD)

-Not used in those with DM1

Front 59

What are the side effects of Sitagliptin?

Back 59

Respiratory tract infection, nasopharyngitis (cold symptoms) and headache

Front 60

What is the intestinal disaccharide inhibitor?

Back 60

Acarbose:

-Alpha-glucosidase inhibitor

-Taken before meals, low dose delays and high dose inhibits carb absorption

-Effective adjunct to sulfonylurea or insulin treatment

Front 61

What are some examples of combined treatments for DM2?

Back 61

-Sulfonylurea+biguanide (glyburide and metformin = Glucovanec)

-Sulfonylurea+insulin augmentation (at HS)

-Sulfonylurea with Acarbose

Front 62

Which drug prevents renal glucose reabsorption?

Back 62

Canagliflozin:

-Modest HbA1c reduction, weight loss, decr. BP (long term CVD risk reduction?)

-Adverse effects: Hypotension, hyperkalemia, impaired renal function, UTI, incr. bone loss and incr LDL-C

-May cause hypoglycaemia with concomitant use of insulin or insulin secretagoguges

Front 63

Which injectable synthetic anti-hyperglycemic drug is an analog of amylin?

Back 63

Pramlintide

-Modulates postprandial glucose levels and is approved for preprandial use in person with DM1 AND DM2

-Adjunct to insulin in patients not achieving target postprandial blood sugar levels

-Suppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has CNS-mediated anorectic effect

Front 64

Over-expression of what drives increased expression, survival and function of osteoclasts? What does this lead to?

Back 64

RANKL --> Osteoporosis

Front 65

What are the anti-resorptive agents for osteoporosis?

Back 65

-Bisphosphonates

-Calcitonin

-Estrogen/HRT

-Selective estrogen receptor modulators : Raloxifene

-Tibolone (not available in USA)

Front 66

What are the bone building agents used for osteoporosis?

Back 66

PTH and Teriparatide

Front 67

What are the drugs with complex mechanisms used to treat osteoporosis?

Back 67

VitD+analogs, Denosumab, Strontium ranelate

Front 68

What are the bisphophonates?

Back 68

Anti-resorptive agents: (-DRONATES)

-Alendronate

-Clodronate

-Etidronate

-Ibandronate

-Risedronate

-Pamidronate

-Zoledronic acid

Front 69

What is the mechanism of action of bisphosphonates?

Back 69

Inhibit bone resorption by attaching to bony surfaces undergoing ACTIVE resorption --> inhibit osteoclastic recruitment onto bone surface --> inhibit action of osteoclasts +induce apoptosis of osteoclasts

-Leads to incr. BMD and reduced fracture risk (may incr. BMD by 2-8%)

-Interfere w/ osteoclastic intracellular biochemical pathways --> inhibit farnesyl diphosphate synthase

-Non-nitrogen containing bisphosphonates are metabolized to toxic analogues of ATP

Front 70

When are bisphosphonates indicated?

Back 70

-Prevention and treatment of osteoporosis in postmenopausal women

-incr. bone mass in men w/ osteoporosis

-Tx glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids

-Treatment of Paget's disease of bone in men and women

Front 71

What are some important adverse effects of bisphosphonates?

Back 71

-Most common: Acid reflux

-Hypocalcemia and hypophosphatemia

-Osteonecrosis of the jaw *

(Others: abdominal pain, dyspepsia, musculoskeletal pain, cramps (recent FDA warning), esophageal ulcer, IV BP may induce visual disturbances)

Front 72

What is the mechanism of action of Calcitonin?

Back 72

-Released when calcium levels in blood are high

-Binds to osteoclastis and inhibits bone resorption

-Promotes renal excretion of Ca, Na, Phosphate, Mg, and K by decr. tubular reabsorption --> acts on osteoclasts

Front 73

What are some adverse effects of nasal spray calcitonin?

Back 73

-Rhinitis

-Irritation of nasal mucosa (withdraw if ulceration occurs)

-Epistaxis, sinusitis, back pain, arthralgia, and headache

Front 74

What are some adverse effects of injection (IM/SQ) calcitonin?

Back 74

-Nausea (10%), flushing (2-5%), headache

-Skin test prior to initiating therapy

-Supplement Ca2+ and Vit D if dietary intake not enough

Front 75

Osteoclastic apoptosis is regulated by what? What effects would deficiency of this have?

Back 75

Estrogen

-Estrogen def. leads to longer-living osteoclats and incr. bone resorption

-In resp. to increased bone resorption, there is incr. bone formation and a high-turnover state develops which leads to bone loss, and perforation of the trabecular plates

Front 76

Pathophysiology of estrogen deficiency

Back 76

Front 77

FDA has approved estrogen/hormone replacement therapy for:

Back 77

-Prevention of osteoporosis

-Treatment of moderate/severe vasomotor symptoms of menopause

-Treatment of moderate/severe symptoms of vulvar and vaginal atrophy associated with menopause

-Consider TOPICAL preps to treat vaginal probs rather than oral (+bisphosphonates for the osteoporosis of menopause)

Front 78

Which selective estrogen receptor modulators (SERMs) do we use for osteoporosis?

Back 78

-Raloxifen (tissue-selective activity that acts as an estrogen agonist on bone, and antagonist on breast and uterus)

-Tamoxifen

-Bazedoxifene (not approved in USA, stops growth of breast cancer cells)

Front 79

When is Raloxifene used?

Back 79

-Prevention and treatment of osteoporosis in POSTmenopausal women

-Adverse effects: Hot flashes, DVT, leg cramps, sm. incr. in risk of fatal stroke

Front 80

Which RANKL inhibitor has been approved for the treatment of post-menopausal osteoporosis?

Back 80

Denosumab

-Suppresses bone resorption+secondarily, bone formation --> reduces the risk of vertebral and non-vertebral fractures w/ comparable effectiveness to the potent bisphosphonates

Front 81

Denosumab mechanism of action

Back 81

Front 82

What are the adverse effects and disadvantages of Denosumab?

Back 82

-Immunosuppression (UTI+URIs), cataracts, constipation, rashes, joint pain

-May be implicated in incr. risk of osteonecrosis of the jaw following tooth extraction or oral surgical procedures (similar to Bps)

-Expensive! ($2000/yr+other fees - more expensive than BP)

Front 83

What are the VitD metabolite analogs used for osteoporosis?

Back 83

Cholecalciferol, ergocalciferol, calcitrol (+ doxercalciferol, paricalcitrol, calcipotriene)

-Acts by incr. gene transcription at the VitD Receptor

-Incr. Ca+ intestinal absorption, bone mineralization, renal Ca2+ and phosphate reabsorption

-Decr. PTH promotes innate immunity and inhibits adaptive immunity

Front 84

Cholecalciferol (VitD3) mechanism of action and effects

Back 84

-Osteoblasts have receptors for Calcitrol (1,25 dihydro-VitD3)

-Incr. activity of both osteoblasts and clasts

-Incr. osteocytic osteolysis (remodelling)

-Incr. mineralization through incr intestinal Ca2+ absorption

-Feedback action of 1,25-OH2-D represses gene for PTH synthesis

Front 85

What are adverse effects of Vit D toxicity?

Back 85

-Hypercalcemia

-Kidney stones

-Excessive renal Ca2+ excretion

-Calcification of soft tissues

-Incr. risk of prostate cancer

-Growth restriction

Front 86

What is Calcipotriene and when is it used?

Back 86

-VitD analog

-Used for osteoporosis, osteomalacia, renal failure, malabsorption, and psoriasis

Adverse effects:

-Hypercalcemia, hypercalciuria

-VitD preps have much longer half-life than the metabolites and analogs

Front 87

What are the anabolic agents administered as drugs for osteoporosis?

Back 87

PTH and Teriparatide

Mech of action: PTH receptors are present on osteoblasts and osteoclasts

-With hyperparathyroidism: chronically high PTH incr. Ca2+ resorption from the bones and incr. Ca2+ levels in the blood & calciuria

Pulsatile dosing: incr. GI absorption of Ca2+ and incr. renal tubular reabs. or Ca2+ and sitmulates osteoblastic function, leading to bone mineralization

Front 88

When is PTH used?

Back 88

Protact (PTH 1-84) and Teriparatide (PTH 1-34)

-Used for osteoporotic postmenopausal women at high risk of fracture, previous osteoporotic fracture, multiple RFs for fracture, extremely low BMD (<2.5) or failed/intolerant to previous treatment

-Also primary or hypogonadal osteoporosis in men at high risk of fracture(dec. risk of new vertebral fractures of non-vertebral fractures)

Front 89

What are the averse effects of Teriparatide

Back 89

-Dizziness, rash, nausea, headache, leg cramps, arthralgia, rhinitis, transient hypercalcemia (s/s: nausea, vomiting, constipation, low energy, muscle weakness)

-Black box warning: Osteosarcoma risk in animals

Front 90

When is PTH and Teriparatide contra-indicated?

Back 90

Paget's disease of bone

Prior radiation therapy to skeleton

Bone mets

Hypercalcemia

History of skeletal malignancy

Pregnant/nursing

Front 91

What are the bacterial cell walls synthesis inhibitors?

Back 91

Penicillins

Cephalosporins

Carabapenems

Monobactam

Vancomycin

Bacitracin

Fosfomycin

Front 92

What are the bacterial protein synthesis inhibitors (ribosomally active antibiotics)?

Back 92

Aminoglycoside

Chloramphenicol

Macrolides

Tetracyclines

Streptogramins

Linezolid

Front 93

What are the nucleic acid synthesis inhibitors?

Back 93

Fluoroquiniolones

Rifampin

Front 94

What are the folic acid synthesis inhibitors?

Back 94

Sulfonamides

Trimethoprim

Pyrimethamine

Front 95

What are bacteriostatic drugs?

Back 95

Inhibit the bacterial growth at drug serum levels achievable at in patients. Intact cellular immunity is required to get rid of the static bacteria

-Not preferred in immunocompromised patients as bacteria will resurface

Ex: Sulfonamides, tetracyclines, erythromycin

Front 96

What are bactericidal drugs?

Back 96

Kill bacteria at drug serum levels achieved in patient

-Preferred for QUICK action (in seriously ill patients) and in immunocompromised patients

Ex: Penicillin, cephalosporin, aminoglycosides, fluoroquinolones

Front 97

What are narrow spectrum antimicrobials?

Back 97

Penicillin G

Isonazid

Front 98

What are extended spectrum antimicrobials?

Back 98

Ampicillin

Front 99

What are broad spectrum antimicrobials?

Back 99

Tetracyclines and chloramphenicol

These can cause super/supra-infections by an organism, such as CANDIDA whose growth is normally kept in check by the presence of other organisms (normal flora)

Front 100

Which drugs exhibit Concentration-dependent killing rates? Which do not?

Back 100

CDKR: Aminoglycosides (such as tobramycin) and Fluroquinolones (such as ciprofloxacin) exhibit CDKR against a large group of gram negative bacteria (incl. Pseudomonas aeruginosa, members of enterobacteriaceae)

-In contrast, penicillins and other beta lactam antibiotics usually do not exhibit CDKR

Front 101

What is the post-antibiotic effect (PAE)?

Back 101

After an antibacterial drug is removed from bacterial culture, if the antibacterial effect still persists on bacterial growth --> PAE

-Most BACTERICIDAL antibiotics show PAE against susceptible pathogens, e.g penicillins show PAE against Gram + cocci, and AGs show PAE against Gram - bacilli

-Prevents any remaining bacteria from replicating for several hours after the drug has been eliminated from the body

Front 102

For which diseases must we give empiric therapy?

Back 102

Neutropenia and Meningitis

Front 103

What is empiric therapy?

Back 103

The treatment that is initiated after specimens for lab analysis have been obtained but before the results of the culture are available.

-Broad spectrum antibiotic is given in case of a life threatening serious infection, before the culture/sensitivity report is available

Front 104

How is microbial sensitivity measured?

Back 104

1. Broth dilution method

2. Disc diffusion method (Kirby-Bauer test)

3. Etest method

Front 105

What is the minimum inhibitory concentration (MIC)?

Back 105

Lowest concentration of antibiotic that inhibits bacterial growth

Front 106

What is the minimum bactericidal concentration (MBC)?

Back 106

Lowest concentration of antibacterial that results in 99.9% decline in colony count after overnight incubation.

Front 107

Accessibility of antimicrobials to a particular organ depends upon what?

Back 107

1. Lipid solubility of the drug (Metronidazole can easily penetrate and reach the CNS, whereas Penicillins can not under normal circumstances)

2. Molecular weight of the drug

3. Protein-binding of the drug

Front 108

What are the sites of infection that all antibiotics cannot reach easily?

Back 108

Prostate

Vitreous body of the eye

CNS (BBB)

Front 109

What is specific treatment?

Back 109

Started after getting the culture and sensitivity (C/S) report of the sample from the infection site

Front 110

What is prophylactic therapy ?

Back 110

Indiscriminate use can result in bacterial resistance and superinfection, so should be restricted to certain clinical situations in which benefits outweigh the risks.

Front 111

What are the 7 situations in which prophylactic therapy is advised?

Back 111

1. Rheumatic heart disease: Prevention of Strep infection; patients may require years of treatment (in prevention of cardiomyopathy)

2. Pretreatment in patients with artificial heart valves who are at high risk for endocarditis (undergoing dental extraction)

3. Treatment of mother with Zidovudine to protect the fetus in case of an HIV-infected pregnant woman

4. Antibacterial treatment prior to some surgical procedures to prevent infection

5. To prevent Influenza type A: Amantadine or Rimantadine

6. To prevent Malaria: Chloroquine, Mefloquine

7. Prevention of TB (INH) or Meningitis (Rifampin) among individuals who are in close contact with infected patients

Front 112

Prophylactic therapy table

Back 112

Front 113

What is an example of synergistic combo antimicrobial therapy?

Back 113

Penicillin + aminoglycoside (ex: Gentamycin)

Front 114

What are indications for the clinical use of combo antimicrobial agents?

Back 114

1. For empiric therapy of an infection in which the cause is unknown

2. For treatment of polymicrobial infection

3. To enhance antimicrobial activity for a specific infection

4. To prevent emergence of resistance, e.g. multi drug therapy for TB infection

Front 115

What are disadvantages of antimicrobial combos?

Back 115

Many antibiotics act only when the organisms are multiplying

Coadministration of bactericidal and bacteriostatic drug may result in interference of bactericidal effect.

Front 116

What are the consequences of drug resistance?

Back 116

1. Inactivation of the drug by the microbial enzymes

2. Decreased accumulation of the antimicrobial drug by the microbes (decr. uptake, incr. efflux)

3. Reduced affinity of the target macromolecule for the drug

4. Altered metabolic pathways

Front 117

Antimicrobial resistance examples

Back 117

Front 118

What is a superinfection?

Back 118

Defined as the appearance of bacteriological and clinical evidence of a NEW infection during the chemotherapy of a primary infection. Use of broad-spectrum antibiotics or combo agents can lead to alterations of normal microbial flora of the URT, intestinal, and GIT. Permits the overgrowth of opportunistic organisms, esp. fungi or resistant bacteria.

-Diff to treat

-Broad spec antibiotics: Tetracyclines, Chloramphenicol

-*Pseudomembrane colitis (C. diff), candida infection

Front 119

What are the cell wall synthesis inhibitors?

Back 119

-Beta lactam antibiotics: Penicillin, cephalosporins, Carbapenems (Doripenem, Ertapenem, Imipenem, Meropenem, Ertapenem), Monobactam (Acteronam)

-Vancomycin

-Teicoplanin

-Bacitracin

-Fosfomycin

-Cycloserine (used for TB as 2nd line therapy)

-Daptomycin

Front 120

Which class of antibiotics inhibit cell wall synthesis?

Back 120

Beta lactams (most important class of antibiotics)

-All cell wall synthesis inhibitors are bacteriCIDAL

-Possess 4 member nitrogen containing beta lactam rings

-The integrity of the beta lactam ring is required for antibacterial activity

Front 121

Penicillin structure

Back 121

Consists of a 5 member SULFUR-containing thiazolidine ring fused to a beta-lactam ring

-Modifications of the R-group side chain (attached to the beta lactam ring) alter the pharmacological properties and resistance to beta-lactamase

Front 122

Penicillin mechanism of action

Back 122

-Bacterial cell wall is a cross-linked polymer of polysaccharides and pentapeptides

-Penicillins interfere with cell wall synthesis (peptidoglycan) by binding to Penicillin Binding Protein (PBP)***, thus inhibiting cross linking of peptide chains (transpeptidation) of the bacterial cell wall

- --> Cell wall-deficient bacteria that are lysed easily

-Cell wall is unique to bacteria, thus non-toxic to humans

Front 123

Which 2 types of antibiotics activate autolysins?

Back 123

Penicillins and Cephalosporins

-Autolysins are bacterial enzymes that remodel and breakdown the cell wall, and are involved in bacterial cell death

Front 124

Other than both being autolysins, what other property do penicillins and cephalosporins share?

Back 124

BACTERICIDAL

-More effective when the cells are actively dividing/growing and synthesizing cell wall

-Activity depends on maintaining the concentration above MIC for the entire dosing interval

Front 125

What are the methods by which organisms have either natural or acquired resistance to beta lactam antibiotics?

Back 125

-Natural resistance: To penicillins occurs in organisms that either lack a peptidoglycan cell wall (e.g. mycoplasma) or have cell walls that are impermeable to the drugs

-Acquired resistance: To penicillins occurs by PLASMID transfer (sig. clinical problem)

Front 126

What are the mechanisms of resistance development against penicillins and other beta-lactam antibiotics?

Back 126

1. Enzymatic hydrolysis of beta-lactam ring by beta-lactamase enzyme (e.g. Staph), results in loss of bactericidal activity (most common mechanism of resistance)

2. Structural changes in PBPs (e.g. MRSA, penicillin-resistant pneumococci, and enterococci)

3. Change in porin structure (reduced permeability in gram - organisms, e.g. pseudomonas)

4. Efflux: Gram- organism may also produce an efflux pump, which efficiently transport some beta lactam antibiotics from the periplasm back across the outer membrane

Front 127

What are the 4 classes of penicillins?

Back 127

1. Standard (natural) penicillins

2. Antistaphylococcal penicillins

3. Aminopenicillins

4. Antipseudomonal pencillins

3&4 are extended spectrum penicillins

Front 128

What are standard/natural penicillins?

Back 128

Narrow spectrum, beta lactamase/penicillinase sensitive

-Penicillin G (Benzyl penicillin): Acid-labile, parenteral, highly water soluble, stable in dry state, solutions are freshly prepared

-Procaine and Benzathine Penicillin G are repository (depot) form of IM injection*

-Phenoxymethal pencillin (Pen V) are acid RESISTANT, thus oral

Front 129

What is the spectrum of standard/natural penicillins?

Back 129

Have the greatest activity against Gram+ and Gram- cocci (streptococci, pneumococci, meningococci), and non-beta lactamase producing anaerobes; not active against gram- rods

-Good activity against Treponema Pallidum

Front 130

Anti-staphylococcal penicillins

Back 130

Very narrow spectrum, beta lactamase/penicillinase resistant penicillin

-Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin

Front 131

What is the spectrum of anti-staph penicillins?

Back 131

Known or suspected staph (NOT MRSA); also against streptococci, but NOT against enterococci, anaerobic bacteria, and gram- cocci and rods

Front 132

Aminopenicillins

Back 132

Extended spectrum, beta-lactamase sensitive

-Ampicillin, amoxicillin

Front 133

Aminopenicillin spectrum

Back 133

Gram+ cocci (NOT staph) and greater activity than penicillins (Pen G) against Gram- bacteria E.coli, H.influenza, Listeria monocytogenes (Ampicillin), Borrelia burgdorferi (Amoxicillin), and H.pylori (Amoxicillin)

Front 134

Antipseudomonal penicillins

Back 134

Extended spectrum, beta lactamase SENSITIVE

-Carboxypenicillins: Carbenicillin, Ticarcillin

-Ureidopenicillins: Piperacillin, Azlocillin, Mezlocillin

Front 135

Crystalline benzyl benicilline is measured in which units?

Back 135

International units (IUs)

1IU of crystalline benzyl penicillin = 0.6ug of standard prep

Front 136

Pharmacokinetics of natural penicillins (PenG)

Back 136

Destroyed by the gastric acid, hence given parenterally (preferred IV than IM because of irritation and local pain from IM inj)

-Except for oral amoxicillins, penicillins should be given 1-2 hours before or after a meal

-Distributed widely, mainly extracellularly (although it does not cross the BBB, during inflammation (meningitis), entry is facilitated)

-Very little metabolized

Front 137

What can increase the concentration of PenG in the plasma by inhibiting tubular secretion?

Back 137

Probenecid (competitor for active secretion)

-Most PenG is excreted unchanged in the urine (via active tubular secretion)

-Probenecid inhibits the tubular secretion of PenG (90% of PenG is eliminated by tubular secretion and 10% by glomerular filtration).

-Blood levels of all penicillins can be raised by simultaneous administration of Probenecid

-Half life of PenG is 30 min

Front 138

What can increase the concentration of PenG in the plasma by delaying absorption?

Back 138

Benzathine and Procaine: results in prolonged blood and tissue concentration

-A single IM inj. of 1.2 million units of Benzathine Pencillin would be suff. for 3 weeks

-A 600 unit of procaine penicillin is suff. for 12-24 hours

Front 139

What is the main adverse effect of penicillins?

Back 139

Allergic reactions: pruritic rash, anaphylaxis

-High therapeutic index, generally well tolerated

-Safe to use in pregnancy as long as patient is not allergic

Front 140

What are the therapeutic uses of PenG Benzyl pen and Pen V?

Back 140

Limited use (esp. Gram+ bacteria) due to high incidence of resistant strains

-Strep, N. gonorrhea, N. Meningitidis, C. Diphtheria, C. tetani, C. Perfringens, Actinomyces, Treponema (Syphilis) (no resistance reported to Treponema)

Front 141

What is used to treat beta-hemolytic strep and syphilis?

Back 141

Benzathine penicillin

-A single inj. every 3-4 weeks for beta-hemol. strep pharyngitis

-2.4 units IM once a week for 1-3 weeks effective for syphilis

Front 142

What is used to treat uncomplicated pneumococcal pneumonia or gonorrhoea?

Back 142

Procaine Penicillin

-Formerly the mainstay med. , rarely used now because of resistance

Front 143

Therapeutic uses of PenG

Back 143

Front 144

What are the penicillinase resistant penicillins?

Back 144

Methicillin,Nafcillin, Isoxazolyl Penicillins (Cloxacillin, Oxacillin, Dicloxacillin)

-Used only against the beta-lactamase/penicinillase producing staph

Front 145

Which penicillinase resistant penicillin is lipid soluble, crosses BBB, and primarily excreted in BILE**, hence can be given with renal impairment?

Back 145

Nafcillin

Front 146

Which penicillinase resistant penicillin causes nephrotoxicity (interstitial nephritis, tubular necrosis) and no longer used?

Back 146

Methicillin

Front 147

What is the mechanism of resistant development (MRSA) used by staph?

Back 147

Alter the PBPs (structure of the PBPs altered) which do not bind with penicillins****

Front 148

What are the anti-staph penicillins that are the drugs of choice for treatment?

Back 148

Methicillin****, Nafcillin, and Cloxacillin

Front 149

Isoxazolyl penicillins

Back 149

Cloxacillin, oxacillin, dicloxacillin

-Food interferes with their absorption, hence the drugs should be administered 1 hour before or after meals

Front 150

What do you give to somebody who is infected by methicillin-resistant staph aureus?

Back 150

Vancomycin*****

Front 151

What do you give to somebody who is infected by Vancomycin-resistant staph?

Back 151

Linezolid, Quinupristin/Dalfopristin

Front 152

Aminopencillins (extended spectrum penicillins)

Back 152

-Have greater activity than Penicillin against Gram- bacteria (bc of their limited enhanced ability to penetrate the Gram- outer membrane)

-Inactivated by many beta-lactamases

-Include Ampicillin and Amoxicillin

- Both have nearly identical spectrum of activity (enhanced activity against aerobic gram+ and gram- bacilli)

-Better oral efficacy

Front 153

What do we combine with aminopenicillins and anti-pseudomonals to protect them from hydrolysis by bacterial lactamase enzymes?

Back 153

Beta-lactamase inhibitors: Clavulanic acid, Sulbactam, and Tazobactam

Front 154

Ampicillin

Back 154

-Extended spectrum amino penicillin used against anaerobes, enterococci, L monocytogenes, Beta-lactamase negative strains of E.coli and Salmonella

-Not degraded by gastric acid, but food interferes with absorption

-Excreted in the bile partly - undergoes enterohepatic circulation

Front 155

What is the drug of choice against Listeria monocytogenes?

Back 155

Ampicillin

-L. monocyto causes meningitis in immunocompromised patients

-Used along with amino glycosides

Front 156

What is the most common side effect of Ampicillin?

Back 156

Diarrhea

-Can also cause pseudomembrane colitis

Front 157

Amoxicillin

Back 157

-Aminopenicillin

-Completely absorbed

-Food DOES NOT interfere with its absorption

-NO diarrhea

-NO pseudomembrane colitis

(Absorption of most oral penicillins (except Amoxicillin) is impaired by food, and the drugs should be administered at least 1-2 hours before or after a meal)

Front 158

Which drug is most commonly used against URT infections? (Pharyngitis, sinusitis, S. Pneumoniae, H. influenza)

Back 158

Amoxicillin

-Addition of beta lactamase inhibitors (Amoxicillin+clavulanic acid or ampicillin+sulbactam) can extend the spectrum to beta-lactamase producing strains

Front 159

What can be used as empiric treatment of suspected bacterial meningitis?

Back 159

Ampicillin+Vancomycin+third generation cephalosporins

Front 160

Which drug is preferred for UTIs?

Back 160

Amoxicillin

-Uncomplicated UTI caused by enterobacteriaceae and E.coli

Front 161

What drug is used against salmonella infections?

Back 161

Ampicillin: good for typhoid carrier state in patients without gall bladder disease and also used for salmonella gastroenteritis

Front 162

What drug is used for Shigellosis?

Back 162

Ampicillin

Front 163

What drug is used as prophylaxis by dentists for patient with abnormal heart valves who are to undergo extensive oral surgery?

Back 163

Amoxicillin, oral

Front 164

Resistance to aminopenicillins

Back 164

A major clinical problem because of inactivation by plasmid-mediated penicillinase (E.coli and H. influenza are frequently resistant)

-Formulation with a beta-lactamase inhibitor, such as clavulanic acid or sulbactam, protects amoxicillin of ampicillin, resp. from enzymatic hydrolysis and extends their antimicrobial spectrum

Front 165

Carboxypenicillins

Back 165

Carbenicillin, Ticarcillin

-Part. active against Pseudomonas aeruginosa

-Preferably used in nosocomial infections by gram- organisms (such as pseudomonal infections in burn patients, CF) - life threatening conditions

-

Front 166

What does a high dose of carboxypenicillins causes?

Back 166

Bleeding by interfering with platelet function

Front 167

What are the 2 classes and subclasses of antipseudomonal penicillins?

Back 167

Carboxypenicillins: Carbenicillin, Ticarcillin

Ureidopenicillin: Piperacillin, Azlocillin, Mezlocillin

Front 168

Ureidopenicillins

Back 168

Piperacillin, Aziocillin, Mezlocillin

-Similar to ticarcillin

-Active agent against Pseudomonas, enterobacter, and many klebsiella

-Combined with amino glycosides or fluroquinolones for pseudomonal infections outside the urinary tract (because of their propensity of the P aeruginosa to develop resistance if used anti-pseudomonal penicillins alone)

Front 169

What is the major adverse effect of all penicillins?

Back 169

Hypersensitivity (Type I and 4): with wide range of reactions ranging from urticarial rashes (common), angioedema (marked swelling of lips, tongue and periorbital areas), and anaphylaxis

-However, if necessary (e.g. treatment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin.

-The major antigenic determinant - Penicilloic acid (degradation products of penicillins and products of alkaline hydrolysis bound to host protein)

-Cross-allergic reactions (cross-sensitizing and cross-reacting)

Front 170

What are other adverse effects of penicillins?

Back 170

1. Nephrotoxicity: Methicillin causes interstitial nephritis, tubular necrosis; hence no longer avail.

2. Neurotoxicity: In response to HIGH doses causing seizures and convulsions if given intrathecally or in patients with renal failure

3. Platelet dysfunction: Carbenillin, Ticarcillin

4. GI distress: nausea, vomiting, and diarrhea (Ampicillin) due to disruption of the normal balance of intestinal microorganisms

5. Cation toxicity: sodium/potassium

6. Jarisch-Herheimer reaction: Penicillin injected in a syphilitic patient (part. 2ndary syphilis) produce fever, malaise, joint pain exacerbation of lesions, hypo tensions, etc. Does not need interruption of therapy

Front 171

What are the beta-lactamase inhibitors?

Back 171

Clavulanic acid, sulbactam, tazobactam

-Lactamases are enzymes produced by gram+ and gram- organisms. They inactivate beta-lactam antibiotics by opening the beta-lactam ring.

-Beta lactamase inhibitors resemble a beta-lactam molecule, but, by themselves do not have sig. antibacterial activity

-They are imp. inhibitors of many but not all bacterial beta lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes.

Front 172

Examples of beta-lactamase inhibitors

Back 172

1. Amoxicillin+Clavulanic acid (oral)

2. Ticarcillin+Clavulanic acid (parenteral)

3. Ampicillin+Sulbactam (parenteral) : Active against beta-lactamase-producing S.aureus and H.influenzae but not against serratia, which produces a beta lactamase that is not inhibited by sulbactam

4. Piperacillin+Tazobactam (parenteral): if a strain of p.aeruginosa is resistant to peiperacilin, it is also resistant against it+beta lactamase inhib. because tazobactam doe not inhibit the chromosomal beta lactamase produced by P.aeruginosa.

Front 173

Cephalosporins

Back 173

Are beta lactam antibiotics, closely related to penicillins, but more stable to many bacterial beta-lactamases and therefore have a broader spectrum of activity.

-Most are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid (obtained from fungus cephalosporin)

Front 174

Cephalosporins are NOT active against what?

Back 174

LAME:

-Listeria monocytogenes

-Atypical (e.g. chlamydia, mycoplasma)

-MRSA

-Enterococci

Another clinical concern is growing resistance by strains of E.coli and Klebsiella (M/A: identical to pens as is M/R)

Front 175

First generation cephalosporins

Back 175

Parenteral: Cefazolin

Oral: Cephalexin, cefadroxil, cephradine

-Resistant to staph penicillase and are v. active against pneumococci, streptococci, and staph.

-Highly active against GRAM+ cocci (not MRSA) but also have weak activity against some gram- organisms (poor activity against pseudomonas)

-Active against gram- bacteria such as proteus mirabilis, E.coli, Klebsiella (PEcK)

Front 176

Uses of first generation cephalosporins

Back 176

-Surgical prophylaxis against Gram+ bacteria (Cefazolin used due to longer half-life and its activity against penicillinase producing S.aureus)

-Cefazolin: orthopedic surgery bc able to penetrate bone

-Cephalexin: URT infection (ex: pharyngitis)

-Used in penicillin and sulfonamide-resistant UTI

Front 177

First generation cephalosporin pharmacokinetics

Back 177

-None enter CNS (cannot treat meningitis)

-Water soluble, eliminated through KIDNEY (glomerular filtration and tubular secretion); dose must be reduced in patient w/ impaired kidney

-Probenezid increases serum level substantially

Front 178

Second generation cephalosporins

Back 178

Parenteral: Cefuroxime, Ceforanice, Cefoxitin, Cefamandole, Cefotetan***

Oral: Cefaclor, cefurozime axetil, cefprozil

-More activity against GRAM- organisms, incl. some anaerobes (B.fragilis, it can cause life-threatening intra-abdominal infections, esp. after bowel rupture/perforation); however, weaker gram+ coverage

-Gram-: H.influenzae, enterobacter aerogenes, N.meningitidis+PeCK (HENPEcK)**

Front 179

Which 2nd generation cephalosporins are active against H.influenzae but no activity against B fragilis?

Back 179

Cefamandole, Cefuroxime, Cefactor

Front 180

Which 2nd generation cephalosporins have weak activity against H.influenzae, but are more active against B.fragilis

Back 180

Cefotetan and cefoxitin

Front 181

Which 2nd generation cephalosporins are active against enterococci or pseudomonas (like 1st gen.)?

Back 181

NONE

-Note: although Cefuroxime crosses the BBB, it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should NOT be use.

Front 182

What are the therapeutic uses for 2nd generation cephalosporins?

Back 182

-Upper+lower RTIs (oral prep)

-Anaerobic infections : Cefoxitin, Cefotetan, Cefmetazole

-Community-acquired pneumonia: Cefuroxime

Front 183

What are the 3rd generation cephalosporins?

Back 183

-Parenteral: Cefotaxime, ceftriaxone, Ceftazidime, Cefoperazone, Ceftizomine

-Oral: Cefixime, Cefdinir, Cefitoren pivoxil, Cefibuten, Cefpodoxime proxetil

Front 184

Compared to 2nd generation agents, what do 3rd gen. cephalosporins offer?

Back 184

Expanded gram- coverage

-Highly active against gram+ cocci (<1st gen.) +gram-, plus enhanced activity against Gram- bacilli (incl. HENPEcK), enterobacteriacae, pseudmonas, and serrate marcescens.

-RESISTANT TO MOST LACTAMASES

Front 185

What are the 3rd generation cephalosporins?

Back 185

-Parenteral: cefotaxime, ceftriazone, ceftazidime, Cefoperazone, Ceftizoxime

-Oral: Cefixime, Cefdinir, Cefitoren pivoxil, cefibuten, cefpodomine proxetil

Front 186

What is an important therapeutic use of 3rd gen. cephalosporin?

Back 186

Empiric management of sepsis of unknown cause in both immunocompromised and immunocompetent patients

-In neutropenic or immunocompromised patients, Ceftazidime is often used in combo with other antibiotics

Front 187

What is the agent of choice in the treatment of meningitis (caused by pneumococci, meningococci, h.influenzae, and susceptible gram- rods, but NOT L.monocytogenes)?

Back 187

Ceftriaxone or Cefotazmine***

Front 188

What 3rd gen. cephalosporin is active against P.aeruginosa?

Back 188

Ceftazidime and Cefoperazone

Front 189

What is used to treat uncomplicated gonococcal urethritis, cervicitis?

Back 189

3rd gen. cephalosporin- Cefixime (oral)

Front 190

What is used to treat typhoid fever?

Back 190

DoC is fluoroquinolones (ciprofloxacin), or can use 3rd gen. cephalosporin because equally effective.

Front 191

What is the only generation of cephalosporin to enter the CNS?

Back 191

3rd gen. - except cefoperazone

Front 192

How is cefoperazone and ceftriazone mainly excreted?

Back 192

Biliary tract - no adjustment required for renal insuff. (others are excreted by kidney and require dosage adjustments)

Front 193

What are the parenteral 4th gen. cephalosporins?

Back 193

Cefepime, Cefpirome (enter the CNS)

-More resistant to beta lactamase

-Combines with gram+ activity of 1st gen. (including strep and staph, but not against MRSA) with the wider gram- spectrum of 3rd gen.

-Cefepime: good activity against pseudomonas, enterobacteriaceae, S. aureus, and S.pneumoniae. Highly active against Hemophilus and Neisseria spp.

Front 194

Which cephalosporin is active against Methicillin-resistant staph (MRSA)?

Back 194

Ceftaroline fosamil***

-A pro-drug of an active metabolite Ceftaroline

-Treats community acquired bacterial pneumonia and acute bacterial skin infections

Front 195

Table of cephalosporin per infection

Back 195

Front 196

Pharmacokinetics of cephalosporins

Back 196

-Majority given by IV or IM (except those mentioned) due to poor oral absorption

-Distribute well in the body fluids. However, adequate therapeutic levels in the CSF regardless of inflammation are achieved only with 3rd gen. cephalosporins ****

-Hence, Ceftriazone are effective in the treatment of neonatal and childhood meningitis, caused by Strep agalactiae, E.coli, H.influenza, N.meningitidis, Strep pneumo)

-Renal clearance similar to penicillin, with active tubular secretion blocked by Probenecid (dose must be adjusted in renal dysfunction)

-Cefoperazone and ceftriaxone are largely eliminated via bile (can be given to those with renal insuff.)

Front 197

What is a major adverse effect of cephalosporins?

Back 197

Hypersensitivity reactions (identical to those of Penicillin)

-Complete cross-allerginicity b/w individual cephalosporins and partial cross-allergenicity with penicillins (so if allergic to one, can't treat with other)

-Patients with a history of anaphylaxis to penicillins should NOT receive cephalosporins

Front 198

If a person is allergic to penicillins, we do not give cephalosporins. So, what do we give to kill a gram+ organism? gram-?

Back 198

Gram+: Macrolides

Gram- rod: Aztreonam

****

Front 199

Which drug causes bleeding due to hypoprothrombinemia?

Back 199

Cephalosporins: cefoperazone, cefamandole, cefotetan, cefmetazole

-Due to MTT: methylthiotetrazole side-chain***

-Administration of VitK corrects the problem

Front 200

Which drugs cause a disulfiram-like reaction?

Back 200

Cefoperazone, cefamandole, cefotetan, cefmetazole

-Due to MTT side-chain

-* causes build-up to aldehyde metabolites by blocking aldehyde dehydrogenase (causes aversion to alcohol in alcoholics)

Front 201

Other side effects of cephalosporins

Back 201

-Pain @ site of injection

-Diarrhea due to alteration of gut ecology

-Nephrotoxicity (esp. cephaloridine, hence withdrawn)

Front 202

What are the carbapenems?

Back 202

Doripenem

Ertapenem

Imipenem

Meropenem

-Are structurally related to beta lactam antibiotics

Front 203

Carbapenem features

Back 203

-M/A same as penicillin and cephalosporin

-Resistant to most beta-lactamases (but not carpapenemases and metallo-beta-lactamases)

Front 204

Carbapenem spectrum

Back 204

-Most potent and widest spectrum lactams

-Active against penicillinase producing Gram+ cocci, gram- rods (e.g. enterobacter and pseudomonas aeruginosa) and anaerobe

-Among them, Ertapenem is insuff. active against P.aeruginosa and should NOT be used for pseudomonal infections

-Overall, very potent!

Front 205

Uses of carbapenems- doripenem, imipenem, meropenem

Back 205

-Imp. in in-hospital agents for empiric use in severe life-threatening infections (due to pseudomonas infections, mixed aerobic and anaerobic infections) --> currently DoC for infections due to enterobacter

-Active against many penicillin-resistant strains of pneumococci

-Used in febrile neutropenic patients in ICU, +/- aminoglycosides

-Cannot be used against MRSA

Front 206

What is imipenems limiting feature?

Back 206

Hydrolysis by dehydropeptidase by brush border tubular cells of the kidney

-Cilastatin is an inhibitor of the renal dehydropeptidase and is used clinically along with imipenem

-Other carbapenems (doripenem, ertapenem, and meropenem) are NOT sig. degraded by dehydropeptidases

Front 207

Pharmacokinetics of Doripenem, Ertapenem, Imipenem, and Meropenem

Back 207

-Administered by IV and IM injection (IM injection of Ertapenem is irritating, hence formulated with 1% lidocaine)

-Imipenem is given with cilastatin

-Metabolites formed by dehydropeptidase are inactive, but potentially nephrotoxic

-All carbapenems undergo renal elimination-hence dose should be decreased in renal dysfunction

Front 208

What are the adverse effects of carbapenems (doripenem, ertapenem, imipenem, meropenem)?

Back 208

-GI distress: nausea, vomiting, diarrhea

-Drug fever: partial cross-allergenicity with penicillin

-CNS effects: Imipenem causes SEIZURES * (in 50% of patients) in overdose and renal dysfunction (like penG)

-Doripenem, ertapenem, meropenem are much less likely to cause seizures than imipenem

Front 209

What is the only monobactam we learned?

Back 209

Aztreonam

-M/A: similar as penicillins and cephalosporins

-Resistant to beta lactamases, given IV or IM

-Only used in IV form for aerobic gram- rods** (Such as H.Influ, pseudomonas, and enterobacteriacease)

-NO activity against Gram+ anaerobes

-Penicillin-allergic patients tolerate it (no cross-allergenicity with penicillins or cephalosporins): if allergic to penicillin, given for gram-rods

Front 210

What is the main indication for aztreonam use?

Back 210

Hospital acquired infection and also useful in patients with pseudomonal infection who are allergic to penicillins***

-If history of penicillin anaphylaxis, treats serious infections such as pneumonia, meningitis and sepsis by susceptible gram- pathogens

Front 211

What are 2 glycopeptide antibiotics which inhibit synthesis of peptidoglycan bacterial cell wall (bactericidal ultimate effect)?

Back 211

Vancomycin, Teicoplanin

-Binds to D-Ala-D-Ala terminus of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation. Prevents elongation of the peptidoglycan chain and interferes with cross-linking.

-Does NOT depend upon binding with PBPs to produce effect (hence active against MRSA)**

Front 212

What is the antibacterial spectrum of vancomycin?

Back 212

Active only against gram+ bacteria

-Enterococci: synergistic action with amino glycosides (streptomycin and gentamicin)

-MRSA

Front 213

Resistance to Vancomycin

Back 213

Rare- however, Vancomycin-resistant staph aureus (VRSA) and vancomycin-resistant enterococcal (VRE) strains are emerging (in surgical and burn wards)

-Resistance involved decreased affinity for the binding site due to replacement of terminal D-Ala by D-Lactate

Front 214

Vancomycin pharmacokinetics

Back 214

"Red man" or "Red neck" syndrome

-Type I HSR

-Characterized by flushing, pruritis, erythema of the head and upper body and hypotension resulting from histamine release after rapid IV injection-due to HISTAMINE release

-Can largely be prevented by prolonging the infusion period (1-2 hours) or pretreatment with anti-histamines

-Ototoxicity (usually permanent, additive with other drugs such as amino glycosides, furosemide, ethacrynic acid)

-Nephrotoxicity (mild, but additive)

Front 215

What is the drug of choice for infections due to MRSA? (bloodstream infections and endocarditis)

Back 215

Vancomycin

-In combo with gentamicin, it is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy

-In combo with cefotaxime, ceftriaxone, or rifampin - also recommended for treatment of meningitis due to penicillin-resistant strains of pneumococcus

-Back up drugs for C.diff enterocolitis (given orally) (Metronidazole is DoC)

Front 216

What do we give for vancomycin-resistance?

Back 216

Linezolid

Quinupristin/daflopristin

-2 protein inhibitors are used for the treatment of vancomycin resistant organisms

Front 217

What is the analog of phosphoenolpyruvate and inhibits bacterial wall synthesis?

Back 217

Fosfomycin

-Active against both gram+ and gram-

-Oral and parenteral preps are also available

-SAFE IN PREGNANCY

-Used for treatment of uncomplicated lower UTI in women

Front 218

What is a mixture of polypeptides that inhibit bacterial cell wall synthesis?

Back 218

Bacitratcin

-Active against Gram+ bacteria

-Restricted to topical application because of its potential nephrotoxicity

-One of the components of "triple antibiotic" (along w/ polymixin or neomycin) used as a topical antibiotic (ointment, dusting powder) for the suppression of mixed bacterial flora in surface lesions of the skin, in wounds, or on mucous membranes)

Front 219

What is a structural analog of D-alanine and inhibits incorporation of D-alanine into peptidoglycan pentapeptide (bound to NAM) by inhibiting alanine racemes and D-alanyl-D-alanine ligase?

Back 219

Cycloserine

-Used to treat TB caused by strains resistant to first-line agents

-Causes dose-related CNS toxicity (headache, tremors, acute psychosis, and convulsions)

Front 220

Daptomycin

Back 220

-Spectrum of activity similar to Vancomycin (may be active against vancomycin-resistant strains of enterococci and S.aureus)

-M/A not fully understood

-However, it binds to the cell-membrane via calcium-dependent insertion of its lipid tail, resulting in depolarization of the cell membrane with potassium efflux and rapid cell death

-Used for skin and soft tissue infections, bacteria, and endocarditis (effective alternative to vancomycin)

-Adverse effect: myopathy and allergic pneumonitis

-Should not be used to treat pneumonia as pulmonary surfactant antagonizes its action

Front 221

Inhibition of protein synthesis by antibiotics

Back 221

Front 222

Summary of mechanisms of protein synthesis inhibitors

Back 222

Front 223

Bacterial protein synthesis inhibitors

Back 223

-Aminglycosides, spectinomycin

-Tetracyclines

-Chloramphenicol

-Macrolides, clindamycin

-Linezolid

-Quinupristine/Dalfopristine (Streptogramins)

Front 224

Drugs that affect 30s ribosomes

Back 224

-Aminoglyocosides (Gentamicin, Streptomycin)

-Tetracylcins (Tetracycline, Doxycycline)

-Spectinomycin

Front 225

Drugs that affect 50s ribosomes

Back 225

-Chloramphenicol

-Macrolides (erythromycin, azithromycin)

-Clindamycin

-Quinupristin-Dalfopristin (Streptogramins)

-Linezolid

Front 226

Aminoglycosides

Back 226

Front 227

Aminoglycoside mechanism of action

Back 227

Aminoglycosides "irreversibly" bind to the 30s subunit

1. interfere with the initiation complex of peptide formation

-interfere with initiation codon functions by blocking association of 50s ribosomal subunit with mRNA 30s (-STATIC)

2. Misreading of mRNA-incorporation of incorrect amino acids into the peptide, resulting in non-functional or toxic protein *** (-CIDAL)

Front 228

Aminglycosides are bactericidal against what?

Back 228

Gram- aerobic bacteria (bacilli)

Front 229

Transport of amino glycosides inside the bacteria depends on what?

Back 229

-O2-dependent process: amino glycosides are actively transported across the cytoplasmic membrane of aerobic gram- bacteria into the cytoplasm (anaerobes are innately resistant)
-Transport may be enhanced by the cell wall-active drugs such as penicillin or vancomycin --> Synergism
-They exhibit concentration dependent killing ** and post antibiotic effect**

Front 230

Resistant to aminoglycosides

Back 230

1. inactivation by acetylation, adenylation, and phosphorylation

-Plasmid-mediated synthesis of enzymes (e.g. acetyl transferases, nucleotidyltransferases, and phosphotransferases) that modify and inactivate aminoglycoside antibiotics

2. Impaired entry into the cell resulting from mutations or deletion of a porin protein or the proteins involved in the O2 dependent transport

3. Mutation of receptor protein on the 30s

Front 231

Which 2 amino glycosides are less vulnerable to the resistance enzymes?

Back 231

Netilmicin and Amikacin***

Front 232

Aminoglycoside pharmacokinetics

Back 232

-Water soluble, poor absorption from the intact intestine, almost the entire oral dose is excreted in feces after oral administration; necessitates their parenteral admin (IM or IV)

-Highly polar compounds, do not enter cells readily -CSF concentration is poor

-Cleared by the kidney, attain a high concentration in urine and excretion is directly proportional to creatinine clearance

-SINGLE daily dose is just as effect (less toxic-ototoxic and nephrotoxic) than multiple smaller doses

-Exhibits CDK and PAE

Front 233

Streptomycin is active against what?

Back 233

-Yerisinia pestis (plague) -DoC

-Francisella tularensis (tularemia) -DoC

-Mycobacterium tuberculosis

(less active against P.aeruginosa)

Many bacteria have developed resistant to streptomycin, severely limiting the usefulness of the drug

-Also used in TB and endocarditis (enterococcal and viridans strep): streptomycin and penicillin

Front 234

What happens if streptomycin is given during pregnancy?

Back 234

Deafness in the newborn --> contraindicated

Front 235

Gentamicin is active against which organisms?

Back 235

P.aeruginosa***, Klebsiella, proteus, Serratia, E.coli

-Used in combo with penicillin (of Vancomycin) for treatment of serious enterococcal, staphylococcal, or viridian group strep infections

-Strep and enterococci are relatively resistant to gentamicin due to failure of the drug to penetrate into the cell--> give with Vancomycin or penicillin

-Given IV, IM, or topical, ocular or intrathecal administration

-Single dose scheme better

Front 236

Amikacin

Back 236

-Same spectrum as gentamicin (more potent against P. aeruginosa)

-Second line drug for MDR TB**

-Resistant to many of the aminoglycoside-resistant enzymes (gentamicin, tobramycin)

-Most expensive --> reserved for use against organisms that are resistant to other AGs (MDR-TB)

-Nephrotoxic and ototoxic (auditory part of CN8)

Front 237

Which drugs are best for treating P.aeruginosa?

Back 237

Tobramycin > Amikacin > Gentamicin

TAG

Front 238

Tobramycin

Back 238

-Almost the same antimicrobial spectrum as gentamicin, greater activity against most strains of P.aeruginosa

-Ototoxic and nephrotoxic

-IM, IV, and inhalation

Front 239

Paramomycin

Back 239

-Only amino glycoside which is active against Entamoeba histolytic, cryptosporidium parvum and various tapeworms (taenia solium)

Front 240

Uses of neomycin and kanamycin

Back 240

-Limited topical use (for minor soft-tissue infection often in combo with bacitracin and polymyxin) and oral use (neomycin) for hepatic encephalopathy (must kill ammonia-producing bacteria) and in prep for elective bowel surgery (along with erythromycin)

-Limited use bc toxic (nephrotoxic +deafness)

-Neomycin part of triple antibiotics (neomycin+bacitracin+polymyxin), ointments, dusting powders

-Can be given topically as solutions on infected surfaces or injected into joints, pleural cavity, tissue spaces, or abscess cavities

Front 241

Aminoglycoside adverse effects

Back 241

-Narrow TI (monitor serum concentrations and individualize the dose depending on the creatinine clearance - renal function)

-Nephrotoxic and ototoxic (more likely if given>5 days, in elderly or with renal insuff)

-Neuromuscular blockade (curare-like effect) with respiration paralysis --> Caution with MG patient (decr. ACh release), enhances muscle relaxant effect

-Contact dermatitis (esp. Neomycin**, topical)

Front 242

Which drugs can be used as antidotes against the neuromuscular blocking effect of amino glycosides?

Back 242

Neostigmine and calcium gluconates

Front 243

Aminoglycoside therapeutic uses

Back 243

Front 244

What is used as an alternative treatment of GONORRHEA in patients who are either allergic to penicillins/cephalosporins or those who are infected with gonococci resistant to other drugs like penicillins, cephalosporins, fluoroquinolones (cipro)?

Back 244

SPECTINOMYCIN

-Aminocyclitol antibiotic that is structurally related to aminoglycosides

-Single dose of 2g, IM

-Not available in USA

Front 245

Tetracyclins

Back 245

-Doxycycline

-Tetracycline

-Chlortetracycline

-Demeclocycline

-Minocycline

-Oxytetracycline

Front 246

Tetracycline mechanism of action

Back 246

-Bacteriostatic antibiotics, inhibits protein synthesis

-Reversible binds to the 30s subunit of the bacterial ribosome

-Prevent the binding of aminoacyl-tRNA to the acceptor site (A) of the 30s ribosomal subunit, prevents addition of AAs to the grown peptide, thereby inhibiting bacterial protein synthesis

Front 247

Summary of protein synthesis inhibitors

Back 247

Front 248

Tetracycline general info (spectrum+use)

Back 248

BROAD spectrum - active against gram+ and gram- organisms (but due to incr. resistance and development of safer drugs, decline in use)

Front 249

Tetracyclines are used against what?

Back 249

Front 250

Tetracyclines and macrolides

Back 250

-Macrolides mimic antimicrobial spectrum with tetracyclines

-But sensitivity test is important before using one in place of another

Front 251

Tetracyclin pharmacokinetics

Back 251

-Different preps of tetracyclines differ in their absorption after oral admin and in their elimination (Minocycline and doxycycline are completely absorbed)

-Oral absorption is impaired by chelation with cations (Ca, Mg, Fe, Al) and dairy foods+antacids

-Excreted mainly in bile and urine

Front 252

What is the effect of tetracycline crossing the placenta?

Back 252

Bone deformities and tooth dysplasia

Front 253

Which tetracyclines are mostly eliminated by the liver and hence require no dose reduction in renal dysfunction?

Back 253

Doxycycline and Tigecycline

Front 254

All tetracyclines enter the CSF, but levels are insuff for therapeutic efficacy except for?

Back 254

MINOCYCLINE

-Enters the brain in absence of inflammation and appears in tears and saliva

-Useful in eradicating meningococcal carrier state (RIFAMPIN is preferred)

Front 255

Which oral tetracycline of choice is given twice daily band its absorption is not significantly affected by food>

Back 255

Doxycycline

Front 256

Tetracyclines are the first choice drugs for which infections?

Back 256

Front 257

2nd uses for Tetracyclines

Back 257

Front 258

3rd uses for Tetracyclines

Back 258

Front 259

Which drug can be used to treat SIADH by blocking the ADH receptor in collecting ducts?

Back 259

Demeclocyclin

-In the same way, a side effect of this drug is Diabetes insipidus

Front 260

Therapeutic uses of Tetracyclines picture

Back 260

Front 261

Adverse effects of tetracyclines

Back 261

-Most common: GI upset

-Tooth enamel dysplasia and possible decr. in bone growth in children (Avoid) - chelates with Ca in tooth and bone --> brown discolouration --> enamel dysplasia (if given during pregnancy or young children), growth inhibition, deformity

-Renal: Fanconi syndrome (with outdated preps-affects proximal tubule) or Diabetes insipidus (Demeclocycline)

-Phototoxicity (Tetracycline, demeclocycline, doxycycline)

Front 262

Which drugs cause photo toxicity?

Back 262

Tetracycline

Demeclocycline

Doxycycline

Sulfonamides

Fluroquinolones

Front 263

Tetracycline adverse effects part 2

Back 263

-Vestibular toxicity: reversible (Minocyclone and Doxycycline)

-Hepatotoxicity (dose dependent, esp. during pregnancy and in ppl w/ pre-existing hepatic insuff and if given in high dose)

Front 264

Which tetracyclines are least hepatotoxic?

Back 264

Oxytetracycline and tetracycline

Front 265

What is the effect of tetracyclines on microflora?

Back 265

Superinfection (C.diff, P.aeruginosa, Proteus, Yeasts) is HIGHER with tetracycline that with other antibiotics

-Pseudomembranous colitis

Front 266

When are tetracyclines contraindicated?

Back 266

-Pregnancy

-Prepubertal children (<8YO)

-Serious hepatic or renal diseases (Doxycycline can be administered in renal disease bc excreted into bile)

-Preps: oral and IV inj. , NOT IM inj (pain+inflam)

Front 267

How is resistance to tetracyclines conferred?

Back 267

Plasmid-mediated decreased intracellular accumulation of drug

-EFFLUX PUMP (P-glycoprotein)

-Decr. activity of uptake system

Front 268

What is the mode of action of Glycylcyclines (Tigecycline)?

Back 268

-BacterioSTATIC

-Binds to the 30s ribosomal subunit and inhibit protein translocation (by blocking the entry of that aminoacyl-tRNA into the "A" site of the ribosome)

-Pharmacokinetics: Slow IV (over 30-60min), primarily eliminated by biliary/fecal excretion

Front 269

What is the antimicrobial spectrum of tigecycline?

Back 269

-MRSA

-MDR S. pneumoniae

-Vancomycin-resistant enterococcus

-Beta-lactamase producing gram- bacteria

-Actinobacter and anaerobes

Clinical uses: treatment of skin- and skin-structure infection, intra-abdominal infections, and CAP

Front 270

What is the mechanism of action of Chloramphenicol?

Back 270

Binds reversibly to the 50s ribosomal subunit and prevents peptidyltransferase enzyme from transferring the growing chain from the "P" (or"D"-donor) site to the bound charged tRNA at the "A" site. This stops protein synthesis.

-Broad spectrum, bacterioSTATIC antibiotic

Front 271

What are the pharmacokinetics of chloramphenicol?

Back 271

-After oral administration, it is rapidly and completely absorbed

-Chloramphenicol palmitate: prodrug, oral

-Chloramphenicol succinate: prodrug, parenteral**

-Distributes in most tissues and secretions; crosses BBB

-Metabolized to glucuronide conjugate by the liver and excreted in urine (less dose required in liver dysfunction and neonates)

-Can ANTAGONIZE bacteriCIDAL drugs such as penicillins or amino glycosides

Front 272

What are the adverse effects of chloramphenicol?

Back 272

-GI upset

-Bone marrow suppression: dose dependent bone marrow suppression: APLASTIC ANEMIA, leukopenia, thrombocytopenia

-Oral or vaginal candidiasis

Front 273

What causes "Grey baby syndrome"?

Back 273

Chloramphenicol

-Mainly in premature neonates

-Newborns lack an effective glucuronide conjugation and detox mechanism

-Dose>50mg/kg/day causes vomiting, flaccidity, hypothermia, grey colour, shock, and vascular collapse

Front 274

Therapeutic uses of chloramphenicol

Back 274

Front 275

How is resistance to chloramphenicol conferred?

Back 275

-Production of an acetyltransferase capable of inactivating the drugs

Front 276

Which drug inhibits CYP450 enzymes in the liver, and prolongs the half-life of several drugs? Which drugs?

Back 276

-Chloramphenicol

Prolongs half life of:

-Phenytoin

-Coumarins (warfarins)

-Tolbutamide (causing hypoglycemia)

Must decr. their dose

Front 277

What are the macrolides?

Back 277

-Erythromycin
-Clarithromycin
-Azithromycin
-Roxithromycin

-THROMYCINs

Front 278

What are the ketolides and what are their uses?

Back 278

Similar to macrolides

-Telithromycin (similar to Azithromycin- used for CAP)

Front 279

Macrolide general features

Back 279

-Contain a LACTONE ring (usually 14-16C) to which deoxy sugars are attached

-Used in patients allergic to beta-lactam antibiotics

-BacterioSTATIC mainly, bactericidal at higher doses

Front 280

Clarithromycin and Azithromycin are semi-synthetic derivatives of erythromycin and are developed to overcome which limitations of erythromycin?

Back 280

-Poor bioavailability

-Frequent dosing (short half-life)

-Poor GI tolerability

-Limited H.influenza coverage

Front 281

What is the mechanism of action of macrolides?

Back 281

-Protein synthesis inhibitors

-Irreversibly binds to 50s subunits of bacterial ribosomes and inhibits the translocation step of protein synthesis, i.e. translocation of the newly synthesized peptidyl tRNA from the acceptor site (A) to the donor site (P)

Front 282

Antimicrobial spectrum of macrolides

Back 282

Front 283

Erythromycin general features

Back 283

-ACID LABILE (Its esters are more acid stable), hence administered with enteric coating

-Food interferes with absorption: Erythromycin estolate is the best absorbed oral prep

-Distributes well to all body fluids EXCEPT to the brain and CSF

-Diffuses into prostatic fluid and has the unique characteristic of accumulating into macrophages

-Extensively metabolized, inhibits many CYP450s

-Excretion is primarily in bile, hence adjustment for renal failure not necessary

Front 284

Erythromycin and Clarithromycin general features

Back 284

-Metabolized by the LIVER and excreted through the bile

-Inhibit CYP450s, several drug interactions

-Less tolerated in pregnancy (Clarithromycin has lower incidence of GI intolerance)

Front 285

Azithromycin general features

Back 285

-Excreted by the KIDNEY

-Does NOT inhibit CYP450, free of drug interactions

-MORE TOLERATED in pregnancy

Front 286

Therapeutic uses of erythromycin

Back 286

Front 287

Clarithromycin general features

Back 287

-Derivative of erythromycin and longer half-life than erythro, permits twice daily dosing

-Has improved acid stability and good absorption as compared with erythromycin

-Antibact activity is almost identical to erythromycin except clarithromycin is MORE active against Mycobacterium avium complex (MAC) and H.pylori***

-Also has activity against M.Leprae, Toxoplasma gondi*, and H.influenza*

-Erythromycin-resistant strep and staph are also resistant to clarithromycin

Front 288

Azithromycin general features

Back 288

-Acid stable derivative of erythro

-Rapidly absorbed and well-tolerated orally (1hr before or 2 hrs after meal)

-Longer half-life, permits once-daily dosing

-Does NOT inhibit CYP450

-Spectrum of activity is identical to clarithromycin (but slightly less active against strep and staph compared to erythro and clarithro)

-Penetrates phagocytic cells extremely well

Front 289

Azithromycin is active against what?

Back 289

-MAC, T,gondi

-H.influenza *** (more active that clarithro and erythro)

-Chlamydia - HIGHLY active

Front 290

When is azithromycin most commonly used?

Back 290

-CAP (pneumococcus, mycoplasma, legionella)

-Pharyngitis and skin infections

-Chlamydial infections (urethritis and cervicitis: single dose treatment with 1g of azithromycin is as effective as 7-day course of doxycycline for chlamydial urethritis or cervicitis)

Front 291

What is used to treat chlamydial urogenital infections during pregnancy?**

Back 291

1st line: Erythromycin 500mg 6 hourly for 7 days

-Azithromycin single dose for alternative

-Chlamodyal pneumonia of infancy and ophthalmia neon atrium: use Erythromycin (tetracyclines are contra-indicated)

Front 292

Therapeutic uses of macrolides

Back 292

Front 293

Adverse effects of macrolides (part 1)

Back 293

-Epigastric distress: common, moreso erythromycin (most common effect of macrocodes)
-Cholestatic jaundice with ESTOLATE form of erythromycin (fever, jaundice, impaired liver function, HSR to the estolate form)
-Ototoxicity: reversible deafness at high doses

Front 294

Adverse effects of macrolides (part 2)

Back 294

-Prokinetic action: macrolides bind with MOTILIN receptors in GIT and incr. intestinal motility (Erythro, Azithro>Clarithro)
-Prolong QT interval and arrythmias (erythromycin+cisapride or Terfenadine--> cardiotoxic drug if high dose, which it does if CYP450 inhibited)
-Contradindicated: hepatic dysfunction

Front 295

Erythromycin and clarithromycin drug interactions

Back 295

Front 296

Macrolide mechanisms of resistance development

Back 296

1. Decr. affinity of the 50s ribosomal subunit: resistance in gram+ bacteria involves production of a methylase that adds a methyl group* to the ribosomal binding site

2. Presence of plasmid associated erythromycin esterase*, that hydrolyzes macrocodes, esp. in enterobacteriacease

3. Inability to penetrate/increased efflux - shown my Gram+ organisms

Cross-resistance is complete between erythromycin and other macrolides

Front 297

Clindamycin uses

Back 297

Front 298

Adverse effects of clindamycin

Back 298

-Skin rashes

-Pseudomembranous colitis***: C.diff is resistant to clindamycin

-Impaired liver function and neutropenia

Front 299

Linezolid mechanism of action

Back 299

-Totally synthetic oxazolidinone antibiotic

-Binds to the 50s subunit and inhibits bacterial protein synthesis by inhibiting the formation of 70s initiation complex (N-formylmethionyl-tRNA-ribosome-mRNA ternary complex)

-Introduced recently to combat resistant Gram+ organisms, such as VRSA and VRE

Front 300

Linezolid therapeutic uses

Back 300

1. Vancomycin-resistant strains of S.aureus (VRSA)**

2. Vancomycin-resistant enterococcus faecium and enterococcus faecalis (VRE)**

3. Drug resistant pneumococci (nosocomial pneumonia)

4. Active against mycobacterium TB (MDR-TB) and nocardia infection

Front 301

Streptogramins: Quinupristin/Dalfopristin

Back 301

Front 302

Folic acid synthesis inhibitors (indirect acting nucleic acid synthesis inhibitors)

Back 302

-Sulfonamides

-Trimethoprim

-Pyrimethamine

Front 303

Sulfonamide and trimethoprim inhibition

Back 303

Front 304

Sulfonamides

Back 304

-Are structural analogs of PABA

-Bacteria rely on PABA for the synthesis of folic acid (Pus has high PABA, hence cannot be given with pus)

-Folic acid is essential for the synthesis of purine and pyrimidines

Front 305

Sulfonamide anti-bacterial spectrum

Back 305

-BacterioSTATIC against Gram+ and Gram-

(Strep pyogenes, E.coli, H.influenza, Klebsiella, Salmonella, Shigella, Enterobacter sp., Toxoplasma, P.JIROVECI, Vibrio cholera, Nocardia)

-Activity is POOR against ANAerobes (P. aerugionsa is intrinsically resistant to sulphonamides)

Front 306

Sulfonamide mechanism of action

Back 306

Front 307

Sulfonamide pharmacokinetics

Back 307

-Well absorbed from the GIT and readily penetrate CSF

-Metabolized by acetylation in the liver**

-Acetylated derivative is insoluble in acidic urine, hence ppt in urine and cause Crystalluria (advise patient to drink a lot of water)

Front 308

Sulfonamides of clinical interest

Back 308

Short acting: Sulfisoxazole

Intermediate acting: Sulfadiazine, Sulfamethoxazole

Long acting: Sulfadoxine

Miscellaneous: Sulfacetamide, Sulfasalazine, Mafenide, Silver sulfadiazine (SSD)

Front 309

Sulfonamide uses

Back 309

Front 310

Sulfacetamide uses

Back 310

For eye infections (bacterial conjunctivitis and as adjunctive therapy for trachoma)- topically (ophthalmic solution or ointment)

Front 311

Mafenide uses

Back 311

Active even in the presence of pus against Pseudomonas, clostridia

-Used in burn dressing

-Causes burning sensation and pain

-Can cause metabolic acidosis (limits its usefulness in burn patients)

Front 312

Silver sulfadiazine uses

Back 312

-Active against many bacteria and fungi- usually topical

-Releases silver ions to exhibit anti-microbial action

-Used in burn dressings and ulcers and preferred to mafenide for prevention of infection of burn wounds due to less toxicity

Front 313

Trimethoprim uses

Back 313

-Weak base, concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs

-Can be given alone orally in acute UTI. Many community-acquired organisms are susceptible to the high concentrations that are found in the urine.

-Also in prostatitis

Front 314

Sulfonamide adverse effects

Back 314

Front 315

What is Cotrimoxazole?

Back 315

-The fixed dose combination of trimethoprim and sulfamethoxazole is called Cotrimoxazole (Combination of TRIMethoprim and sulfamethOXAZOLE)

-Trimethoprim selectively inhibits bacterial dihydrofolate reductase

-Cotrimoxazole causes the sequential blockade of folate metabolism

Front 316

Cotrimoxazole antibacterial spectrum and dosage

Back 316

-Spectrum includes: S.aureus, S. pneumoniae, H.influenzae, Klebsiella pneumoniae (but NOT M.pneumoniae), E.coli, Salmonella, Shigella, Toxoplasma, Pneumocystis carinii (P.jiroveci)

-The dose ratio is 5:1 (S:T), leads to plasma concentration of 20:1**- for max synergy (optimal for the combined effects of these drugs in vitro)

-Trimethoprim has high tissue distribution compared to sulfamethoxazole

Front 317

What is the ultimate effect of sulphonamides alone or trimethoprim alone? What is the ultimate effect of sulfonamides+trimethoprim?

Back 317

-Either alone: BacterioSTATIC

-Together: BacterioCIDAL

-Combo of both decreases resistance, and hence offer synergistic action by sequential blockade in folate synthesis

Front 318

Therapeutic uses of Cotrimoxazole

Back 318

KNOW PNEUMOCYSTIS JIROVECI**

Front 319

How is sulfamethoxazole resistance acquired?

Back 319

May occur as a result of mutations that

1) cause overproduction of PABA

2) Cause production of folic-acid-synthesizing enzyme that has low affinity for sulphonamides

3) Impair permeability to the sulfonamides

Front 320

How is resistance to trimethoprim acquired?

Back 320

Results from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding*

Front 321

Direct inhibitors of nucleic acid synthesis

Back 321

Quinolones

Fluoroquinolones

Front 322

What is the first member of the quinolone group?

Back 322

-Quinolones are synthetic anti-microbials which are active primarily against gram- bacteria

-NALIDIXIC ACID is the first member of this group:

-Active against gram- bacteria: E.coli, proteus, Klebsiella and Shigella

-BacteriCIDAL, act by inhibiting bacterial DNA gyrase (topoisomerase II)

-Does NOT achieve systemic antibacterial levels

-High concentration in urine-lethal to urinary pathogens, hence used as urinary antiseptic and also useful in treatment of lower urinary tract infections

Front 323

Why are quinolones of minor significance today?

Back 323

-Limited therapeutic utility

-Rapid development of bacterial resistance

Front 324

Adverse effects of Nalidixic acid

Back 324

-Neurological toxicity: Seizures*

-Hemolysis in G6PD deficiency

Front 325

Fluoroquinolones

Back 325

-Synthetic fluorinated analogs of nalidixic acid

-Have extended anti-microbial activity

-BacteriCIDAL

-Have CDK

-Have PAE

Front 326

Fluoroquinolone variety

Back 326

-The FLOXACINS

Front 327

Fluoroquinolone mechanism of action

Back 327

-Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV (resp. for separation of replicated DNA during cell division)

-DNA gyrase (Topo II) in bacteria required for replication in orde to remove supercoil, and even in order to introduce negative supercoil in DNA double helix

-This is a required step to unwind the helix, ahead of the polymerase so that there is easier access to do replication

Front 328

What is the action of topoisomerase and how is it inhibited by fluoroquinolones?

Back 328

-Topos change the configuration or topology of DNA by a nicking, pass through, and re-sealing mechanisms

-Binding of the FQs to both the enzyme (TopoII and IV) and the DNA forms a ternary complex that inhibits the resealing step, and can cause cell death by inducing cleavage of DNA

Front 329

Ciprofloxacin general features and spectrum

Back 329

-BacteriCIDAL and highly potent

-Active against beta-lactam and aminoglycoside-resistant organisms

Spectrum: Gram- organisms (E.coli, salmonella typhi, H.infl, N.gonorrheae, N.meningitidis, Vibrio, P.aeruginosa--> most potent FQ), gram+ strep, TB, Legionella, Brucellosis, and ANTHRAX*

Front 330

Norfloxacin

Back 330

-Least active of the FQs against both gram- and gram+ organisms, however, used in treating complicated and uncomplicated UTIs and prostatitis

-Does not achieve adequate serum concentration hence not effective in systemic infections

Front 331

Trovafloxacin and Moxifloxacin

Back 331

-Not only have enhanced activity against Gram+ organisms (e.g. S.pneumoniae) but also have excellent activity against anaerobes (E.g. B.fragillis)

-Although P.aeruginosa is suscp. to Trova, it is usually given with AGs

-Trovafloxacin (NOT used because of liver toxicity)

-Moxifloxacin- very poor activity against P.aeruginosa

Front 332

Gatifloxacin

Back 332

Excellent activity against respiratory infections due to S.pneumoniae

Front 333

Levofloxacin

Back 333

Has superior activity against Gram+ organisms, incl. Strep Pneumo

Front 334

Pharmacokinetics of FQs

Back 334

-orally well absorbed, metabolism in LIVER

-High tissue penetration- bone, prostate, and phagocytes exceeds that in plasma

-FQs CHELATE Ca, Mg, Fe, and Zn

-Excreted primarily in kidney by filtration and active secretion (inhibited by PROBENECID)

-Reduce dose in renal dysfunction (EXCEPT Moxifloxacin)

Front 335

FQ therapeutic uses (part 1)

Back 335

Front 336

FQ therapeutic uses (part 2)

Back 336

Front 337

Adverse effects of fluoroquinolones

Back 337

-Cartilage damage, tendonitis (arthropathy)**-achilles rupture

-GI distress: nausea, vomiting, diarrhea

-Phototoxicity: rashes

-CNS: insomnia, dizziness, headache, and seizures

-QT prolonged: ALL FQs (esp. Spar and Moxi)

Front 338

FQ drug interactions

Back 338

-Plasma concentrations of theophylline, warfarin (by cipro and ofloxacin) are increased due to inhibition of metabolism of these drugs

-Antacides impair absorption

-NSAIDs enhance the CNS toxicity of FQs (SEIZURES are reported)- NSAIDs displace the drugs from protein-binding sites

Front 339

When are FQs contraindicated?

Back 339

-Pregnancy and in children (inhibition of chondrogenesis)

Front 340

FQ development of resistance

Back 340

-Altered target: mutations in DNA gyrase and Topo IV

-Inactivation of the drug: amino glycoside acetyltransferase can also inactivate Ciprofloxacin

Front 341

Causative agents of UTIs

Back 341

-E.coli (80-95% of UTIs)

-Klebseilla

-Proteus

-Pseudomonas

-Enterococcus

-Staph saprophyticus

Front 342

Antimicrobial treatment of acute uncomplicated cystitis in a non-pregnant woman

Back 342

-Cotrimoxazole (trimethoprim+sulfamethoxazole) for 3 days, as long as the local rate of resistance to cotrimoxazole among urinary pathogen is <20%

-Nitrofurantoin for 5 days (eff. alternative with a low rate of E.coli resistance)

-Fosfomycin (single dose)

Front 343

Antimicrobial treatment of acute uncomplicated cystitis in a pregnant woman

Back 343

-Nitrofurantoin, Amoxicillin, or cephalosporin

-However, nitrofurantoin should NOT be given in the 3rd trimester or during labor and delivery due to risk of hemolytic anemia of newborn

Front 344

Which drugs have become the most common class of antibiotics prescribed for UTI, but shouldn't be used as first-line agents for EMPIRIC treatment of acute uncomplicated cystitis?**

Back 344

-FQs (esp. Ciprofloxacin)

Front 345

Antimicrobial treatment of acute uncomplicated pyelonephritis for non pregnant women

Back 345

-7-day course of Ciprofloxacin, or

-5-days of Levofloxacin (if resistance to FQs aong uropathogens is <10%)

-Cotrimoxazole (alternative, if uropathogens are susceptible)

-2nd alternative: single IV inj. of Ceftriazone, followed by 7-14 days of an oral antimicrobial to which the patient is susceptible

-Oral beta lactams are generally considered less effective for treatment of pyelonephritis than FQs or cotrimoxazole

Front 346

Antimicrobial treatment of complicated UTIs

Back 346

-Occur in patients with indwelling urinary catheters or anatomic or functional abnormalities of the urinary tract

-Most likely to be caused by antibiotic-resistant gram- bacilli, S.aureus, Enterococci (incl. Vancomycin-resistant strains)

-FQs (such as Ciprofloxacin or Levofloxacin)-First choice

-Alternative: Cotrimoxazole, amoxicillin+Clavulanate or an oral 3rd generation cephalosporin (such as Cefinir or Ceftibuten)

Front 347

Antimicrobial treatment of hospitalized patients with complicated UTIs

Back 347

-Empiric parenteral treatment with Cefepime, Ceftriaxone, a FQ, Ticarcillin+Clavulanate, Piperacillin+Tazobactam, or a Cabapenem is generally recommended

Front 348

What are the first line drugs for TB?

Back 348

-Isonazid (INH): BacterioCIDAL

-Rifampin (RIF): BacterioCIDAL

-Pryazinamide (PZA): BacterioCIDAL

-Ethambutol (ETH): BacterioSTATIC

-Streptomycin

First 4 are the main first-line drugs. They must be given together for active TB.

Front 349

Isonazid (INH)

Back 349

-Prodrug: structural congener of pyridoxine (vitB6)

M/A:

-Activated by KatG **, a mycobacterial catalase-peroxidase

-Activated form covalently complexes with an acyl-carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase --> blocks mycolic acid synthesis and kills the cell

-Mycolic acids are unique to mycobacterium and are incorporated into a waxy sheath

-Produces profound early bacteriCIDAL activity against rapidly dividing organisms

Front 350

Isonazid (INH) resistance - part 1

Back 350

-Associated with mutations resulting in over expression of inhA, which encodes an NADH-dependent acyl carrier protein reductase
-Mutation or deletion of the katG gene
-Promoter mutations resulting in overexpression of ahpC, a putative virulence gene involved in protection of the cell from oxidative stress; and mutations in kasA

Front 351

INH resistance- part 2

Back 351

-Overproducers of inhA express low-level isonazid resistance and cross resistance to ethionamide

-KatG mutants express high level isonazid resistance and often are NOT cross-resistant to ethionamide

Front 352

Adverse effects of INH

Back 352

-HEPATITS: most common (incr. enzyme elevation)

-Peripheral neuropathy: slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uraemia (prophylaxis with vitB6)

-SLE-like effects

-CNS effects (dizziness, drowsiness, irritability)

-Monoamine (histamine/tyramine poisoning)

-Diarrhea

-Urine color (red)

-HSR

Front 353

What is used to monitor INH compliance for TB?

Back 353

-Urine color

Front 354

Rifampin**

Back 354

-Derivative of rifamycin (from Streptomyces mediterrani)

-BacteriCIDAL (in vitro activity against gram+ and gram- cocci, mycobacteria, some enteric bacteria and chlamydiae)

Front 355

Rifampin mechanism of action

Back 355

-Binds to beta subunit and inhibits bacterial DNA-dependent RNA polymerase ***

-Particularly effective against rapidly growing organisms, and semi-dormant organisms

Front 356

Rifampin resistance

Back 356

Any one of several possible POINT MUTATIONS in rpoB (gene for the beta subunit of RNA polymerase)

Front 357

Rifampin adverse effects

Back 357

-Hepatotoxicity --> hepatitis

-Pruritis and rash, fever, "flu-like" symptoms

-Thrombocytopenia

-Orange discolouration of body fluids --> permanently stain contact lens (harmless) **

Front 358

Rifampin precautions

Back 358

-Contraindicated or use with extreme caution in HIV-infected patients, esp. those taking protease inhibitors and/or nucleotide reverse transcriptase inhibitors (use Rifabutin or rifapentine as alternative)

Front 359

Rifampin drug interactions

Back 359

-Potent ENZYME INDUCER (1A2, 2C9, 2C19, 2D6, 3A4) -->decr serum levels of oral contraceptives, WARFARIN, glucocorticoids, hypoglycemic agents, digitalis, ketoconazole, and cyclosporine

Front 360

Rifabutin and Rifapentine**

Back 360

-Alternatives to rifampin for use in patients taking drugs susceptible to inducer metabolism e.g. HIV/AIDs* on PIs and NNRTIs

Front 361

Pryazinamide (PZA)

Back 361

BacteriCIDAL
M/A:
-inhibits mycobacterial FA synthesis by targetting FA synthase I complex
-Most active against dormant and semi-dormant organisms contain w/i macrophages or the acidic environment of caseous foci

Front 362

PZA adverse effects

Back 362

-Hepatotoxicity

-Hyperuricemia

- Asympt: an expected effect

- Acute gouty arthritis: rare (give NSAIDs)

Front 363

PZA monitoring

Back 363

-Initial serum uric acid and liver chemistry measurements

Front 364

PZA cautions/contraindications

Back 364

-Should NOT be used in patients with GOUT

-Should be used with care in patients with liver disease

Front 365

Ethambutol

Back 365

-BacteriCIDAL at HIGH doses and bacterioSTATIC at low doses

-Effective against rapidly growing organisms

-Mainly used to prevent growth of drug -resistant organisms

Front 366

Ethambutol M/A

Back 366

-Inhibits formation of arabinogalactan polysacc layer that binds the mycolic acid shell to the interior cell membrane of mycobacterium

Front 367

Ethambutol adverse effects

Back 367

-Hyperuricemia- an expected effect

-Retrobulbar neuritis: decr. visual acuity, missing words during reading from central scotomas (blind spots), and decr. green and red colour discrimination

-Monitoring requires a visual acuity test and testing for colour discrimination (Ishawara test) as a baseline when starting the drug

Front 368

Standard treatment of active TB

Back 368

Initial phase - 2 months: Empiric 4 drug regiment until susceptibility results are available:

-Isonazid

-Rifampin

-Pyrazinamide

-Ethambutol

Continuation phase: 4 to 7 months

-Continue with 3 drug combo (INH, RIF and PZA); if PZA not used (liver disease? - use ETH instead)

Note: with resistance, add streptomycin (if the person is sick and hospitalized)

Front 369

Recommended duration of therapy of active TB

Back 369

*not tested

Front 370

Treatment of latent TB infection (LTBI)

Back 370

Standard treatment: Isonazid (is susceptible, 9 months)

-Alternative: Combo: Isonazid and Rifapentine (DOT) weekly, 9 months, in a patient 12YO+

-MDR LTBI: 2 DRUGS to which the organism is susceptible (e.g pyrazinamide plus either ethambutol or a fluoroquinolone for 9-12 months)

-Similar treatment for somebody who is receiving prophylactic treatment after being exposed to somebody with active TB

Front 371

Drug resistance in TB infections

Back 371

Divided into 2 types:

1. Primary resistance: causes initially infected with resistant organisms

2. Acquired resistance: develops during TB therapy

Front 372

Multi-drug resistance TB (MDR TB)

Back 372

-TB bacteria no longer susceptible to at least isoniazid (INH) and rifampin (RIF)

-More diff to treat than ordinary TB and requires up to 2 years of multi drug therapy

-Use a combo of 2nd line drugs (may have more side effects, treatment may last longer, and cost may be up to 100 times more than first-line therapy)

-MDR-TB strains can also grow resistant to 2nd line drugs

Front 373

Extensively drug-resistant TB (AKA XDR-TB)

Back 373

-Less common form of multi drug resistant

-Resistant to INH and RIF, plus most of the alternative drugs used against MDR-TB

-Any fluoroquinolone and at least one of the other 3 injectable anti-TB drugs: amikacin, kanamycin, or caprenomycin

-May also be resistant to additional drugs

-Most challenging to treat and needs up to 2 years of extensive drug treatment

Front 374

Mycobacteria: Resistance Mechanisms

Back 374

Front 375

2nd and 3rd line anti-TB drugs

Back 375

-Aminoglycosides (Streptomycin, Amikacin, and Kanamycin)

-Capreomycin

-Fluoroquinolones (Levofloxacin, Moxifloxacin, Ciprofloxacin)

-Thionamides (Ethionamide, Prothionamide)

-Cycloserine (and Terizidone)

-Para-aminosalicylic acid (PAS)

Front 376

Aminoglycosides and Capreomycin

Back 376

Aminoglycosides:

-Streptomycin, amikacin, kanamycin

Capreomycin (3rd line): Cyclic glycopeptide- inhibits protein synthesis

M/A: Action similar to amino glycosides --> interferes with several ribosomal functions including:

-Formation of 30s subunit initiation complex

-Blockage of tRNA translocation from the A to the P site

Front 377

Capreomycin

Back 377

Has significant cross-resistance with viomycin, kanamycin, and neomycin

Adverse effects:

-Ototoxicity (subclinical hearing loss: 11%; clinical loss: 3%)

-Renal: nephrotoxicity (36%), increased BUN (1-10%)

-Incr. neuromuscular blocking effects of several drugs

-Electrolyte disturbances

Front 378

Fluoroquinolones

Back 378

Levofloxacin, gatifloxacin, moxifloxacin

M/A: Target DNA gyrase

-Levofloxacin: preferred drug, esp. in patients with drug resistant TB

Adverse effects of levofloxacin:

-GI (nausea and bloating)

-Cutaneous (rash and photosensitivity)

-Neurological (dizziness and insomnia)- very uncommon

-Fluoroquinolones should be given at least 2 hours before or after antacids, and/or other medications containing divalent cations

Front 379

Thionamides

Back 379

Ethionamide and Prothionamide (related to INH)
M/A: Inhibit mycolic acid synthesis
-Will have cross-resistance with INH if via inhA mutation
-Poorly tolerated due to GI upset
Side effects:
-Hepatotoxicity , neuropathy (give B6)
-HYPOTHYROIDISM

Front 380

Cycloserine

Back 380

-Analog of D-alanine

-BacterioSTATIC

-No cross-resistance with other anti-TB drugs

-Widely distributed in tissues and body fluids: CSF penetration (80-100% of serum concentration), higher if meninges inflamed

-Additive nervous system side-effects (psychiatric and seizures) with Ethionamide and Isonazid

-May incr. levels; combo with alcohol, incr. risk of seizures

-VitB6 decreases CNS adverse effects

Front 381

Para-Aminosalicylic Acid (PAS) - M/A and side effects

Back 381

MoA: Folate synthesis antagonist - effective drug

-Widely used in 50s and 60s (INH+SM+PAS)

Side effects:

-GI symptoms universal (NV); hepatotoxicity (hepatitis)

-Malabsorption (steatorrhea and low folate levels)

-Can indue hypothyroidism

-Coagulopathy (doubles the prothrombin time)

-Monitor with baseline liver function and TSH levels every 3 months

Front 382

Drugs for Leprosy

Back 382

-Clofazamine

-Dapsone

-Rifampin

Objectives:

-interrupt transmission of leprosy by sterilizing infectious patients as rapidly as possible with bacterioCIDAL drugs

-Ensure early detection and treatment of cases to prevent deformities

-Prevent drug resistance - never use single drug

Front 383

Multi-drug therapy (MDT) drugs for Leprosy

Back 383

-Combination of rifampin, clofazamine, and dapsone for multibacillary (MB) patients

-Combination of rifampin and damson is used for paucibacillary (PB) patients

-Ethionamide and prothionamide (more expensive than other drugs --> used when clofazamine cannot be used --> quinolones and minoclycline)

Front 384

Rifampin

Back 384

-Only drug highly bacteriCIDAL against M.Leprae

-Given once/month (big advantage)

-Turns urine RED (warn patient)

Front 385

Dapsone

Back 385

-Cheap and effective

-Weakly bactericidal against M.leprae

-Common side effects: Hemolytic anemia, hepatitis and neuropathy, agranulocytosis

-Can cause dapsone-syndrome (fever, enlarged lymph nodes, exfoliative dermatitis, hepatitis, and maculo-papular rash has also been reported) --> potentially fatal

-Prescribe iron routinely with dapsone

Front 386

Clofazamine

Back 386

-Originally designed for treatment of TB but found to be more useful in Leprosy

-Has anti-leprosy and anti-inflammatory properties --> suppresses and prevents reactions

Front 387

Clofazamine mode of action

Back 387

-Binds to bacterial DNA guanine bases --> blocks template function of DNA --> BacterioCIDAL

-Incr. release of bacterial phospholipase A2 --> release and accumulation of lysophospholipids which are toxic to bacteria

Front 388

Adverse effect of Clofazamine

Back 388

Darkens skin color

Front 389

Ofloxacin

Back 389

-Fluoroquinolone effective in leprosy, side effects are rare and generally mild

Front 390

Minocycline

Back 390

Moderately active against leprosy at 100mg QD

Front 391

Anti-viral strategies

Back 391

Front 392

Drugs active against Herpes Virus (Varicella Zoster and Herpes Simplex)

Back 392

-Acyclovir/Valacyclovir

-Famciclovir/Penciclovir

-Ganciclovir/Valganciclovir

-Foscarnet

-Adefovir

-Cidofovir

Other causes: Adenovirus, enterovirus, cidofovir, pleconaril

Front 393

Drugs for HSV infections

Back 393

Front 394

Acyclovir mechanism of action

Back 394

-Sequentially activated first by viral thymidine kinase, then by host cellular kinase (2 steps) to triphosphate form (acyclovir-TP)

-Triphosphate competes with dGTP for viral DNA polymerase --> incorporated into viral DNA by binding to DNA template and terminating chain elongation

Front 395

Acyclovir mechanism of action (2)

Back 395

Activation through 3 phosphorylation steps, first to monophosphate

-Requires viral kinase

-Viral kinase requirement provides selectivity for infected cells

-Selected activation results in triphosphate accumulation only in infected cells

-Acyclovir triphosphate accumulates in infected cells and inhibits viral DNA synthesis

Front 396

Acyclovir M/A picture

Back 396

Front 397

Resistance to Acyclovir

Back 397

-Mutation in viral thymidine kinase

-Also alteration of DNA polymerase - less important

Front 398

Acyclovir acts against which viruses?

Back 398

-HSV1 and HSV2 treatment and prophylaxis

-Varicella (VZV), Epstein Barr (EBV)

-HSV1> HSV2>VZV=EBV

-CMV is practically resistant

Front 399

Acyclovir pharmacokinetics

Back 399

-Acyclovir has poor oral absorption (15-30%)

-Cleared primarily by glomerular filtration and tubular secretion

-t1/2 varies enormously dependent on renal function

-Drug tissue levels vary from 50 to 100 % of serum levels

Front 400

Acyclovir indications

Back 400

-Genital herpes (HSV2)

-Mucocutaneous herpes (HSV1): remains localized to lips and gums

-H. simplex encephalitis (HSV1)

-H.simplex keratitis (HSV1): good corneal penetration

-Herpes zoster (VZV): Shingles, adults

-Chicken pox (VZV): children

Front 401

Adverse reactions of Acyclovir

Back 401

Generally few

-Most frequently toxicity (if renal dysfunction)

Occasional:

-GIT: nausea, vomiting, diarrhea

-CNS: tremor, lethargy

Front 402

How is acyclovir given? Side effects?

Back 402

IV administration

-Infusion site phlebitis/inflammation infection (or extravasation)

-Reversible kidney dysfunction due to crystalline nephropathy (risk by rapid infusion, dehydration, high dosage, renal insuff)

Front 403

What are the other clovirs?

Back 403

Primarily PRO-DRUGS

-Valacyclovir: Prodrug metabolized to acyclovir (prolonged release of acyclovir)

-Famciclovir: Prodrug metbaolized to Penclovir

Front 404

Penclovir

Back 404

-Not absorbed orally but similar activity to acyclovir when given by IV route

-Not chain-terminating but achieves higher intracellular levels than acyclovir

-Not available commercially for IV use

Front 405

Acyclovir resistance

Back 405

In HSV and VZV:

-Alteration in viral thymidine kinase

-DNA polymerase mutation

-Def. in thymidine kinase activity (cross resistance with valacyclovir, famciclovir, penciclovir, and ganciclovir)

-Resistant HSV infections in HIV-positive patients associated with: chronic cutaneous lesions and invasive disease (rarely)

Front 406

Foscarnet

Back 406

A tri-sodium salt of phosphonoformate (inorganic pyrophosphate)

Front 407

Foscarnet mechanism of action

Back 407

-Specifically inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase by competing for the PP binding site

Front 408

Indications of use for Foscarnet

Back 408

-Drug of choice for acyclovir resistant HSV or VZV infections

-Immunocompromised patients with CMV retinitis and mucocutaneous acyclovir-resistant HSV infections

-Alternative drug for CMV retinitisF

Front 409

Foscarnet side effects

Back 409

Renal impairment (the major toxicity) --> hypokalemia and hypomagnesemia

Front 410

Anti-herpes group drugs

Back 410

Front 411

Anti-herpes virus drugs (Table)

Back 411

Front 412

Drugs for CMV infection

Back 412

Front 413

Influenza virus picture

Back 413

Front 414

Which drugs are active only against Influenza A?

Back 414

Amantadine

Rimantadine

Front 415

Which drugs are active against both Influenza A and B?

Back 415

Oseltamivir

Zanamivir

Front 416

Amantadine and Rimantadine mechanism of action

Back 416

Prevent uncoating of Influenza A by binding M2 protein

-Appear to be viruSTATIC by preventing uncoating of virus particle

-Affect maturation of Influenza HA glycoprotein in trans-golgi network

Note: NOT active against Infl. B (No M2 protein)

-Resistance is high, not currently recommended to treatment

Front 417

Amantadine and Rimantadine resistance

Back 417

-Fairly common, 2ndary to mutations of the M-2 protein (e.g. associated with adding it to ANIMAL FEED)A

Front 418

Amantadine and Rimantadine uses

Back 418

Prophylaxis and early treatment of Infl. A

Front 419

Amantadine and Rimantadine toxicity

Back 419

-GI: nausea

-CNS: lightheadedness, insomnia (5-33%)

(Amantadine>Rimantadine, occur more commonly in elderly)

Front 420

Oseltamavir and Zanamivir mechanism of action

Back 420

-Selectively inhibit viral neuraminidases of infl. A and B, incl. H1N1 and H5Na --> prevent virion release

Front 421

Oseltamavir and Zanamivir resistance

Back 421

-Results from viral neuraminidase mutations (~1% of adults and 4% of children)

Front 422

Oseltamivir

Back 422

-Pro-drug activated in the LIVER

-Used for prophylaxis and early treatment

-Oseltamivir toxicity: GI

-Zanamivir toxicity: bronchospasm

Front 423

Schematic representation of influenza virus attachment, internalization, replication and exit from the host respiratory cell and steps inhibited by antiviral drugs

Back 423

Front 424

Drugs active against hepatitis virus

Back 424

-Interferons
-Ribavirin
-Lamivudine
-Adefovir
-Entecavir
-Telbivudine
-Tenofovir
-Telaprivir
-Boceprevir

Front 425

Interferons

Back 425

-Group of proteins produced naturally by cells in the immune system after exposure to viruses

General classes of interferons: alpha, beta, gamma

-Secreted by diff types of cells

-Administration by parenteral routes only (IM, SQ, topical-nasal spray)

Front 426

Interferon

Back 426

BROAD spectrum anti-viral activity

DNA viruses:

-HSV 1 and 2

-Herpes zoster

-HPV (genital warts)

-Chronic hepatitis B and C

RNA viruses:

-influenza, common cold

-Chronic hepatits B and C

-Also used for breast cancer, lung cancer, Kaposi sarcoma (AIDs-associated cancer)

Front 427

Interferon mechanism of action

Back 427

Front 428

Interferon adverse effects

Back 428

-Flu-like symptoms (headache, fatigue or asthenia, myalgia, arthralgia, fever, chills)

-Neuropsychiatric: depression, emotional liability, insomnia

-Alopecia

-Thyroiditis: can unmask or exacerbate; IFN-induced disease may not be reversible after stopping treatment

Front 429

Interferon indications

Back 429

HepB:

-HBeAg+ carriers with chronic active hepatitis

-Response rate: 30-40%

HepC:

-Interferon may be considered for chronic active hepatitis

-Response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment

Front 430

Lamivudine

Back 430

-Nucleoside analog

-Inhibits HBV DNA polymerase

-Also inhibits HIV reverse transcriptase

-Well tolerated, most patients will respond favorably

-Tendency to relapse on cessation of treatment

-Rapid emergence of drug resistance

Front 431

Adefovir

Back 431

-Adefovir dipivoxil-adenin nucleotide analog phosphorylated by cellular kinases to active diphosphate metabolite --> competitively inhibits HBV DNA polymerase and causes chain termination after incorporation into viral DNA

-In vitro activity against a wide range of DNA and RNA viruses, incl. HBV, HIV, and herpesvirus

-Less likely to develop resistant than lamuvidine

-May be used to treat lamivudine-resistant HBV

-More expensive and toxic

Front 432

Entecavir

Back 432

-Guanosine nucleoside analog

-Powerful antiviral similar to Adefovir

-Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA and seroconversion to HBeAg

Front 433

Entecavir mechanism of action

Back 433

-Competitively inhibits all 3 functions of HBV: DNA polymerase, incl. base priming, reverse transcription of the negative strand and synthesis of the positive strand of HBV DNA

-Oral bioavailability ~100%

Front 434

Drugs used to treat viral Hepatitis B

Back 434

Front 435

Hepatitis B drug summary

Back 435

Front 436

Drugs used to treat viral HepC interferons and ribavirin

Back 436

Front 437

Ribavirin (for Hep C)

Back 437

-Guanosine analog phosphorylated by host cell enzymes to active drug

-Used in combo with interferon and ribavirin

Front 438

Ribavirin mechanism of action

Back 438

-Interferes with synthesis of GTP; inhibits viral RNA-dependent DNA polymerase and capping of viral mRNA

-Triphosphate inhibits replication of a wide range of DNA and RNA viruses, incl. Influenza A and B, parainfluenza, RSV, paramyxovirus, HCV, and HIV1

Front 439

Antiviral treatment summary

Back 439

Front 440

Summary of antiviral targets

Back 440

Front 441

HIV structure

Back 441

Front 442

HIV enzymes

Back 442

It is and RNA retrovirus with two major strains (HIV-1 and -2)

-Reverse transcriptase: converts HIV RNA genome into a DNA copy

-Integrase: Inserts the HIV DNA copy into the host genome

-Protease: cleaves and processes immature HIV proteins into mature, functioning proteins

Front 443

HIV infection and replication process

Back 443

Front 444

HIV clinical course summary

Back 444

1. Viral transmission

2. Primary HIV infection

3. Sero-conversion: Ab development after 6-8 weeks

4. Asymptomatic chronic infection with or without persistent generalized lymphadenopathy

5. Symptomatic HIV infection

6. AIDS (presence of AIDS indicator conditions or CD4 cell count <200/mL)

7. Advanced HIV infection (CD4 cell count < 50/mL)

Front 445

Opportunistic infections gained by weakened immunity

Back 445

Front 446

Pathophysiology of HIV infection

Back 446

-AIDS now defined as CD4 count <200/mL

-Infected and untreated people develop S&S typical of HIV infection (AIDS-related infections and cancers)

-Infections acquired as CD4 counts decrease are common with CD4 counts below 350/mL

-HSV infections with lesions in mouth or genitals and occurring more frequently and more severely than previously

Front 447

Infections common in those with HIV

Back 447

Front 448

HIV/AIDS disease progression (markers) *note timeline

Back 448

Front 449

At what viral load do we start to treat somebody with HIV?

Back 449

500CD4/mL

Front 450

Goals of therapy and treatment approach for HIV

Back 450

Pharmacological goals are to:

-Maximally and durably suppress HIV viral load

-Restore and preserve immunologic function

Treatment approach:

-Current recommendation for primary therapy is to administer 2 NRTIs+ either a protease inhibitor or an NNRTI

Front 451

Prior to Zidovudine, what was the focus of treatment for HIV?

Back 451

Decreasing occurrence of opportunistic infections that caused a high degree of morbidity and mortality in AIDs patients

Front 452

What is the plan of treatment for those with HIV?

Back 452

-Highly active regimen (combo drugs) is used to suppress HIV replication and restore the number of CD4 cells and immunocompetence

-5 classes of antiretroviral drugs, each of which targets one of four viral processes

Front 453

5 HIV drug classes

Back 453

1. Entry (fusion) inhibitors

2. Integrase inhibitor

3. Nucleoside and Nucleotide reverse transcriptase inhibitors (NRTIs)

4. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

5. Protease inhibitors

Front 454

What are the several key proteins involved in HIV entry into cells?

Back 454

Front 455

What is the small peptide entry inhibitor available in injectable form only?

Back 455

Enfuviritide

Mechanism of action:

-Mimics the components of the HIV-1 fusion machinery and displaces them, preventing GP120 from deforming to allow the viral protein GP41 to embed itself into the host cell's plasma membrane

-Expensive

-Used as a reserve for "salvage" therapy in patients with multi-drug resistant HIV

Front 456

What are the side effects of Enfuviritide?

Back 456

-Injection site reactions (COMMON)

-HSR (uncommon)

-Eosinophilia

-Increased risk of pneumonia on Phase III studies

Front 457

How is resistance to enfuviritide acquired?

Back 457

-Changes in gp41

Front 458

Which entry inhibitor interferes with binding of HIV to CD4+ receptors and chemokine co-receptors?

Back 458

Maraviroc

Mechanism of action:

-Blocks the chemokine receptor CCR5

-Because HIV can also use another co-receptor, CXCR4, and HIV tropism test such as trofile assay must be performed to determine if the drug will be effective

Front 459

What are the reverse transcriptase inhibitors?

Back 459

Front 460

What are Nucleoside Reverse Transcriptase Inhibitors? What is the difference with nucleotide variants?

Back 460

Inactive drugs PHOSPHORYLATED to active metabolites that compete with endogenous nucleosides for incorporation into viral DNA

-Competitively inhibit HIV reverse transcriptase and terminate synthesis of DNA chains

(Nucleotides are the same thing but do NOT require phosphorylation)

Front 461

NRTIs Mechanism of Action: Nucleoside analogs (e.g. AZT)

Back 461

-Analogs of thymidine, cytosine, adenine, or guanine

-Tri-phosphorylated inside the cells to the active compound

-Incorporated into the growing HIV viral DNA strand by reverse transcriptase

-When administered as a single anti-retroviral anent, HIV rapidly develops resistance

Front 462

NRTIs Mechanism of Action: Nucleotide analogs (e.g. Tenofovir (TDF))

Back 462

-Do NOT need to be tri-phosphorylated, only di-phosphorylated to active compound

Front 463

Zidovudine (AZT or Azidothymidine)

Back 463

-Sometimes co-formulated with Lamivudine

-Active orally, widely distributed

-Hepatic metabolism, renal excretion

-Used to prevent vertical transmission of HIV from mother to child (HAART is preferred in pregnant women and is very effective in preventing resistance)

-Resistance via reverse transcriptase inhibitors

-High grade resistance requires serial multiple mutations (hence, overcome by increasing the dose)

-First line NRTI in paediatric patients and pregnancy *

Front 464

What are the adverse effects of Zidovudine?

Back 464

-Bone marrow suppression

-GI complaints

-CNS: headaches, insomnia, peripheral neuropathy

-Mitochondrial toxicity, myalgia, myopathy, cardiomyopathy

-Lactic acidosis*: severe and can be fatal

-Cholestatic hepatitis, lipodystrophy

-NOT tertatogenic, can be started as early as 14 weeks gestation

Front 465

Lactic acidosis caused by Zidovudine

Back 465

-Damage to mitochondria in cells

-Elevated lactate, low pH/bicarb, N/V, SOB, if untreated can lead to death

Front 466

Hepatomegaly with steatosis caused by Zidovudine

Back 466

-Build up of fat droplets inside liver cells

-Enlarged liver

Front 467

NRTIs: Agent-specific side effects (part 1)

Back 467

Front 468

NRTIs: Agent-specific side effects (part 2)

Back 468

Front 469

NRTI combinations

Back 469

-Combivir is first choice, Trizivir is alternative

-1 tablet helps with compliance and resistance

Front 470

NNRTI mechanism of action

Back 470

-Directly bind to reverse transcriptase to inhibit transcription

-NNRTIs do not require phosphorylation to be active

Front 471

HIV drugs and location of effect picture

Back 471

Front 472

NNRTIs

Back 472

Front 473

What do NNRTIs and Rifampin have in common?

Back 473

CYP3A4 inducers!! So cannot treat TB and HIV with these at the same time, or risk compromising treatment as a whole

Front 474

Protease inhibitors

Back 474

Viral protease gene encode viral enzyme which cleave polyprotein into core structural proteins

-Protease inhibitors are designed to block active site of viral protease

-Generally, used in combo with NRTIs and NNRTIs

-Resistance due to protease gene mutations

-High grade resistance requires serial, multiple mutations

Front 475

What is a protease inhibitor for HIV and a potent cytochrome P450 inhibitor?

Back 475

RITONAVIR

-First line drug when combined with other PIs (Lopinavir)

-Low doses will "boost" serum levels and half lives of other Protease inhibitors --> allows use of lower doses and reduce toxicity

-Good availability but TASTES BAD

Front 476

What are the adverse effects of Ritonavir?

Back 476

-Common when used in FULL dose

-GI, esp. taste sensation

-Hypertriglyceridemia

-Rare paresthesias

-multiple drug interactions (inhibits p450)

Front 477

What is the most potent protease inhibitor (HIV)?

Back 477

LOPINAVIR (LPV)

-Co-formulated with Ritonavir in order to take advantage of P450 inhibition by Ritonavir, increases antiviral effect of LPV

-Well tolerated with some GI toxicity and hyperlipidemia

-1st line when combined with ritonavir

Front 478

What is a protease inhibitor that contains a sulphonamide moiety (HIV)?

Back 478

FOSAMPRENAVIR (FPV) and DARUNAVIR

-1st line when combined with ritonavir

-Therapeutic failure when used "unboosted"

Front 479

What are the adverse effects of Fosamprenavir and Darunavir (protease inhibitors - HIV)?

Back 479

-Stevens-Johnson syndrome

-Headache

-Fosamprenavir: transaminase elevation, hyperglycemia and hyperlipidemia

-Darunavir: GI and metabolic disturbances

Front 480

What is a protease inhibitor that is sensitive to gastric pH (HIV)?

Back 480

Atazanavir (ATV)

-1st line drug when combined with ritonavir

Front 481

Atazanavir (protease inhibitor-HIV) toxicity

Back 481

-Cardiac, hyperlipidemia, nephrolithiasis

-NOT to be used with NVP

-Inhibits cytochrome enzymes --> drug-drug interactions

Front 482

What is HAART and what is the selection of appropriate drugs for combinations based on?

Back 482

Highly active anti-retroviral therapy

1. Avoiding the use of 2 agents of the same nucleoside analog

2. Avoiding overlapping toxicities and genotypic and phenotypic characteristics of the virus

3. Patients factors, e.g. disease symptoms and concurrent illnesses

4. Impact of drug interactions

5. Ease of adherence to complex regimen

Front 483

Drugs for HIV: combinations

Back 483

Rationale: delay resistance

-2 nucleoside/-tide reverse transcriptase inhibitors + 1 protease inhibitor +/- ritonavir

-2 NRTI + 1NNRT

Front 484

Summary: sites of action of anti-HIV drugs

Back 484

Front 485

What are the major invasive fungal organisms?

Back 485

1. Candida

2. Aspergillus

3. Blastomyces

4. Coccidioides

5. Cryptococcus

6. Histoplasma

7. Zygomycosis (Mucor)

8. Sporotrix

Front 486

What leads to increased susceptibility to fungal infections?

Back 486

1. Immunosuppressive disease (congenital or acquired)

2. Immunosuppressive therapy (Cancer, HIV/AIDs, organ transplant)

3. Use of broad-spectrum antibiotics

4. IN-DWELLING CATHETERS

Front 487

Classification of anti-fungal drugs

Back 487

Front 488

What is the mechanism of action of polyenes?

Back 488

-Binds to ergosterol in the fungal cell membranes, forms pores, and increases the permeability to proteins and monovalent ions, esp. K+ and divalent cations

-Eventually leads to cell death

-Polyenes attach with higher affinity to ergosterol-containing membranes than cholesterol-containing ones (i.e. mammalian)

Front 489

What are the adverse effects of polyenes?

Back 489

AmphoB may also induce oxidative damage in fungal cells and has been reported to stimulate host immune cells

-Causes the release of inflammatory cytokines by circulating monocytes, resulting in fever, chills, rigour, nausea, vomiting, myalgias, arthralgias, and headache during IV infusions

-At higher concentrations, amphoB binds to cholesterol in mammalian cell membranes, leading to various organ toxicities, esp. nephrotoxicity

Front 490

What are the indications for Amphotericin B?

Back 490

-Systemic mycotic infections including aspergilliosis, blastomycosis, and coccidomycosis

-Nephrotoxicity may occur when given in high doses

-HYPOKALEMIA might occur (pregnancy category B)

Front 491

Amphotericin B spectrum of activity

Back 491

-BROAD spectrum antifungal

-Active against most holds and yeasts

-Holes: C. lusitanae, fusarium, Tricosporon, Scedosporium

Front 492

AmphoB activity spectrum picture

Back 492

Front 493

AmphoB resistance mechanisms

Back 493

-Resistance in a previously susceptible species is uncommon

-Leads to reductions in ergosterol biosynthesis

-Synthesis of alternative sterols that lessen the ability of AmphoB to interact with the fungal membrane

Front 494

Which polyene increases fungal cell membrane permeability and is only good for candida infections?

Back 494

NYSTATIN

-Topical, GI, GU drug only

-Oral, intestinal, and vaginal candidiasis

S/E:

-PO: anorexia, MD (large doses), stomach cramps, rash

-Vaginal: Rash, burning sensation

Contraindications: HSR, pregnancy (vaginal)

Front 495

Which anti-fungal inhibits ergosterol synthesis by inhibiting CYP-450-dependent lanosterol 14-alpha demethylase?

Back 495

AZOLE

-Leads to depletion of ergosterol in fungal cell membrane

-Impair fungal ATPase function

-Broad spectrum activity: Candida, cryptococcus, blastomyces, histoplasma, coccidiodes, dermatophytes

Front 496

Fluconazole

Back 496

-Low molecular weight and high water solubility, leading to rapid absorption and high bioavailability

-Effectively penetrates the CSF, brain and eyes (50-90% plasma levels)

->90% renal excretion

S/E:

-Very well tolerated, even up to 1600 mg/day

-GI, reversible transaminase elevation

Advantage: IV and oral interchangeable (>90% bioavailability), azole of choice for treatment and 2nd prophylaxis of cryptococcal meningitis

Front 497

Which azole is fungicidal in vitro against ASPERGILLUS?

Back 497

VORICONAZOLE

-Also fungicidal for scedosporium, and fusarium spp.

-Fungistatic in vitro against Canadida spp.

Indications:

-Invasive aspergillosis, esophageal candidiasis

-Fungal infections caused by Scedosporium and fusarium spp. in patients intolerant of or refractory to other therapy

Front 498

What are the adverse effects of Voriconazole?

Back 498

-Visual disturbances: decr. electrical currents in the retina

-Incr. liver function tests, skin reacions

Front 499

Which azole tends to inhibit mammalian CYT P450 enzymes and are less selective for fungal P450 than newer azoles?

Back 499

KETOCONAZOLE (no longer used much in USA)

-Inhibits mammalian steroid synthesis (cortisol, testosterone --> gynecomastia)

Drug interactions: Serum levels DECREASED by Rifampin (used for TB) and other inducers

Front 500

Itraconazole

Back 500

-Only ionized at low pH, leading to wide inter patient variability in plasma concentrations

-nonlinear serum PK

-Extensively metabolized in the liver*

Adverse effects:

-Hepatotoxicity (~5%), negative inotrope (decr. heart contractility)

Drug interactions:

-Substrate and inhibitor of CYP3A4

-NB also affects and affected by the enzyme inducers - rifampin, phenytoin, phenobarbital

Front 501

Itroconazole spectrum of activity

Back 501

-Paracoccidiomycosis

-Blastomycosis

-Histoplasmosis

-Sporotrichosis

-Cutaneous and mucosal candiasis

-Aspergillosis

Front 502

Azole antifungal spectrum of activity

Back 502

Front 503

Which anti-fungal drug inhibits squalene2,3-epoxidase?

Back 503

ALLYAMINES (Terfinafine, nafitifine, amorolfine, butenafine)

-Effective against dermatophytes (aspergillus sp., and candida and pityrosporum yeasts)

- Fungistatic against Candida but can cure in after 2-4 weeks

-Inhibition of the epoxidase leads to the accumulation of squalene (toxic/cidal to sensitive organism)

-Used ORALLY for dermatophytes

Front 504

Which anti-fungal drug is extensively distributed to the hair follicle, nail plate, and sebum rich skin and can be detected in the nail clippings three weeks after the initiation of therapy?

Back 504

TERBINAFINE (Allyamine)

-Well absorbed from GIT

-Metabolized then excreted in urine

S/E:

-Alcohol and hepatotoxic medications may increase risk of liver damage

-Potentiates the effects of caffeine and theophylline

Front 505

Terbinafine drug interactions

Back 505

Substrate of CYP1A2, 2C9/19, and 3A4

-Cimetidine decr. clearance by 33%

-Rifampin incr, clearance by 100% (avoid combo)

Strong inhibitor of CYP-2D6

-Increase levels or t1/2 or Cmax of tricyclic antidepressants (TCAs, e.g. notriptyline, amitriptyline, desipramine)

-Avoid combo or adjust dosages

Front 506

Which fungistatic anti-fungal is a pro-drug deaminated to 5-fluoroacil (5-FU)?

Back 506

FLUCYTOSINE (5-FC)

-Incorporated into RNA and disrupts protein synthesis

-Resistance develops during therapy, esp. monotherapy

-Single point mutation leading to loss of permease necessary for cytosine transport

-Decr. activity of UMP phosphorylase or cytosine deaminase

-Incr. synthesis of pyrimidines which compete for 5-FU metabolites, leading to decreased antimycotic activity

Front 507

Flucytosine Mechanism of Action

Back 507

Front 508

What is the spectrum of activity of Flucytosine (5-FC)?

Back 508

Cryptococcus neoformans*

-Candida spp. (except C.kusei)

-Little to no activity against Aspergillus sp. and other molds

Pharmacokinetics: ORAL DOSING ONLY

-Distribution: CSF levels (75%)

Elimination: 90% excreted via GFR, t1/2 is 6 hours, adjust dose in RF

Front 509

Adverse effects of flu cytosine (5-FU)

Back 509

-Dose-dependent bone marrow suppression (decr. WBC, decr. platelets)

-GI: nausea/vomiting/diarrhea

Front 510

Flucytosine clinical uses

Back 510

-Cryptococcal meningitis, hepatosplenic candiasis, candida endophthalmitis

-Used in COMBO ONLY (usually with Amphotericin B, ampho potentiates uptake, minimizes development of resistance)

Front 511

Which fungistatic drug is mostly used topically and disrupts fungal mitotic spindles and inhibits mitosis?

Back 511

GRISEOFULVIN

-Used for microsporum, epidermophyton, trichophytons (tinea capitis, corporis, and cruris), athletes foot

S/E:

-Headache (15%), peripheral neuropathy, confusion

-Antabuse (disulfiram-like) reactions

-Photosensitivity and drug interactions

Front 512

Griseofulvin

Back 512

-Hepatic metabolism

-Weak inducers of CYPs 1A2, 2C9, 3A4

-Decreased effectiveness of cyclosporine (dec. 40%), estrogens, warfarin

-Monitor effectiveness of treatment

-Phenobarbital and omeprazole decreased absorption (may require increase in dose)

-Theophylline dose reduction when administered together

Front 513

Which group of antifungals irreversibly inhibit Beta-1,3-D glucan synthesis (enzyme complex that forms glucan polymers in the fungal cell wall)

Back 513

Echinocandins : Caspfungin, micafungin, anidulafungin

-Glucan polymers provide rigidity to cell wall, leading to disruption of beta-1,3-D glucan synthesis and reduced cell wall integrity, cell rupture, and cell death

Front 514

Spectrum of activity of Echinocandins

Back 514

Front 515

Anti-fungals summary (part 1)

Back 515

Front 516

Anti-fungals summary (part 2)

Back 516

Front 517

What is the most severe form of Malaria and can be fatal (accounts for up to 80-90% of deaths)?

Back 517

Plasmodium falciparum

-Can infect RBCs of ALL ages, resulting in high levels of parasitemia

-End-organ disease may develop rapidly specifically involving CNS, lungs, and kidneys leading to hypoglycaemia, lactic acidosis, severe anemia, and multi-organ dysfunction due to hypoxia

Front 518

Symptoms of malaria

Back 518

-Flu-like illness with moderate to severe shaking/chills

-High fever, headache, muscle aches and tiredness

-Profuse sweating as body temp falls

-Nausea, vomiting, and diarrhea

-Anemia and jaundice

-Chills, fever, headache, anemia

P.falciparum: if not treated, can cause kidney failure, seizures, mental confusion, coma, and death

Front 519

Which malarial parasite can cause a severe form of disease similar to falciparum?

Back 519

P. knowlesi

Front 520

Which malarial parasites only infect YOUNG RBCs?

Back 520

P. vivax and P.ovale

-Benign TERTIAN fever, every 3rd day

-Have exo-ertythrocytic stage

Front 521

Which malarial parasite is a quartan malaria (only every 4th day) with NO EXO-ERYTHROCYTIC STAGE?

Back 521

P. Malariae

Front 522

Malaria infective cycle

Back 522

Front 523

What are the 4-aminoquinolone derivatives of anti-malarials?

Back 523

-Hydroxychloroquine

-Chloroquine

-Quinine and quinidine

-Mefloquine

Front 524

What are the 8-aminoquinolone derivatives of antimalarials?

Back 524

Primaquine

Front 525

What are the atermisinins of antimalarials?

Back 525

Artesunate

Artemether

Front 526

What are the sulfones and sulphonamide of antimalarials?

Back 526

-Sulfadiazine

-Dapsone

Front 527

What are the dihydrofolate reductase inhibitors of antimalarials?

Back 527

-Chloroguanide, Pyrimethamine, Trimethoprim

Front 528

Which 2 antibiotics are used against malaria?

Back 528

Tetracyclines

Doxycycline

Front 529

What are common drug combinations used against malaria?

Back 529

-Pyrimethamine and sulfadioxine --> fansidar

-Pyrimethamine and dapsone --> maloprim

-Halofrantrine- N/A in USA;/Lamifantrine (in Coartem)

Front 530

What is the drug classification of antimalarials?

Back 530

Classification based on selective actions of drugs on different phases of the parasite life cycle

1. Tissue schizonticides: Eliminate developing or dormant (hypnozoites) liver forms

2. Blood schizonticides: Act on erythrocytic parasites

3. Gametocides: Kill sexual stages and prevent transmission to mosquitoes

NB: No ONE available agent can reliably effect a RADICAL CURE

Front 531

Which synthetic 4-aminoquinoline anti-malarial is formulated as the phosphate salt for oral use?

Back 531

CHLOROQUINE

-Plasmodium accumulate chloroquine in food vaculoes

-Drug is incorporated into the DNA chain of plasmodium - inhibits proliferation

-Prevents the polymerization of hemoglobin breakdown product (heme) into hemozoin --> buildup of free heme toxic toparasite

-Increases the cellular pH --> decreases plasmodium protease activity

Front 532

Chloroquine mechanism (malaria)

Back 532

Front 533

How is resistant to chloroquine acquired? (malaria)

Back 533

Thought to be due to increased efflux of the drug

-Very common among strains of P.falciparum and uncommon but increasing for P.vivax

Front 534

What are the pharmacokinetics of chloroquine? (malaria)

Back 534

-Rapidly and almost completely absorbed from GIT

-Very large apparent volume of distribution of 100-1000L/kg

-Necessitates the use of a loading dose to rapidly achieve effective serum concentrations

-Slowly released from tissues and metabolized

-Principally excreted in the urine

Front 535

What is the anti-malarial action of chloroquine?

Back 535

-Highly effective blood schizonticide

-Moderately effective against gametocytes of P.vivax, P.ovale, and P.malariae but NOT against P.falciparum gametocytes

-Not active against liver storage parasites*

-Also has immunosuppressive action

Front 536

What are the clinical uses of chloroquine? (malaria)

Back 536

-Treatment of sensitive falciparum and non-falciparum

-Combined with PRIMAQUINE of radical cure of P.vivax and P.ovale because chloroquine does not eliminate dormant liver forms of these species

Front 537

When is chloroquine used for chemoprophylaxis?

Back 537

-For areas WITHOUT resistant falciparum malaria in malarious regions

-Amebic liver abscess *

-NB: Not effective for treating intestinal or other extra-hepatic amebiasis

Front 538

What are the adverse effects of chloroquine? (malaria)

Back 538

-Usually very well tolerated

-Pruritis is common

-Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurred vision, and utricaria are uncommon

-Dosing after meals may reduce some adverse effects

-Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis, seizures, hypotension, ECG changes

-Teratogenesis? Pregnancy risk category C

Front 539

What is an alkaloid derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South American and used against malaria?

Back 539

QUININE and QUINIDINE

-Remains the 1st line therapies for P.falciparum infection, esp. severe disease

-Quinine is the levorotatory stereoisomer of quinidine

Pharmacokinetics: Rapidly absorbed after oral administration

Front 540

Which anti-malarial drug complexes with dsDNA to prevent strand separation, hence blocking DNA replication and transcription to RNA?

Back 540

QUININE

-Rapidly absorbed orally and is metabolized before renal excretion

-IV administration possible in severe infections

-Solely a blood schizonticide

-Used against P.falciparum infections that are resistant to chloroquine in patients who can tolerate oral treatment

-Used with doxycycline or clindamycin to shorten the duration of therapy and limit toxicity

Front 541

What is the anti-malarial drug that is the dextrorotatory stereoisomer of quinine?

Back 541

QUINIDINE

-IV use in the US for treatment of severe falciparum malaria

-Drugs should not be used routinely for prophylaxis to delay emergence of resistance

Front 542

Which anti-malarial drug causes Cinchonism and what does it consist of?

Back 542

Toxicity by QUINIDINE/QUININE

-GI distress, headache, vertigo, blurred vision, and tinnitus

Front 543

What are the toxic reactions caused by the anti-malarials Quinine/Quinidine?

Back 543

-Severe overdose --> disturbances in cardiac conduction that resemble quinidine toxicity

-Hematotoxic effects: Hemolysis in G6PD-deficient patients

-Blackwater fever (IV hemolysis) --> rare and sometimes fatal complication in quinine-sensitized persons

-Quinine is contraindicated with pregnancy

Front 544

Which drug is used for chloroquine-resistant falciparum malaria, esp. for cerebral malaria?

Back 544

QUININE

-Oral treatment of falciparum malaria

-Malarial chemoprophylaxis

-Both Quinine and Quinidine are administered PARENTERALLY for treatment of severe falciparum malaria

-Quinine is also used for Babesiosis infection

Front 545

What are the cautions and adverse effects associated with Quinine (anti-malarial)?

Back 545

-Cinchonism

-Cardiovascular effects: severe hypotension and arrhythmia can follow TOO RAPID IV infusion

-Idiosyncrasy: hemolysis with G6PD deficiency

-Others: hypoglycaemia through stimulation of insulin release; stimulate uterine contractions

Front 546

Which anti-malarial 4-quinoline derivative is used as the 1st line drug for prophylaxis in all areas with chloroquine resistance and alternative drug to quinine in acute attacks resulting from P.falciparum?

Back 546

MEFLOQUINE

-Only given orally due to local irritation, and absorption is variable

-Mechanism of action is unknown

-Resistance has emerged in regions of southeast asia

Front 547

What are common adverse effects of Mefloquine? (malaria)

Back 547

-Psychiatric disorders

-Neurologic symptoms

-Seizures

-GI distress, skin rash, headache, dizziness

-At high doses can cause cardiac conduction disturbances

Front 548

Which anti-malarial forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants?

Back 548

PRIMAQUINE

-Tissue (liver)schizonticide, also limites transmission by acting as a gametocide

Front 549

Which drug eradicates the liver stages of P.vivax and P.ovale and should be used in conduction with a blood schozonticide?

Back 549

PRIMAQUINE

-Not active alone in acute attacks of P.vivax and P.ovale malaria

Front 550

Clinical use and adverse effects of Primaquine?

Back 550

-14 day course of primaquine is standard after treatment with chloroquine (RADICAL cure)

S/E:

-Usually well tolerated but may cause GI distress, pruritis, headaches and methemoglobinemia

-Serious toxicity involves hemolysis in G6PD-deficient patients

-Contraindicated in pregnancy

Front 551

What is Atovaquone?

Back 551

-Anti-malarial drug, also used against. J.Jiroveci (PCP), and Babesia

-M/A unknown but probably inhibits mitochondrial electron transport --> inhibiting metabolic enzymes (and may also inhibit folate metabolism?)

-Used orally (poorly absorbed) and should be given with food to maximize bioavailability

-Eliminated mostly via feces unchanged

Front 552

How is resistance to Atovaquone in malaria acquired?

Back 552

Mutations in cytochrome B associated (in vivo and in vitro)

Front 553

What are the common adverse effects of Atovaquone (anti-malarial)?

Back 553

-Rash, cough, NVD, fever, and abnormal liver function tests

-Should be avoided in patients with a history of cardiac conduction defects, psychiatric disorders, or seizures

Front 554

Which 2 anti-malarial drugs rely on the fact that malaria synthesizes folate and the host does not?

Back 554

SULFONAMIDES and SULFONES

-Sulfonamides: inhibit dyhydropteroate synthetase

Front 555

Which 2 anti-malarial drug bind dihydrofolate reductase, inhibit formation of tetrahydrofolate, and inhibit production of purines and synthesis of nucleic acids?

Back 555

PROGUANIL and PYRIMETHANINE*

-Only inhibit plasmodia in exoerythrocytic stage

-Always used in combo with other agents

Combinations:

-Sulfadoxide/pyrimethamine (Fansidar)

-Atovaquone/proguanil (Malarone)

Front 556

Which anti-malarial drugs are used for chemoprophylaxis for travellers to geographical areas with both chloroquine- and mefloquine-resistant P.falciparum?

Back 556

TETRACYCLINE AND DOXYCYCLINE

Front 557

Which anti-malarial drug is active against the erythrocytic stage of all 4 human malaria species, including chloroqune-resistant falciparum?

Back 557

HALOFRANTINE

-M/A is unknown

-Active against erythrocytic stages of all 4 human malaria species, including chloroquine-resistant falciparum

-Not used for chemoprophylaxis due to its potential for cardiotoxicity (QT prolongation) and embryoxicity

Front 558

What are the Artemisinin anti-malarials?

Back 558

ARTESUNATE AND ARTEMETHER

-Metabolized in the food vacuole of the parasite to free radicals

-Alkylate heme via free radical formation

-Very effective blood schizonticides active against P.falciparum, including MDR strains

-Not used for chemoprophylaxis because of their short half lives?

Front 559

Which Artemisinin combination drug is highly effective in Southeast asia where resistance to many antimalarials is common?

Back 559

ARTESUNATE-MEFLOQUINE

-1st line therapy in some countries in SE Asia and South America

-Relatively high cost and poor tolerability

Front 560

Which Artemisinin combination drug is now the standard treatment for uncomplicated falciparum malaria in most countries in African and additional endemic countries elsewhere?

Back 560

ARTESUNATE-AMODIAQUINE OR ARTMETHER-LUMEFANTRINE

Front 561

Which new Artemisinin combination drug is the new regimen with excellent efficacy?

Back 561

DIHYDROARTEMISININ-PIPERAQUINE

-1st line therapy for falciparum malarian in Vietnam

Front 562

Drugs for chemoprophylaxis of malaria

Back 562