Antibiotic, Antifungal, and Antiviral Agents PDF

Section 1: Antibiotic, Antifungal and Antiviral Agents Intro to antibiotic, antifungal and antiviral agents - Advances of modern medicine has let to treatable infection cures - Selective Toxicity: use of drugs to harm an invading organism without harming the host - Antibiotics, Antifung...

Section 1: Antibiotic, Antifungal and Antiviral Agents Intro to antibiotic, antifungal and antiviral agents - Advances of modern medicine has let to treatable infection cures - Selective Toxicity: use of drugs to harm an invading organism without harming the host - Antibiotics, Antifungals and Antivirals all take advantage of differences between the invading organism and human cells What is an antibiotic - Antibiotic: A chemical substance that suppresses the growth of bacteria and may eventually destroy them. - Antibiotics are commonly used to refer to synthetic and non-synthetic compounds - Purpose of an antibiotic is to stop a bacterial infection through: 1. Bacteriostatic: Inhibits the growth and reproduction of bacteria 2. Bactericidal: Directly kills bacteria Structure of bacterial cells - Cell wall: Rigid outer layer → contains a peptidoglycan layer → Cross linked polymer of polysaccharides polypeptides (gives cell its structural rigidity and maintains the cells shape.) - Cytoplasmic membrane: surrounded by cell wall Gram-positive vs Gram-negative Bacteria - Bacteria are classified as either gram negative or gram-positive depending on their cell walls composition - Gram-Positive - Bacteria have a thick peptidoglycan layer and no outer membrane Gram-negative - Bacteria have a thick peptidoglycan layer and an outer membrane Classification of antibiotics by spectrum 1. Narrow Spectrum - Narrow spectrum antibiotics are only useful against articular species - Penicillin G is primarily effective against gram positive bacteria 2. Broad Spectrum - Effective against a wider range of microorganisms including both gram positive and gram negative bacteria - Tetracyclines are an example Classification of antibiotics by biochemical pathway - You can classify antibiotics based on the biochemical pathways targeted in the bacterial cell - Antibiotics target and interfere with essential components of biochemical reactions in bacteria, killing the bacteria. 4 groups of antibiotics: 1. Cell wall synthesis inhibitors - Function to stop the proper formation of the bacterial cell wall and or membrane influencing the structural integrity of the cell 2. Protein synthesis inhibitors - Inhibit protein translation within bacteria and thereby protein synthesis 3. DNA synthesis inhibitors - Inhibits DNA replication in bacteria preventing bacterial growth 4. Metabolic Inhibitors: - Block the formation of key bacterial metabolic substrates needed for bacteria to survive and reproduce Cell Wall synthesis: Penicillins - Alexander fleming discovered that Penicillin mold could produce and excrete antibacterial substances in 1929, but wasn't successfully isolated from the mold until the second world war (1939-1945) Natural and Semi-synthetic types of penicillins  1. Penicillin G - Extracted and purified from penicillium mold - Narrow spectrum antibiotic that destroy Gram-positive bacteria - Treats: pneumonia, middle ear infections, skin infections and meningitis and treats syphilis. 2. Methicillin - Organisms can produce penicillinase (an enzyme that breaks down penicillin) and become resistant to penicillin G. Methicillin is an antibiotic resistant to attack by penicillinase 3. Ampicillin and amoxicillin - Ampicillin and amoxicillin are antibiotics that have a broader spectrum of antibacterial activity than penicillin G and are useful against a range of infections caused by gram-negative bacteria. 4. Amoxicillin and Clavulanic Acid - Amoxicillin and Clavulanic acid is a combination of a semisynthetic penicillin plus an inhibitor of penicillinase that was introduced into therapy to combat penicillinase-producing strains of bacteria. Mechanism of Action: Penicillin - Related to D-alanyl-D'Alanine (chemical component that builds new bacterial cell walls) - Penicillin interferes with the new bacterial cell wall formation and resulting cells are formed without cell walls These are known as protoplasts. - Human cells do not have cell walls and are unaffected by penicillin (toxic to bacteria) Adverse effects of Penicillin - Gastrointestinal distress (nausea and diarrhea) from disturbance of healthy gut flora - Penicillin allergy (1-10% of the population is allergic to penicillin) - Effects of allergy: rash, fever, face and tongue swelling, itchy hives, severe difficulty breathing, low BP and anaphylactic shock. Cell Wall synthesis inhibitor - Cephalosporins → inhibit cell wall synthesis → more resistant to penicillinase Adverse effects of Cephalosporins - Similar to penicillins - Gastrointestinal side effects like nausea and diarrhea - Uncommon that a person allergic to penicillin is also allergic to cephalosporins Mechanism of Action of Penicillin and Cephalosporins DNA synthesis Inhibitors (Fluoroquinolones) - Chemically distinct class of antibiotics that inhibit bacterial DNA synthesis - Ciprofloxacin is used for oral or intravenous therapy of infections caused by a wide variety of Gram-positive and Gram-negative microorganisms. Protein Synthesis Inhibitors: Tetracyclines - Tetracyclines were one of the first broad-spectrum antibiotics developed. Mechanism of Action - Tetracyclines bind to the 30s subunit of the mRNA ribosome complex and prevent the addition of amino acids to the protein chain inhibiting protein synthesis. Adverse effects - Gastrointestinal effects such as nausea, vomiting and diarrhea as well as discoloration of teeth and diminished bone growth. Use in special populations Storage - Tetracyclines have a strong affinity for calcium therefore they are used cautiously during pregnancy or in children under 12 Storage - Can deteriorate into toxic degradation products if stored for long periods of time so it is important to discard outdated supplies. Protein Synthesis Inhibitors: Macrolides - Active against several bacterial infections caused by Gram-positive microorganisms - Macrolides can be good alternatives for penicillin - Erythromycin can treat infections caused by gram-negative bacteria - Macrolides bind to the 50S ribosomal subunit on tRNA amd block peptide bond formation  - Adverse effects: nausea, vomiting, diarrhea (most common cause of discontinuing treatment with erythromycin) Metabolic Inhibitors - Antifolates are inhibitors of folate metabolism in bacteria - Tetrahydrofolic acid (a folate) is essential for bacteria to synthesize DNA and protein - If tetrahydrofolic acid is not formed bacterial growth will slow - Sulfonamides and trimethoprim are both classified as antifolate 1. Sulfonamides - Sulfamethoxazole (member of the sulfonamide group of drugs) inhibits an upstream step on the synthesis of tetrahydrofolic acid, by inhibiting para-aminobenzoic acid (PABA) incorporated into dihydropteroic acid. - Sulfonamides are selectively toxic to bacteria 2. Trimethoprim - Trimethoprim inhibits the enzyme dihydrofolic acid reductase inhibiting tetrahydrofolic acid formation. - Greater inhibitory action on the bacterial enzyme than on the human enzyme Combination Antifolates - By inhibiting sequential steps in the metabolic pathway, a synergistic antibacterial effect is produced. - Combination product containing sulfamethoxazole and trimethoprim was developed - Sulfamethoxazole-trimethoprim (co-trimoxazole) is useful in treatment of UTIs, respiratory tract infections and GI tract infections Antibiotics used in combination Used for: - Therapy of severe infections where the microorganism is so powerful it must be treated with an antibiotic - Treatment of a mixed bacterial infection where no single antibiotic could eliminate all the different bacterial responsible for the function - Treats tuberculosis where emergence of resistant mycobacterium is an important hazard - Infections treated by 2 antibiotics that act synergistically DIsadvantages - Unnecessary additional cost if a single antibiotic is effective  - Increased chance of toxicity - Enhanced opportunity for resistant bacteria to arise when the combination of antibiotics being used is not effective for the particular bacterial infection - Decreased number of normal populations of different bacteria, removing their inhibitory influence on potentially dangerous bacteria Antimicrobial Resistance - Problem: emergence of resistant strains - During replication, bacteria can mutate and evolve to have different properties and can therefore become resistant to antibiotics - The WHO issued a report outlining the seriousness of the development of resistant strains of organisms → some infections that are not treatable with currently available antibiotics Factors associated with Antibiotic Resistance 1. Evolution of bacteria 2. Clinical and environmental factors (misuse of antibiotic both clinically and in the environment) Causes of Antibiotic resistance 1. Overprescription - Physicians over-prescribe antibiotics because of lack of diagnostic equipment, or pressure from durg companies and patients 2. Inappropriate use - Inappropriate use contributes to antibiotic resistance - Premature discontinuation of treatment or using drugs from others - Some countries allow the sale of antibiotics over counter 3. Use in agriculture - Use of antibiotics in agriculture may expose animals to an unnecessary antibiotic which increases the risk of drug resistance development Antibiotics for the Flu - The flu and common cold are caused by viruses  - Taking antibiotic for a cold contributes to the emergence if resistant bacteria How organism become resistant 1. Uptake - Small molecules gain access to the inside of the microorganism by moving through pores in the membrane - Mutation of these pores makes the organism resistant 2. Target - A mutation in the target for the antibiotic can reduce the binding of the drug to its target and be ineffective. 3. Inactivation - Microorganisms develop an enzyme that inactivates the antibiotic - Formation of penicillinase which inactivates penicillin 4. Efflux pumps - Some microorganisms will over express transporters that pump the drug out of the microorganism before the cell can be injured. Antifungal Drugs - Only a few effective antifungal drugs are available 1. Echinocandids - Newer class of antifungals and are commonly used - They inhibit the synthesis of a component of the cell wall resulting in disruption of the cell wall and fungal death - 2 examples are micafungin and caspofungin - Very well tolerates in patient and are administered intravenously 2. Imidazoles (or Azoles) - Effective taken orally and intravenously for systemic fungal infections - Inhibit a fungal cytochrome P450 which inhibits ergosterol synthesis - Selective toxicity of the azoles lies in their higher affinity for the fungal P450 than the human P450’s that are involved in drug metabolism - Available as over the counter drugs for the treatment of yeast infections Viruses and Antiviral Drugs - A virus is a small, infectious agent that can only multiply within the living cells of other organisms including animals, plants and bacteria - Viruses can be deadly and there is great need for additional and more effective antiviral drugs Types of Antivirals 1. Oseltamivir (Tamiflu) - Neuraminidase inhibitor that treats influenza - Neuraminidase is an enzyme that allows the spread of a virus from cell to cell. - Drugs of this class prevent neighboring cells from being infected with the virus 2. Acyclovir - Acyclovir is taken up into an infected cell, and the virus activates acyclovir to the active form. - Active acyclovir then inhibits viral DNA replication, and therefore acyclovir is only selective for cells that are infected with the virus - Treats serious infection caused by herpes simplex virus Section 2- Regulation of Fertility Intro to regulation of fertility and contraception - Hormonal Contraception only Monthly Ovarian Cycle - Intricate and coordinated interaction of a number of hormones and factors - Mechanism of action of hormonal contraceptives is associated with the changes to the - hormones in the ovarian cycle making it important to understand the ovarian cycle. Mechanism of action of hormonal Contraceptives 1. Inhibit hormone release - They inhibit the release if gonadotropin-releasing hormone (GnRH) from the hypothalamus - As a result the pituitary gland is not stimulated to release follicle stimulating hormone (FSH) and luteinizing hormone (LH) resulting in no follicular maturation and the inhibition of ovulation 2. Inhibit sperm migration - Hormonal contraceptives usually contain progestins which alter the secretion of the endocervical gland ti a scant thick fluid not optimal for sperm migration 3. Inhibit Ovum Implantation - Cause endometrium to not fully develop making it unsuitable for implantation of a fertilized ovum Hormonal Contraceptives 1. Oral Contraceptives - A products that contain both estrogen and a progestin - When both are available in a single contraceptive they are the most effective oral contraceptives to date. Types: 1. Fixed combination - Fixed dose Combination of estrogen and progestin - One preparation is intended to be taken for 21 days out if a 28 day cycle (7 other days are period) - Some are 28 days which skips the period (good for people with difficult periods) 2. Multiphasic - Contain a fixed amount of estrogen and variable amounts of progestin (progestin increases from week to week) - The hormone dose is kept to a minimum and adverse events are believed to be reduced as compared to the fixed dose combination  - Hormonal sequence closely mimics the pattern of hormones released in the normal ovarian cycle 3. Progestin only pill (mini pill) - Contains daily low dose of progestin and taken as long as needed - Patient acceptability is less than with the estrogen-progestin combinations since bleeding between periods is often a problem. - Efficacy in preventing pregnancy is slightly less than with the combination products Mild and Moderate adverse effects of combination oral Contraceptives - Approx 20 million females in NA are taking these daily → toxicities can occur and range from mild to serious Mild: - Nausea→ caused by estrogen component and usually abates after one or two cycles - Edema → estrogen and progestin cause water retention - Headache → If severe, drug must be stopped Moderate: - Breakthrough bleeding, weight gain, skin pigmentation, acne, hirsutism - Post drug amenorrhea (no period) occurs in a few patient and may persist for months Adverse effects: Blood clots: - Estrogens induce the production of some of the factors that are required for blood coagulation Heart Attack: - Small increased risk of a heart attack - Greater if patient is obese, smokes - Associated with progestin component Stroke - Higher risk if over 35 years old Hypertension - More prevalent in users over 35 years old Cancer - Endometrial and ovarian cancer risk are reduced and there is no apparent increased risk of developing breast cancer - No response to cervical cancer Non- Contraceptive benefits - Reduced risk of ovarian cysts - Reduced risk of ovarian and endometrial cancer  - Reduced incidence of ectopic pregnancy (fertilized egg outside of uterus) - Less iron deficiency anemia as menstrual flow is reduced - Less Acne and Hirsutism (for those containing newer progestins with less androgenic effects) 2. Depo-provera - A slow release formulation contraceptive injection - Progestin dose is injected intramuscularly every 3 months and provides contraception for roughly the same time frame Adverse effects Similar to mini pill effects Breakthrough bleeding, small increase in risk of coronary vascular disease 3. IUD - Implanted into uterus by a medical professional - Common type released levonorgestrel (progestin) and some can be effective up to 8 years Adverse effects: Heavy menstrual flow after insertion (resolves after a couple months) , pelvic discomfort, and increased UTIs 4. Transdermal patch - Estrogen and progestin patch that is applied to the skin - Drug is delivered constantly for 7 days (3 patch per cycle) - Same effect as oral contraceptives PROS AND CONS EFFICACY OF HORMONAL CONTRACEPTIVES Male Contraceptives - Attempt to inhibit spermatogenesis have been largely unsuccessful with most of the drugs studied have resulted in unacceptable rates of fertility Potential male Contraceptives  - 4 main compounds have been tested for use as male contraceptives (primarily administered orally or are injected). Types: 1. Androgen Based - Androgens can inhibit the release of GnRh and thus spermatogenesis - 2 major problems were encountered when androgen was injected intramuscularly: Only 80% of the subjects responded with a lowering of sperm count to less than four million/mL The excess androgen enhanced the secondary sec characteristics including aggression 2. Estrogens - When administered to men, suppress GnRH release and therefore spermatogenesis - Testosterone production decreases as does sec drive and men develop feminine characteristics (infertile and lost sex interest) - Androgen was added and therefore on;ly 60% of the subjects became infertile 3. Progestin and Androgen - Synthetic progestin is used to inhibit the release of GnRH resulting in a loss of spermatogenesis as well as testosterone production - More promising than other methods 4. Gossypol - Derived from cottonseed - Destroys elements of seminiferous tubules decreasing sperm productions but doesn’t alter sec drive or other functions of testosterone - Low potassium is a major problem with this drug Hormones in Transgender Individuals - Used to alter hormones that are biologically assigned