ERS37 Drugs Used In Sexually Transmitted Disease

Question 1

STD causative agents

Answer 1

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

Question 2

Bacteriostatic vs Bactericidal

Broad spectrum vs Narrow spectrum

Answer 2

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

Question 3

Why combination antibiotics?

Answer 3

1. ***Synergistic action in eradication of bacterial infection
2. Treat ***mixed bacterial infection (e.g. Co-infection in STI)
3. ***Overcome resistance to antibiotics
4. ***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)

Question 4

Chlamydial infections

Answer 4

Urethritis, Cervicitis

Empirical treatment:

1. ***Azithromycin (Oral)
2. Doxycycline (7 days, Oral, use Azithromycin if pregnancy)
3. Tetracycline / Erythromycin / Ofloxacin

SE:

• GI
• mild to moderate

Question 5

Syphilis

Answer 5

***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

Question 6

Gonococcal infections

Answer 6

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)

Question 7

Infection involving >1 agents

Answer 7

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)

Question 8

Pelvic inflammatory disease

Answer 8

Ascending infections that affect upper female reproductive tract
—> may leave Fallopian tube and further spread to other parts of body

Causative agents:

1. Neisseria gonorrhoeae
2. Chlamydia trachomatis
3. 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)

Question 9

Vaginal infections

Answer 9

1. Bacterial Vaginosis
   - **Metronidazole (Oral / Intravaginally)
   OR
   - **Clindamycin (Oral / Intravaginally)
2. Trichomoniasis (caused by **Trichomonas vaginalis: protozoan parasite)
   - **Metronidazole (single dose)
   OR
   - Tinidazole (single dose)
3. Vulvovaginal candidiasis (caused by Candida overgrowth)
   - Azole antifungal agents
   —> **Clotrimazole / Miconazole (intravaginal)
   —> **Fluconazole (oral)
   - AmB deoxycholate / Flucytosine (resistant case)

Question 10

Metronidazole, Tinidazole

Answer 10

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

Question 11

***Anti-fungal agents MOA

Answer 11

1. 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

2. Nucleoside analogue:
   —> 5-Flucytosine: fluorinated pyrimidine analog —> stop DNA replication / synthesis
3. Cell wall synthesis:
   —> Echinocandins (e.g. Caspofungin): inhibit ***beta-glucan synthesis in fungal cell wall
4. Disrupt microtubules:
   —> Griseofulvin

Question 12

Genital warts

Answer 12

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)

Question 13

Genital herpes

Answer 13

• 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

Question 14

***Acyclovir

Answer 14

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

Question 15

Acyclovir derivatives

Answer 15

1. Valacyclovir
   - ester of ACV
   —> converted to ACV by hepatic / intestinal enzymes
   —> ***↑ bioavailability from 15% to 55%
2. Famciclovir
   - metabolised to active ***Penciclovir
   —> similar action to ACV in viral shedding, lesion healing, resolution of symptoms

Question 16

Retrovirus and HIV: Life cycle of Retroviral virus

Answer 16

Retrovirus (+ve sense ssRNA virus)
—> use own ***Reverse transcriptase (RT)
—> Proviral DNA
—> Incorporate into host DNA by ***Integrase
—> Viral mRNA
—> Viral protein

Question 17

Targets of Antiretroviral drugs

Answer 17

1. Entry inhibitors
2. NRTIs / NNRTIs
3. Integrase inhibitors
4. Protease inhibitors (inhibit packaging of retrovirus)

Question 18

Monotherapy vs Triple therapy

Answer 18

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)

Question 19

HIV infection and AIDS

Answer 19

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

1. NRTIs (e.g. Zidovudine, Lamivudine)
2. NNRTIs (e.g. Efavirenz)
3. Protease inhibitors (e.g. Lopinavir)
4. Entry inhibitors (e.g. Enfuvirtide)
5. 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

Question 20

Primary goals for initiating ART

Answer 20

1. ↓ HIV-associated morbidity + ↑ Duration, QOL
2. Maximally + Durably suppress plasma HIV viral load
3. Restore + Preserve immunologic function (CD4 count can even be higher than normal person)
4. Prevent HIV transmission

Question 21

NRTI

Answer 21

1. ***Zidovudine / Azidothymidine (ZDV / AZT) —> Thymidine analogue
2. ***Lamivudine (3TC) —> Cytidine analogue
3. 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

Question 22

Tenofovir

Answer 22

Nucleo***tide analogue (NtRTI) —> Nucleoside + Phosphate

Deoxyadenosine 5’-monophosphate analogue

Question 23

NRTI vs NtRTI

Answer 23

NRTI:
Rate-limiting step: Convert Nucleoside to Nucleoside-monophosphate (i.e. Nucleotide)

NtRTI:
No need rate-limiting step

Question 24

NNRTIs

Answer 24

1. Nevirapine (NVP)
2. Efavirenz (EFV)
3. 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

Question 25

Protease inhibitors

Answer 25

1. Saquinavir (prototype) 2. Ritonavir 3. Lopinavir 4. 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

Question 26

INSTI

Answer 26

1. Raltegravir (RAL) - inhibit catalytic activity of HIV-1 Integrase 2. 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

Question 27

Viral-entry inhibitors

Answer 27

1. Enfuvirtide (ENV) - Fusion inhibitor - inhibit fusion of viral transmembrane glycoprotein gp41 with host cell surface - SE: mostly injection site reactions 2. 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

Question 28

HAART-associated SE

Answer 28

1. ***Lactic acidosis / Hepatic steatosis (all NRTIs) 2. Hepatotoxicity (NVP, DRV, TPV) 3. Insulin resistance / Diabetes (all PIs) 4. Lipodystrophy (all NRTIs, all PIs) 5. Hyperlipidemia (all PIs) 6. Increased bleeding in haemophiliacs (all PIs) 7. DDI (NNRTIs, PIs) 8. Rash (all NNRTIs esp. NVP)

Question 29

***Exam Key points

Answer 29

1. Chlamydia - Azithromycin (Oral single dose) 2. Gonorrhoea - Ceftriaxone (IM single dose) + Azithromycin (Oral single dose) 3. Syphilis - Parenteral Penicillin G (for ALL stages of Syphilis) (Long-acting preparation) 4. 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)

Question 30

***Summary

Answer 30

1. Chlamydia - Azithromycin (Oral single dose) 2. Gonorrhoea - Ceftriaxone (IM single dose) + Azithromycin (Oral single dose) 3. Syphilis - Parenteral Penicillin G (for ALL stages of Syphilis) 4. Pelvic inflammatory disease - Ceftriaxone (IM single dose) + Doxycycline (Oral) +/- Metronidazole 5. Vaginal infection - Bacterial Vaginosis —> Metronidazole (Oral / Intravaginally) - Trichomoniasis (Trichomonas vaginalis) —> Metronidazole (single dose) - Vulvovaginal candidiasis (caused by Candida overgrowth) —> Azole / AmB deoxycholate / Flucytosine 4. Genital warts (HPV) - Imiquimod cream (on visible lesions) —> Immune response modifier 5. Genital herpes (HSV) - Acyclovir (***Guanosine analogue) - Famciclovir / Valacyclovir (Acyclovir derivatives) - Foscarnet / Cidofovir (reserved for severe / complicated infections) 6. 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)