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ERS > ERS37 Drugs Used In Sexually Transmitted Disease > Flashcards

ERS37 Drugs Used In Sexually Transmitted Disease Flashcards

1
Q

STD causative agents

A

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
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2
Q

Bacteriostatic vs Bactericidal

Broad spectrum vs Narrow spectrum

A

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
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3
Q

Why combination antibiotics?

A
  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)

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4
Q

Chlamydial infections

A

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
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5
Q

Syphilis

A

***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
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6
Q

Gonococcal infections

A

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)
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7
Q

Infection involving >1 agents

A

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)

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8
Q

Pelvic inflammatory disease

A

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)
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9
Q

Vaginal infections

A
  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)
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10
Q

Metronidazole, Tinidazole

A

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
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11
Q

***Anti-fungal agents MOA

A
  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
  1. Nucleoside analogue:
    —> 5-Flucytosine: fluorinated pyrimidine analog —> stop DNA replication / synthesis
  2. Cell wall synthesis:
    —> Echinocandins (e.g. Caspofungin): inhibit ***beta-glucan synthesis in fungal cell wall
  3. Disrupt microtubules:
    —> Griseofulvin
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12
Q

Genital warts

A

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)
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13
Q

Genital herpes

A
  • 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
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14
Q

***Acyclovir

A

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
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15
Q

Acyclovir derivatives

A
  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
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16
Q

Retrovirus and HIV: Life cycle of Retroviral virus

A 
Retrovirus (+ve sense ssRNA virus)
—> use own ***Reverse transcriptase (RT)
—> Proviral DNA
—> Incorporate into host DNA by ***Integrase
—> Viral mRNA
—> Viral protein
17
Q

Targets of Antiretroviral drugs

A
  1. Entry inhibitors
  2. NRTIs / NNRTIs
  3. Integrase inhibitors
  4. Protease inhibitors (inhibit packaging of retrovirus)
18
Q

Monotherapy vs Triple therapy

A

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)

19
Q

HIV infection and AIDS

A

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
20
Q

Primary goals for initiating ART

A
  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
21
Q

NRTI

A
  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
22
Q

Tenofovir

A

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

Deoxyadenosine 5’-monophosphate analogue

23
Q

NRTI vs NtRTI

A

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

NtRTI:
No need rate-limiting step

24
Q

NNRTIs

A
  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

25
Q

Protease inhibitors

A
  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
26
Q

INSTI

A
  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
27
Q

Viral-entry inhibitors

A
  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

28
Q

HAART-associated SE

A
  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)
29
Q

***Exam Key points

A
  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)
30
Q

***Summary

A
  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
  6. Genital warts (HPV)
    - Imiquimod cream (on visible lesions) —> Immune response modifier
  7. Genital herpes (HSV)
    - Acyclovir (***Guanosine analogue)
    - Famciclovir / Valacyclovir (Acyclovir derivatives)
    - Foscarnet / Cidofovir (reserved for severe / complicated infections)
  8. 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)

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