ERS37 Drugs Used In Sexually Transmitted Disease Flashcards
STD causative agents
Bacteria, Fungi, Parasites —> Can be treated + cured
- Chlamydia (CT)
- Gonorrhoea (GC)
- Syphilis (Treponema pallidum)
- Candida albicans
Virus —> cannot be cured by drugs, only controlled
- Genital herpes (HSV)
- Genital warts (HPV)
- HIV infections
Bacteriostatic vs Bactericidal
Broad spectrum vs Narrow spectrum
Bacteriostatic:
- inhibit growth
- needs body immune system to get rid of bacteria
- infection may relapse when drug is discontinued
- e.g. Tetracycline
Bactericidal
- kill bacteria directly
- for infections requiring “cidal” action (e.g. Meningitis, Bacteremia, Endocarditis)
- e.g. Penicillins
Broad spectrum
- effective against a wide range of bacteria (Gram +ve + Gram -ve)
- for infection caused by more than 1 type of bacteria (e.g. superinfection)
- for ***empirical treatment without known causative agent
- e.g. Tetracyclines, Amoxicillin, Augmentin
Narrow spectrum
- effective against a selected group of bacterial type (e.g. Gram +ve / -ve)
- treat ***specific disease with known type of causative bacteria
- e.g. Penicillin G, Vancomycin
Why combination antibiotics?
- ***Synergistic action in eradication of bacterial infection
- Treat ***mixed bacterial infection (e.g. Co-infection in STI)
- ***Overcome resistance to antibiotics
- ***Reduce toxicity of one drug by using it at a lower dose
For STD, main reason of combination is Drug resistance (∵ cause is already well known)
Chlamydial infections
Urethritis, Cervicitis
Empirical treatment:
- ***Azithromycin (Oral)
- Doxycycline (7 days, Oral, use Azithromycin if pregnancy)
- Tetracycline / Erythromycin / Ofloxacin
SE:
- GI
- mild to moderate
Syphilis
***Parenteral Penicillin G (for ALL stages of Syphilis)
- IV: for severe stage
- IM: early latent stage
-
**Long-acting preparation
—> slow release into circulation
—> single IM **Benzathine Penicillin G at weekly intervals for early latent stage to treat bacteria that are sensitive to prolonged low concentrations (2-4 weeks) - Oral have low compliance
Gonococcal infections
Urethritis, Cervicitis
- if not treated successfully —> may cause ***Pelvic inflammatory disease
Treatment:
**Ceftriaxone (IM single dose) + **Azithromycin (Oral single dose)
- Dual therapy desired
- Highly effective against Penicillin-/Tetracycline-resistant Neisseria gonorrhoeae
- However, GC may soon develop resistance to these 2 antibiotics
- Oral Cephalosporins (e.g. Cefixime) / Fluoroquinolones no longer recommended as 1st line (∵ resistance)
Infection involving >1 agents
E.g. Neisseria gonorrhoeae + Chlamydia trachomatis co-infection
Treatment:
1. Ceftriaxone (IM single dose) + Azithromycin (Oral single dose)
OR
2. Ceftriaxone (IM single dose) + Doxycycline (Oral 7 days)
Pelvic inflammatory disease
Ascending infections that affect upper female reproductive tract
—> may leave Fallopian tube and further spread to other parts of body
Causative agents:
- Neisseria gonorrhoeae
- Chlamydia trachomatis
- Anaerobic bacteria
Treatment:
Inpatient / Outpatient regimen:
- **Ceftriaxone (IM single dose) + **Doxycycline (Oral) +/- ***Metronidazole
Inpatient Empirical parenteral regimen: ***Broad spectrum antibiotic coverage - Cefoxitin / Cefotetan (2nd gen) (IV) + Doxycycline (Oral) OR - Clindamycin + Aminoglycoside (IV)
Vaginal infections
- Bacterial Vaginosis
- **Metronidazole (Oral / Intravaginally)
OR
- **Clindamycin (Oral / Intravaginally) - Trichomoniasis (caused by **Trichomonas vaginalis: protozoan parasite)
- **Metronidazole (single dose)
OR
- Tinidazole (single dose) - Vulvovaginal candidiasis (caused by Candida overgrowth)
- Azole antifungal agents
—> **Clotrimazole / Miconazole (intravaginal)
—> **Fluconazole (oral)
- AmB deoxycholate / Flucytosine (resistant case)
Metronidazole, Tinidazole
Metronidazole:
- Antibacterial + Antiparasitic
Tinidazole:
- Antiparasitic
MOA: - Enter bacteria via diffusion - Activated via single reduction step by bacteria —> forms highly reactive ***Nitro radical anion —> damages DNA, inhibit DNA synthesis —> cell death
***Anti-fungal agents MOA
- Cell membrane:
- Polyene: bind to ***Ergosterol and disrupt cell membrane (more crystalline, less fluid)
—> Nystatin (topical), Amphotericin B (systemic)
- Azole: inhibit ***Ergosterol synthesis (from lanosterol)
—> Fluconazole (systemic), Itraconazole - Terbinafine
- Nucleoside analogue:
—> 5-Flucytosine: fluorinated pyrimidine analog —> stop DNA replication / synthesis - Cell wall synthesis:
—> Echinocandins (e.g. Caspofungin): inhibit ***beta-glucan synthesis in fungal cell wall - Disrupt microtubules:
—> Griseofulvin
Genital warts
Causative agent:
***HPV
Treatment:
- ***Imiquimod cream (on visible lesions)
—> Immune response modifier
Other treatment:
- Podofilox solution / gel (Antimitotic drug)
- Sinecatechins ointment (no known MOA)
- Intralesional Alfa IFN (for recurred warts, local use seems more effective)
Genital herpes
- Painful blisters / Open sores in genital area
Causative agent:
***HSV
Treatment:
Antiviral drugs
—> **Acyclovir
—> **Famciclovir / Valacyclovir (Acyclovir derivatives)
—> ***Foscarnet / Cidofovir (reserved for severe / complicated infections)
- Severe / Frequent recurrent Genital herpes
- Control Symptoms but do not eliminate virus from body
- Suppressive antiviral therapy —> Prevent occurrence / transmission
***Acyclovir
MOA:
Acyclic **Guanosine analogue (Guanine + Ribose)
- Enter cell
—> phosphorylated by Viral **Thymidine kinase
—> Acyclovir monophosphate
—> Acyclovir diphosphate
—> **Acyclovir triphosphate (~ structure to **dGTP)
—> Competitive inhibition
—> ***Incorporate into DNA chain
—> Nonfunctional complex
—> Stop DNA replication
Use:
- Oral: primary infections (less effective in treating recurrence)
- IV: serious infections by HSV
- Topical: less effective than oral
- Long term prophylaxis: ↓ frequency of recurrences of Genital herpes
Acyclovir derivatives
- Valacyclovir
- ester of ACV
—> converted to ACV by hepatic / intestinal enzymes
—> ***↑ bioavailability from 15% to 55% - Famciclovir
- metabolised to active ***Penciclovir
—> similar action to ACV in viral shedding, lesion healing, resolution of symptoms
Retrovirus and HIV: Life cycle of Retroviral virus
Retrovirus (+ve sense ssRNA virus) —> use own ***Reverse transcriptase (RT) —> Proviral DNA —> Incorporate into host DNA by ***Integrase —> Viral mRNA —> Viral protein
Targets of Antiretroviral drugs
- Entry inhibitors
- NRTIs / NNRTIs
- Integrase inhibitors
- Protease inhibitors (inhibit packaging of retrovirus)
Monotherapy vs Triple therapy
Monotherapy:
↓ viral load a bit then go back ↑ (viral turnover very quick —> new mutations evolved easily)
**Triple therapy:
Effectively ↓ viral load (effectively **↓ resistance development + **↓ viral load + **↓ drug toxicities)
HIV infection and AIDS
Highly Active Antiretroviral therapy (HAART)
- Combination of Antiretroviral drugs
—> Maximise inhibition of viral replication + Minimise drug toxicities in HIV-infected individuals
—> Recommended for ALL HIV-infected individuals
- NRTIs (e.g. Zidovudine, Lamivudine)
- NNRTIs (e.g. Efavirenz)
- Protease inhibitors (e.g. Lopinavir)
- Entry inhibitors (e.g. Enfuvirtide)
- Integrase strand transfer inhibitors (INSTI) (e.g. Raltegravir)
Treatment:
- 3 drug regimen (2 NRTI + INSTI / NNRTI / PI)
- New data support 2 drug regimen (Dolutegravir (INSTI: DTG) + Lamivudine (NRTI: 3TC)) (approved in DH but not HA) —> Fewer ADR
- Guideline keeps changing
- ADR: ***Cardiometabolic, Osteoporosis, Psychiatric diseases
Primary goals for initiating ART
- ↓ HIV-associated morbidity + ↑ Duration, QOL
- Maximally + Durably suppress plasma HIV viral load
- Restore + Preserve immunologic function (CD4 count can even be higher than normal person)
- Prevent HIV transmission
NRTI
- ***Zidovudine / Azidothymidine (ZDV / AZT) —> Thymidine analogue
- ***Lamivudine (3TC) —> Cytidine analogue
- Other NRTI (Didanosine, Stavudine, Abacavir)
ZDV MOA: ***Structurally ~ ***Thymidine —> Compete with Thymidine in DNA synthesis —> Stop Reverse transcription —> Daughter chain termination
ZDV:
- Deoxythymidine derivative
—> bioactivation by cellular kinases to Triphosphate form (ZDV-TP)
—> ZDV-TP (activated) competitively **inhibit HIV reverse transcriptase + act as **viral DNA chain terminator
—> stop Reverse transcriptase + Reverse transcription
—> prevent HIV from replicating
—> ↓ circulating viral antigen titres
—> ↑ circulating CD4 T cells + ↓ opportunistic infections in HIV patients
—> slow disease progression + prolong survival
Pharmacokinetics (X rmb):
- oral formulation well absorbed + well distributed
- t1/2: 1 hour
- substantial 1st pass to glucuronide (60% bioavailability)
- used in combination with other Anti-HIV drugs to ↑ activity, retard resistance
- SE: anaemia, neutropenia
Tenofovir
Nucleo***tide analogue (NtRTI) —> Nucleoside + Phosphate
Deoxyadenosine 5’-monophosphate analogue
NRTI vs NtRTI
NRTI:
Rate-limiting step: Convert Nucleoside to Nucleoside-monophosphate (i.e. Nucleotide)
NtRTI:
No need rate-limiting step
NNRTIs
- Nevirapine (NVP)
- Efavirenz (EFV)
- Delavirdine (DLV), Etravirine (EVR), Rilpivirine (RPV)
MOA:
Directly inhibit ***HIV-1 reverse transcriptase by binding reversibly and non-competitively
—> rapid emergence of resistance (∵ enzyme a.a. sequence can change easily)
Use:
Part of potent anti-retroviral therapy to suppress viral replication
Protease inhibitors
- Saquinavir (prototype)
- Ritonavir
- Lopinavir
- Atazanavir, Darunavir, Fosamprenavir etc.
MOA:
Specific inhibitors of **HIV-1 protease (enzyme for production of mature infectious virion)
—> virus **cannot be packed into mature form
—> remain as immature virion (non-infectious)
Use:
- In combination with Reverse transcriptase inhibitors to delay resistance
- Ritonavir administered concurrently to ***boost bioavailability of another PI
Pharmacokinetics:
- Oral —> GI problems
- ***Inhibit CYP450 —> used as booster to ↓ other drug dose (but more severe SE, more DDI)
SE:
- ***Hyperlipidemia
- Insulin resistance, Diabetes
- Lipodystrophy
- Elevated liver function
- Possible increased bleeding risk in haemophiliacs
- DDI
INSTI
- Raltegravir (RAL)
- inhibit catalytic activity of HIV-1 Integrase - Dolutegravir, Elvitegravir (Newer agent)
MOA:
Block HIV-1 Integrase (help integrate viral DNA into host CD4 cell DNA)
—> prevent HIV from replicating
Use:
- Preferred due to ***fewer SE, DDI
- Treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains ***resistant to multiple antiretroviral agents
Viral-entry inhibitors
- Enfuvirtide (ENV)
- Fusion inhibitor
- inhibit fusion of viral transmembrane glycoprotein gp41 with host cell surface
- SE: mostly injection site reactions - Maraviroc (MVC)
- CCR5 antagonist (CCR5: chemokine co-receptor on CD4 cells)
- prevent interaction between HIV gp120 and CCR5 protein
—> prevent HIV fusion
- Use:
—> multidrug-resistant (MDR) CCR5-tropic HIV-1 (***Salvage therapy)
Not recommended as part of 3 drug regimen (2 NRTI + INSTI / NNRTI / PI)
—> ∵ need to administered IV + expensive
HAART-associated SE
- ***Lactic acidosis / Hepatic steatosis (all NRTIs)
- Hepatotoxicity (NVP, DRV, TPV)
- Insulin resistance / Diabetes (all PIs)
- Lipodystrophy (all NRTIs, all PIs)
- Hyperlipidemia (all PIs)
- Increased bleeding in haemophiliacs (all PIs)
- DDI (NNRTIs, PIs)
- Rash (all NNRTIs esp. NVP)
***Exam Key points
- Chlamydia
- Azithromycin (Oral single dose) - Gonorrhoea
- Ceftriaxone (IM single dose) + Azithromycin (Oral single dose) - Syphilis
- Parenteral Penicillin G (for ALL stages of Syphilis) (Long-acting preparation) - HIV (HAART: 3 drug regimen —> 2 NRTI + INSTI / NNRTI / PI)
- NRTIs (**Zidovudine (ZDV: **Thymidine analogue), ***Lamivudine (3TC))
—> inhibit HIV reverse transcriptase + act as viral DNA chain terminator
- NtRTIs (Tenofovir)
- NNRTIs (**Nevirapine (NVP), **Efavirenz (NVP))
—> inhibit HIV-1 reverse transcriptase by binding reversibly and non-competitively - Protease inhibitors (Saquinavir, ***Lopinavir, Ritonavir)
—> inhibit HIV-1 protease
—> virus cannot be packed into mature form - Entry inhibitors (**Enfuvirtide (ENV), **Maraviroc (MVC))
—> Enfuvirtide (ENV): inhibit fusion of HIV gp41 with host cell surface
—> Maraviroc (MVC): CCR5 antagonist (CCR5: chemokine co-receptor on CD4 cells) —> prevent interaction between HIV gp120 and CCR5 protein - Integrase strand transfer inhibitors (INSTI) (***Raltegravir (RAL))
—>Block HIV-1 Integrase (help integrate viral DNA into host CD4 cell DNA)
***Summary
- Chlamydia
- Azithromycin (Oral single dose) - Gonorrhoea
- Ceftriaxone (IM single dose) + Azithromycin (Oral single dose) - Syphilis
- Parenteral Penicillin G (for ALL stages of Syphilis) - Pelvic inflammatory disease
- Ceftriaxone (IM single dose) + Doxycycline (Oral) +/- Metronidazole - Vaginal infection
- Bacterial Vaginosis —> Metronidazole (Oral / Intravaginally)
- Trichomoniasis (Trichomonas vaginalis) —> Metronidazole (single dose)
- Vulvovaginal candidiasis (caused by Candida overgrowth) —> Azole / AmB deoxycholate / Flucytosine - Genital warts (HPV)
- Imiquimod cream (on visible lesions) —> Immune response modifier - Genital herpes (HSV)
- Acyclovir (***Guanosine analogue)
- Famciclovir / Valacyclovir (Acyclovir derivatives)
- Foscarnet / Cidofovir (reserved for severe / complicated infections) - HIV (HAART: 3 drug regimen —> 2 NRTI + INSTI / NNRTI / PI)
- NRTIs (**Zidovudine (ZDV: **Thymidine analogue), ***Lamivudine (3TC))
—> inhibit HIV reverse transcriptase + act as viral DNA chain terminator
- NtRTIs (Tenofovir)
- NNRTIs (**Nevirapine (NVP), **Efavirenz (NVP))
—> inhibit HIV-1 reverse transcriptase by binding reversibly and non-competitively - Protease inhibitors (Saquinavir, ***Lopinavir, Ritonavir)
—> inhibit HIV-1 protease
—> virus cannot be packed into mature form - Entry inhibitors (**Enfuvirtide (ENV), **Maraviroc (MVC))
—> Enfuvirtide (ENV): inhibit fusion of HIV gp41 with host cell surface
—> Maraviroc (MVC): CCR5 antagonist (CCR5: chemokine co-receptor on CD4 cells) —> prevent interaction between HIV gp120 and CCR5 protein - Integrase strand transfer inhibitors (INSTI) (***Raltegravir (RAL))
—>Block HIV-1 Integrase (help integrate viral DNA into host CD4 cell DNA)
