Module 4 - Common Prescription Drugs PDF

## Module 4 - Common Prescription Drugs ### 01 - Antibiotic, Antifungal, and Antiviral Agents **Selective Toxicity** - the use of drugs to harm an invading organism without harming the host. - The development of drugs to treat infections is based on this - the development of drugs and antivirals...

## Module 4 - Common Prescription Drugs ### 01 - Antibiotic, Antifungal, and Antiviral Agents **Selective Toxicity** - the use of drugs to harm an invading organism without harming the host. - The development of drugs to treat infections is based on this - the development of drugs and antivirals is all based on the difference between invading organisms and human cells. **Antibiotic** - a chemical substance that suppresses the growth of bacteria, and may eventually destroy them. - their purpose is to stop a bacterial infection. - is accomplished through **bacteriostatic or bactericidal** effects **Structure of Bacterial Cells** - It is important to understand this to understand how antibiotics are classified. - these cells have **Cell Walls** - rigid outer layer that surrounds the cyto plasmic membrane - contains a peptidoglycan layer - complex cross-linked polymer of polysaccharides and polypeptides - responsible for maintaining the cell’s shape and integrity, are - the cross links, the cell wall is structural rigidity, are - preventing the cell from high osmotic pressure. - bacteria are classified as either **Gram-negative or Gram-positive** based on the composition of their cell walls. - **Gram-positive** bacteria have a thick peptidoglycan layer and no outer membrane. - **Gram-negative** bacteria have a thin peptidoglycan layer and an outer membrane. **Classification of Antibiotics by Spectrum** - Based on the spectrum of microorganisms affected. - **Narrow Spectrum** - these antibiotics are only useful against particular species of microorganisms. - **Broad Spectrum** - these antibiotics are effective against a wider range of microorganisms, including both Gram-positive and Gram-negative. **Classification of Antibiotics by Biochemical Pathway** - antibiotics utilize the concept of selectivity directly by targeting and interfering with essential components of biochemical reactions in bacteria. Employing the bacteria cell in classifying antibiotics this way allows for the discussion of antibiotics with similar mechanisms of action - **Cell wall synthesis inhibitors** - function to stop the proper formation of the bacterial cell wall and/or **penicillin**, and **cephalosporins** - the cell wall membrane, affecting the structural integrity of the cell. - **DNA Synthesis inhibitors** - inhibit DNA replication, preventing bacterial growth. - ex. **Fluoroquinolones** - **Protein synthesis inhibitors** - inhibit protein translation and thereby protein synthesis. - ex. **Tetracyclines** and **macrolides** - **Metabolic inhibitors** - block the formation of key bacterial metabolic substrates needed for the bacteria to survive and reproduce (ex. **antifolate drugs**) **Penicillins** - Cell wall synthesis inhibitor - Two types exist: natural and semisynthetic. - **Penicillin G** - natural penicillin, extracted and purified from Penicillium mould, it is a narrow spectrum antibiotic that destroys mainly Gram-positive bacteria. - useful in the treatment of pneumonia, middle ear infections, skin infections, meningitis, and syphilis. - **Methicillin** - an antibiotic resistant to breakdown by penicillinase. - penicillinase is an enzyme that breaks down penicillin that organisms can produce and become resistant to penicillin G. - **Ampicillin and Amoxicillin** - antibiotics that have a broader spectrum of antibacterial activity than penicillin G and are useful against a range of Gram-negative bacterial infections (ul. UTIs). - **Amoxicillin + Clavulanic Acid** - a combination of semisynthetic penicillin plus an inhibitor of penicillinase - was introduced into therapy to combat penicillinase-producing bacteria strains. **Adverse Effects** - Most common one is gastrointestinal distress (nausea and diarrhea) due to disturbance of healthy gut flora. - 1-10% of the population is allergic to penicillin. - causes rash, fever, face + tongue swelling, and itchy hives. - in rare cases it may cause anaphylactic shock. **Cephalosporins** - Cell Wall Synthesis Inhibitor. - Chemically similar to penicillin, but are generally more resistant to penicillinase. - Divided into five generations, mainly depending on their spectrum of activity. **Adverse Effects** - Similar to penicillin. - gastrointestinal side effects. - there is potential for people allergic to penicillin to also be allergic to cephalosporins, though this is uncommon. **Mechanism of Action of Penicillin and Cephalosporins** - Penicillin and cephalosporin resemble D-Alanine in structure and compete with it for the binding spot on **transpeptidase**. - Transpeptidase is the enzyme that connects two glycopeptide chains in the cell wall. - Without the formation of these cross-links the cell wall is not functional. - Without a functional cell wall the cell will be unable to maintain its high internal pressure causing it to break open and die. - The cells that form without a cell wall are known as **protoplasts**. - They are fragile and can readily burst **Fluoroquinolones** - DNA Synthesis Inhibitor. - Chemically distinct class of antibiotics that inhibit bacterial DNA synthesis - ex. **Ciprofloxacin** - Can be used for oral or intravenous therapy of infections caused by a wide variety of Gram-pos and Gram-neg microorganisms. **Tetracyclines** - Protein Synthesis Inhibitors. - Were one of the first broad spectrum antibiotics developed - Though be of widespread use for many years, many bacteria have become resistant to them. **Mechanism of Action** - They bind to the 30s subunit of the mRNA ribosomal complex, which prevents the addition of amino acids to the protein chain, thereby inhibiting protein synthesis. **Adverse Effects** - Gastrointestinal effects, discoloration of teeth, and diminished bone growth - They have a strong affinity for calcium. - So they are used very cautiously during pregnancy or in children under 12. **Storage** - Can deteriorate into toxic degradation products if stored for long periods of time, so it’s important to discard outdated supplies. **Macrolides** - Protein Synthesis Inhibitors - Active against several bacterial infections caused by Gram-positive microorganisms. - Erythromycin is a type of macrolide that is also effective in treating some Gram-negative bacterial infections. - May be an effective alternative for those allergic to penicillin. **Mechanism of Action** - Bind to the 50s ribosomal unit on tRNA, which blocks peptide bond formation. **Adverse Effects** - Nausea, vomiting, and diarrhea. - Most common cause of discontinuing erythromycin treatments. **Metabolic Inhibitors - Antifolates** - Inhibit folate metabolism in bacteria. - Tetrahydrofolic acid (a folate) is essential for bacteria to synthesize DNA and protein. - If it’s not formed bacterial growth will slow down. - Sulfonamides and trimethoprim are both classified as antifolate drugs. - Sulfonamides competitively inhibit an upstream step in the synthesis of tetrahydrofolic acid. - Trimethoprim inhibits an enzyme used later in the pathway. - This enzyme (dihydrofolic acid reductase) is also found in humans, trimethoprim is still selectively toxic to bacteria be it has greater inhibitory actions on the bacterial enzyme than the human enzyme. **Combination Antifolates** - By inhibiting sequential steps in the metabolic pathway, an enhanced antibacterial effect is produced. - So a combination product containing sulfamethoxazole and trimethoprim was developed. - also known as **Co-trimoxazole** - Used to treat UTIs, respiratory, and GI tract infections. **Antibiotic Combinations** - Used for therapy of a severe infection when there is not enough time to determine the microorganism responsible. - Treatment of mixed bacterial infections where no single antibiotic could eliminate the whole infection. - Treating tuberculosis, to decrease the chance of emergence of resistant tubercle bacilli **Disadvantages** - Unnecessary additional cost if single antibiotic is effective. - Increased chance of encountering toxicity. - Enhanced opportunity for resistant bacteria to arise if combo is not effective. - Decreased number of normal populations of different bacteria, removing their inhibitory influence on potentially dangerous bacteria. **Antimicrobial Resistance** - Antimicrobials - an Agent that Kills or inhibits the growth of microbes. - Include antibiotics, antifungals, antivirals, and antiparasitics. - During replication bacteria can mutate and evolve to have different properties and therefore become resistant to antibiotics. - Due to this, although rare, there are some infections that are not treatable with the currently available antibiotics. - The initial bacterial population is diverse, with bacteria with different traits. - Some of these may already be resistant to antibiotic effects, so over time these ones will survive, reproduce and form a new resistant population. **Causes of Antibiotic Resistance** - **Over-prescription** (the premature discontinuation) - **Inappropriate Use** (may expose animals to an unnecessary antibiotics) - Use in agriculture - **How organisms become resistant** - **Uptake -** Some basic molecules gain access to the inside of the microorganism by moving through pores in the membrane. Mutation or lack of these pores makes the organism resistant - **Target** - mutation in the target for the antibiotic can reduce the binding of the drug to its target and be ineffective - **Inactivation** - Microorganisms develop an enzyme that inactivates the antibiotic (i.e. the formation of penicillinase) - **Efflux pumps** - some microorganisms will over express transporters that pump the drug out of the microorganism before the cell can be injured. **Antiviral Drugs** - The incidence of serious fungal infections continues to increase particularly in patients who are required to take immunosuppressive drugs - They very few inhibiting class of antifungal drugs are available - Echinocandins - are a newer class of antifungals that are commonly used - they act by inhibiting the synthesis of a component of the wall, resulting in disruption of the cell wall and in fungal death - ex. **micafungin and caspofungin** - are well tolerated in patients and are only available for intravenous administration - **Synthesis of Azoles** - all inhibit a fungal cytochrome p450, thereby inhibiting ergosterol synthesis. - ergosterol is critical for fungal cell wall function and survival - effective when taken orally or intravenously for systemic fungal infections - higher selective toxicity lies in their higher affinity for the fungal p450 than the human p450 - a number of these agents are available as over-the-counter drugs for the treatment of yeast infections - **Viruses and Antiviral drugs** - virus is a subcellular infectious agent that is only able to multiply within the living cell of other organisms - they can be deadly, and there is a great need for additional and more effective antiviral drugs - **Viral Cycle -** is served as a means of identifying targets for drug therapy of viral disease. - it first must gain access to the core of the cell to make multiple copies of the virus in the cytoplasm. - viruses use specific and convine the cells they infect. - In the cell, viral DNA is transcribed to mRNA, and then the host cell transcribes those instructions into the enzymes needed to virus. - Specific receptors on the surface of the target cells; when ready they emerge from the host cell, often killing it in the process. - As they emerge some viruses retain parts of the host cell membrane forming an envelope around the virus - this gives the virus some protection from the host’s immune system - **Each new virus is now capable of infecting another host cell and repeating this process.** **Types of Antivirals** - **Oseltamivir (Tamiflu)** - is a neuraminidase inhibitor used to treat influenza - Neuraminidase is an enzyme that allows the spread of the virus from cell to cell - Drugs of this class prevent neighbouring cells from being infected with the virus. - **Acyclovir** - Is taken up by the infected cell and activated by the virus - The active form inhibits viral DNA replication, so it is selective to cells that are infected with the virus. - The drug of choice for treatment of serious infections caused by herpes simplex virus. - Long-term use of this will markedly decrease the frequency of reccurence of genital herpes. - Diso useful in combating infections/viruses that cause chickenpox and shingles. **02-Regulation of Fertility** **Contraception -** the prevention of conception. **Mechanism of Action of Hormonal Contraceptives** - They inhibit the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. - This causes the pituitary gland to not be stimulated and therefore not release FSH and LH, resulting in no follicular maturation and the inhibition of ovulation. - They commonly include progestins which alter the secretions of the endocrinal gland to a scant, thick fluid not optimal for sperm migration. - They cause the endometrium to not fully develop making it unsuitable for the implantation of a fertilized ovum. **Hormonal Contraceptives** - **Oral Contraceptives** - Usually refers to a product containing both an estrogen and a progestin. - These are the most effective oral contraceptives developed so far. - **Fixed Combination** - these pills have a fixed combination of estrogen and progestin - One type is taken 21/28 days of the cycle with menstruation occuring during the 7 days pill-free. - Another type is taken all 28 days. - Eliminates menstruation during therapy. - **Multiphasic** - usually contain a fixed amount of estrogen but variable amounts of progestin. - The amount of progestin increases week to week. - Hormone dose is kept to a minimum and adverse effects are believed to be reduced. - The hormone sequence more closely mimics the pattern of hormones released in the normal ovarian cycle. - **Progestin Only Pills** - contain a daily low does of progestin, also known as the mini-pill. - Is taken as long as the drug is needed. - Patient acceptability is less than combo-pills, because breakthrough bleeding is often a problem. - Efficacy in preventing pregnancy is slightly less than combo-pills. - **Mild adverse effects:** nausea, edema, and headaches - **Moderate adverse effects:** breakthrough bleeding, weight gain; increased skin pigmentation; acne, hirsutism (abnormal growth of body hair), and increased vaginal and urinal infections. - Post-drug amenorrhea (absence of menstruation) occurs in some patients and may last months. - **Serious adverse effects:** - **Blood clots** - estrogens induce the production of some of the factors required for blood coagulation - Increases death rates from 1/100000 to 3/100000 – small. - **Heart Attack** - estrogen-progestin pills are associated with an increased risk of heart attack - Risk is greater if the patient is obese or smokes. - Believed to be greater associated with the progestin component. - Some newer progestins may be free of this effect. - **Stroke** - all have a increased risk, but for females over 35 its greater. - **Hypertension** - cardiovascular disease is more prevalent in females over 35 who use oral contraceptives. - **Cancer** - current consensus is that endometrial and ovarian cancer risks are reduced, no effect on risk of breast cancer, but there is no clear decision in respect to cervical cancer (as it is complicated by HPV infection) **Non-contraceptive benefits of oral contraceptives:** - Reduced risk of ovarian cysts. - Reduced risk of ovarian and endometrial cancer. - Reduced incidence of ectopic pregnancy when the fertilized egg is implanted outside of the uterus, typically in the fallopian tubes. - Less iron deficiency anemia. - Less acne and hirsutism. - In those containing newer progestins with less androgenic effects. **Depo-Provera (Depot)** - A slow-release formulation contraceptive injection. - A progestin dose is injected intramuscularly every 3 months and provides contraception for roughly the same time period. - **Adverse effects:** similar to those of the mini-pill as they are both progestin-only contraceptives - Frequent breakthrough bleeding. - Small increase in risk of CHD. - Be some older progestins alter the profile of plasma lipids, increasing LDLs and decreasing HDLs. **Intrauterin Devices (IUD)** - Implanted into the uterus by a medical professional. - Most common type releases **levonorgestrel** (a progestin) - Some are effective for up to 8 years. - **Adverse effects:** - Heavy menstrual flow after insertion (resolves within a couple months) - Pelvic discomfort - Increased urinary infections. **Transdermal patch** - Contain estrogen and progestin. - Drug is delivered at a constant rate for 7 days. - So 3 patches per cycle are required. - Same mechanism of action as combo-pills. **Pros and Cons of Hormonal Contraceptives** | Type of Contraceptive | Pros | Cons | |---|---|---| | Enternal oral contraceptives | Most convenient and least expensive, non-invasive, and self-administered. Patients do not control dosing, delivers steady supply for set period and avoids first pass effect. || Variable amount of absorption between patients due to differences in intestinal motility, and subject to the first pass effect. Volume of drug is limited and is a more invasive procedure. | | Paternal (the shot) | Convenient, delivers steady supply for set period, and avoids first pass effect. || Expensive and can cause local irritation. | | Topical (the patch) | | **Efficacy of Hormonal Contraceptives** | Method | Perfect use effectiveness (%) | Typical rate effectiveness (%) | |---|---|---| | Estrogen-progestin | 99.7 | 92 | | Patch | 99.7 | 92 | | Mini-pill | 98 | 92 | | Depot | 99.7 | 97 | | IUD | 99.9 | 99.9 | **Male Contraceptives** - In recent years, research has begun on contraceptives for male-bodied individuals. - Male contraceptives, which can be taken orally or injected have not yet reached the Canadian Market. - Attempts to inhibit spermatogenesis have been largely unsuccessful. - Most of the drugs and processes studied have resulted in unacceptable rates of fertility. - Attempts have been made to inhibit the release of GnRH but then they also decrease testosterone production, which leads to adverse effect of a decreased sex drive. **Potential Male Contraceptives** - **Androgen-based** - Androgens can inhibit the release of GnRH an thus spermatogenesis. - Two major problems were encountered: - Only 80% of the subjects responded with a lowering of sperm count less than four million/mL - The excess androgen enhanced the secondary sex characteristics (ex. aggression) - **Estrogens** - When administered in males they suppress GnRH release and in turn spermatogenesis. - Though testosterone production decreases. - Attempts were made to overcome the deleterious effects of estrogen by adding small amounts of androgens to the regimine - Only 60% were infertile and the adverse effects were too numerous - **Progestin and androgens** - A synthetic progestin is used to inhibit the release of GnRH and androgen is added to replace lost testosterone. - Hence the secondary sex characteristics are maintained. - This method has shown more promise than others. - **Gossypol** - But finding the appropriate dose of the androgen is a major challenge. - This is a compound obtained from cottonseed that destroys elements of the seminiferous tubules. - This in turn decreases sperm production without altering sex drive or other functions of testosterone. - Clinical trials in China have shown 99% infertility of subjects. - Recovery of sperm count is not always guaranteed, however it is more likely to occur if the sperm count does not fall too low and duration of treatment does not exceed two years. - Hypokalema (low potassium) has been a major problem reported, resulting in transient paralysis -