Pharmacodynamics of Antiviral Drugs
Session 25: Pharmacodynamics of Antiviral Drugs
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Antiviral Drugs
Describe drug interactions associated with Antiviral Drugs
Describe side effects of Antiviral Drugs
Describe contraindications of Antiviral Drugs
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Antiviral Drugs
Mechanism of Action of Antiviral Drugs
2
2
45 minutes
45 minutes
Buzzing
Mechanism of Action of Antiviral Drugs
Mechanism of Action of Antiviral Drugs
Buzzing
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With Antiviral
Drug Interactions Associated With Antiviral
3
3
20 minutes
20 minutes
brainstorming
Drugs
Drugs
brainstorming
Drugs
Drugs
4
4
20 minutes
20 minutes
Presentation
Side Effects of Drugs for Antiviral Drugs
Side Effects of Drugs for Antiviral Drugs
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Antiviral Drugs
Contraindications of Antiviral Drugs
5
5
20 minutes
20 minutes
Brainstorming
Contraindications of Antiviral Drugs
Contraindications of Antiviral Drugs
Brainstorming
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 193 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Antiviral Drugs (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do Antiviral Drugs produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
Anti-HIV Drugs
Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs): Zidovudine(ZDV), lamivudine (3-TC), stavudine (d4T), didanosine(ddI), emtricitabine (FTC) and abacavir (ABC).
o Anti retroviral drugs targets several steps which are involved in the replication of HIV.
o The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins.
o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse).
o The parent drug, ZDV, enters virally infected cells by diffusion and undergoes phosphorylation first to its monophosphate (ZDV-MP) then to the diphosphate (ZDV-DP), the rate-limiting step, and finally to the triphosphate (ZDV-TP).
o ZDV-TP is a competitive inhibitor of the HIV-1 reverse transcriptase and when incorporated into nascent viral DNA causes chain termination.
o Human cells lack reverse transcriptase and human nuclear DNA polymerases are much less sensitive (by at least 100-fold) to inhibition by ZDV-TP, thus producing a selective effect on viral replication.
o This mechanism of action is common to all anti-HIV nucleoside analogues.
PST 05104 Pharmacology & Therapeutics 194 NTA Level 5 Semester 1 Facilitator Guide
Non -Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs): nevirapine,
delavirdine, efavirenz and Second-generation: etravirine
o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse).
o The nNRTIs bind to a site distant from the active site of the reverse transcriptase, and induce a conformational change in the enzyme.
o This conformational change greatly reduces the activity of the enzyme. o Unlike the NRTIs, the nNRTIs have no activity against DNA polymerase.
o Also, because the binding of nNRTIs to the reverse transcriptase is very specific, nNRTIs act specifically on the HIV-1 strain and lack activity against HIV-2.
o Conversely, the NRTIs indirectly inhibit reverse transcriptase and are therefore not specific for HIV-1.
Protease Inhibitors: Saquinavir, indinavir, nelfinavir, ritonavir, atazanavir, fosamprenavir, amprenavir, lopinavir and darunavir
o Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins.
o These polyproteins are then cleaved into smaller viral proteins by proteases as they are released from the cell.
o This process is called viral maturation.
o These smaller viral proteins perform important functions, either structural or acting as enzymes such as reverse transcriptase, integrase, or protease itself.
o Protease inhibitors bind to these proteases and prevent them from performing this important step in viral maturation.
o This results in the production of immature, non-infectious virus particles.
o The selective toxicity of the protease inhibitors is based on structural differences between human proteases and viral proteases.
Integrase Inhibitors:
o Integrase inhibitors are a newer class of drugs for HIV infection that inhibit HIV by preventing the virus from incorporating its DNA into the host genome.
o The integrase enzyme incorporates viral DNA into the host genome.
o Specifically, integrase binds to viral DNA and joins it with host DNA. The divalent cations in the catalytic core of integrase enable it to form covalent bonds with DNA.
o This is followed by cellular repair activities that seal the viral DNA into the chromosome.
o Integrase inhibitors prevent the formation of covalent bonds with host DNA. This prevents incorporation of HIV into the host genome.
PST 05104 Pharmacology & Therapeutics 195 NTA Level 5 Semester 1 Facilitator Guide
Fusion Inhibitors: enfuvirtide ibalizumab
o Enfuvirtide mimics the HIV machinery required to fuse to the CD4 cell. It competes with the HIV proteins and prevents entry of the virus into the CD4 cell:
o Glycoprotein gp120 binds HIV and activates gp41.
o Glycoprotein gp41 changes conformation and creates an entry channel (pore) into the cell.
o Specifically, enfuvirtide binds gp41 and prevents conformation change.
STEP 3: Drug Interactions Associated with Antiviral Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with antiviral drugs?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
The following are the drug interactions of Anti-HIV Drugs
Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs).
Didanosine is easily degraded in an acidic environment and is therefore formulated with buffers such as calcium carbonate and magnesium hydroxide.
Agents that bind to divalent cations (e.g., calcium and magnesium) should be administered separately from didanosine.
Examples of these agents include fluoroquinolones such as ciprofloxacin.
The same is true for agents whose dissolution is pH dependent, such as itraconazole.
Stavudine and zidovudine compete for intracellular phosphorylation and should not be used in combination with each other
Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
Many of the nNRTIs are CYP3A4 substrates (nevirapine, delavirdine, efavirenz, and etravirine). Given the number of CYP3A4 inducers and inhibitors, these drugs might be more likely to have their metabolism inhibited or induced by other drugs.
CYP450 inducers: Efavirenz, nevirapine, and etravirine are moderate inducers of CYP3A4.
CYP450 inhibitors: Delavirdine (CYP3A4) Etravirine (CYP2C9 and CYP2C19)
Protease Inhibitors:
Ritonavir is by far the most potent CYP3A4 inhibitor and is purposely combined with other protease inhibitors that are substrates of CYP3A4 in order to prolong the half-life of these agents.
PST 05104 Pharmacology & Therapeutics 196 NTA Level 5 Semester 1 Facilitator Guide
As potent CYP3A4 inhibitors, PIs will affect plasma concentrations of many drugs when administered together.
Indinavir absorption is also affected by pH; therefore agents that raise pH such as antacids should not be administered simultaneously.
Integrase Inhibitors:
Raltegravir is not a substrate for CYP450 enzymes. It also does not inhibit or induce
CYP450 enzymes. It is primarily metabolized by glucuronidation (UGT1A1), and it is a Pgp substrate.
Atazanavir is a UGT1A1 inhibitor, and concomitant administration of raltegravir and atazanavir has been shown to elevate raltegravir levels.
Rifampin is a strong inducer of UGT1A1; therefore concomitant administration of these two agents can significantly reduce raltegravir levels.
STEP 4: Side Effects of Antiviral Drugs (20 minutes)
The following are the side effects of Anti-HIV Drugs;
Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs).
NRTIs also inhibit host cell DNA polymerase, although this likely contributes more to
their toxic effects than their efficacy.
Inhibition of DNA polymerase in mitochondria leads to depletion of mitochondrial DNA and subsequent depletion of mitochondrial RNA and peptides involved in oxidative phosphorylation.
This leads to mitochondrial dysfunction, and this is believed to be the cause of several of the important toxicities associated with drugs of this class.
Myalgia: One of the most common and earliest side effects associated with NRTIs, myalgia was also the first indication of the mitochondrial toxicity that has become
associated with these agents.
The mitochondrial toxicity is believed to be caused by the inhibition of DNA polymerase by the NRTI.
Diarrhoea is most associated with didanosine, likely as a result of the buffers used in
oral formulations, some of which contain magnesium, a known laxative.
Lactic acidosis: The impairment of mitochondrial function leads to a reliance on anaerobic metabolism, which produces excessive amounts of lactate.
Lipodystrophy is most associated with stavudine.
Peripheral neuropathy (didanosine, stavudine, zalcitabine) is likely caused by mitochondrial toxicity. Typically this effect will improve or resolve completely as
long as the drug is stopped as soon as the symptoms appear.
Pancreatitis (didanosine, stavudine, zalcitabine) is a rare but potentially fatal adverse effect, likely caused by mitochondrial toxicity. It is more common with didanosine
and particularly common when two of these agents are combined.
Hepatotoxicity (didanosine, zidovudine) is rare but potentially fatal.
Bone marrow suppression is likely the result of toxic effects on erythroid stem cells.
PST 05104 Pharmacology & Therapeutics 197 NTA Level 5 Semester 1 Facilitator Guide
Special for Abacavir: Hypersensitivity, characterized by fever, GI problems including abdominal pain, rash, malaise, and fatigue may occur.
If fever, abdominal pain, and rash occur within 6 weeks of initiation of therapy, the
drug should be discontinued.
Special for Tenofovir: Acute renal failure is a rare side effect, and although tenofovir is an antiviral nucleotide like cidofovir and adefovir, it is not believed to share their nephrotoxic effects.
Stomatitis and oral ulcers (zalcitabine): Zalcitabine may be toxic to rapidly dividing cells, but the mechanism is unclear.
Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
Rash: Macular or papular rash, often pruritic and also self-limiting, may occur with continued drug administration. In a minority of individuals, rash can progress to more
serious Stevens-Johnson syndrome.
Hepatitis can be severe and fatal; it is more common in female patients, especially
during pregnancy. Most cases are the result of a hypersensitivity reaction. Delavirdine has not been associated with fatal hepatitis.
Neutropenia is a rare effect.
Efavirenz only: CNS effects: The mechanism has not been established. These side effects are typically transient, resolving after a few hours or up to several weeks. These include dizziness, impaired concentration, dysphoria, vivid dreams, psychosis and insomnia
Protease Inhibitors:
GI (nausea, vomiting, diarrhea): Diarrhea in particular is a common and troublesome adverse effect of protease inhibitor therapy. The mechanism is not established and is complicated by the fact that diarrhea is a complication of HIV infection.
Hyperlipidemia: A side effect common to all protease inhibitors, hyperlipidemia
might occur less frequently with atazanavir. Protease inhibitors appear to stimulate lipogenesis in hepatocytes.
Lipodystrophy: Fat redistribution is a problem in HIV that appears to be exacerbated with the use of protease inhibitors.
The nature of the fat redistribution may depend to an extent on the total body fat at baseline as well as energy balance.
Hyperglycemia, insulin resistance: Protease inhibitors appear to inhibit the activity of the glucose transporter (GLUT-4), inhibiting insulin-stimulated glucose uptake by cells.
Atazanavir may be less likely to cause this side effect compared with other protease
inhibitors.
Crystalluria, nephrolithiasis (Indinavir only): Indinavir has poor solubility and precipitates easily.
Patients are advised to increase fluid intake while on indinavir.
Hyperbilirubinemia (atazanavir only) is not considered to be a serious side effect or sign of hepatotoxicity.
PST 05104 Pharmacology & Therapeutics 198 NTA Level 5 Semester 1 Facilitator Guide
Integrase Inhibitors:
o Because the antiretroviral are typically administered in combination regimens, it is difficult to determine the side effects that are associated with a specific class or drug within that class.
o Generally well-tolerated: In controlled trials, raltegravir did not elicit more adverse effects than placebo.
o As with most antiretrovirals, the safety of integrase inhibitors in pregnancy has not been established.
Fusion Inhibitors:
o Injection site irritation
o Peripheral neuropathy (can cause pain, numbness, or weakness in extremities)
STEP 5: Contraindications of Antiviral Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of antiviral drugs? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
The following are the contraindications of Anti-HIV Drugs;
Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs).
Avoid in patients with history of pancreatitis or neuropathy: particularly true with didanosine, stavudine, and zalcitabine .See adverse/side effects above
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs).
Pregnancy (efavirenz): Of all the antiretrovirals, efavirenz carries the clearest risk in pregnancy, as it has demonstrated teratogenicity in primates.
Protease Inhibitors:
Drug interactions (CYP3A4): Ritonavir is such a potent CYP3A4 inhibitor that its use is contraindicated with drugs that are highly dependent on CYP3A4 for their elimination, and where elevated plasma levels of these agents would lead to unacceptable toxicity.
Integrase Inhibitors:
None of major significance
PST 05104 Pharmacology & Therapeutics 199 NTA Level 5 Semester 1 Facilitator Guide
STEP 6: Key Points (5 minutes)
Drugs active against HIV have different mechanisms of Action
Antiretroviral drugs show serious drug interactions
Resistance to antiretroviral drugs has developed
STEP 7: Evaluation (5 minutes)
What is the mechanism of action of Zidovudine?
What are adverse effects of efavirenz?
Why do NRTIs cause lactic acidosis?
PST 05104 Pharmacology & Therapeutics 200 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 201 NTA Level 5 Semester 1 Facilitator Guide
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