Anti-virals

Drug Class Examples Mechanism of Action Therapeutic Use Resistance Mechanism Adverse Effects

Viral DNA Acyclovir Inhibits viral DNA synthesis via a chain Herpesviruses. Absent/deficient viral Oral: nausea,
Polymerase (ACV) termination mechanism. Terminated DNA thymidine kinase (HSV-1 diarrhoea, rash or
Inhibitors template containing acyclovir binds the viral DNA TK) activity. headache.
polymerase and leads to irreversible inactivation. Very rare: Renal
insufficiency or
Prior to interaction → phosphorylated neurotoxicity.
intracellularly in three steps → 1st step completed
by HSV specific kinase → therefore only targets
virus-infected cells.

Cidofovir Inhibits viral DNA synthesis by terminating chain CMV retinitis in Mutations in viral DNA Nephrotoxicity, blood
elongation. Metabolised to its active diphosphate HIV-infected polymerase gene. disorders, ocular
form by cellular enzymes. patients problems (anterior
uveitis, low intraocular
Phosphorylated by a cellular (not viral) kinase → ACV-resistant pressure).
able to inhibit ACV-resistant, TK deficient, or mucocutaneous
 TK-altered HSV/VZV strains. HSV infections

Neuraminidase Zanamivir Mechanism is a sialic acid analogue that Influenza A and B Mutations within the Inhaled → generally
Inhibitors (NAIs) specifically potently inhibits neuraminidases of sialic acid binding site or well tolerated,
influenza A and B viruses. Low other mutations that although wheezing
bioavailability → influence binding site and bronchospasm
This inhibition results in viral aggregation at the delivery oral conformation. reported.
cell surface → reduced spread of virus within inhalation of dry Majority of recent flu Underlying asthma or
resp. tract. powder. susceptible to NAIs. COPD → acute
deteriorations

Nucleoside Tenofovir Phosphorylated within the cell to generate HIV (adults + Mutations at reverse Headache, GIT
reverse alafenamide synthetic substrates for HIV reverse transcriptase. children) transcriptase. Specific (diarrhoea, vomiting,
transcriptase (TAF) resistance occurs with a flatulence), rash, and
inhibitors (NRTIs) Fully phosphorylated analogues block replication PreP → K65R substitution. fatigue.
of the viral genome both by (1) competitively prevention of
inhibiting incorporation of native nucleotides and vertical High plasma
by (2) terminating elongation of proviral DNA. transmission concentrations of TFV
are linked to renal and
ADME bone adverse effects.
TAF is a prodrug of tenofovir (TFV) → metabolism
occurs via carboxylesterase 1 (hepatocytes) or
 cathepsin A (lymphocytes and macrophages).
Renal excretion of intact TAF is a minor pathway.

Non Nucleoside Etravirine Binds directly to HIV-1 reverse transcriptase HIV-1 (adult and Requires multiple Rash, diarrhoea,
reverse (hydrophobic pocket of p66 subunit) resulting in pediatric substitutions in the hypertriglyceridaemia,
transcriptase allosteric inbhibition of RNA- and DNA-dependent patients). reverse transcriptase. nausea.
inhibitors DNA polymerase activity.
(NNRTIs) NNRTIs should
ADME never be used as
Etravirine is a substrate and inducer of CYP3A4 the sole addition
and an inhibitor of CYP2C9 and CYP2C19 → to a failing
significant drug-drug interactions. Not renally regimen.
excreted. Food increases AUC by ~50% → thus
taken with food.

Protease Darunavir Darunavir is a non-peptidic PI that is active HIV-1 or 2 High-level resistance Diarrhoea, nausea,
Inhibitors against both HIV-1 and 2. infection requires accumulation of headache, rash,
Inhibitor of the dimerisation and catalytic activity (in combination multiple resistance increases in plasma
of HIV-1 protease → inhibits cleavage of HIV with other ARV mutations (at least 3 for triglycerides and
encoded Gag-Pol polyproteins in virus infected agents). darunavir). cholesterol,
cells, thereby preventing the formation of mature hepatotoxicity.
infectious virus particles.
 ADME
Metabolised by CYP3A4 and inhibits CYP3A4.
Should be taken with meals to improve
bioavailability.

Bioavailability can be boosted with a

pharmacokinetic enhancer. CYP3A4 inhibitors
used to inhibit gut and first-past metabolism in the
liver → increases systemic circulation.

Integrase strand Raltegravir Blocks the catalytic activity of HIV-encoded HIV-1 or 2 in Ocuurs through Generally well
transfer inhibitors integrase → prevents integration of viral DNA into adults or children mutations close to the tolerated, most
(INSTIs) host chromosome. (>4 weeks of integrase active site. common complaints
age) → headache, nausea,
asthenia, and fatigue.

Combination Antiretroviral Therapy (cART):

Current WHP recommendations for initial HIV drug regimen;

1. Two nucleoside reverse transcriptase inhibitors (NRTIs), in combination with a 3rd aactive ARV drug from one of three drug
classes;
a. An integrase strand transfer inhibitor (INSTI)
b. A Non-nucleoside reverse transcriptase inhibitor (NNRTI)
c. A protease inhibitor (PI) with a pharmacokinetic (PK) enhancer.

cART works to accomplish several goals;

1. Prevent the virus from replicating and reduce the viral load
 2. Help restore CD4 counts and immune function
3. Reduce complications from HIV and improve survival
4. Reduce transmission of HIV to others.

Treatment of Asthma

Drug Class Examples Mechanism of Action Therapeutic Use Adverse Effects

Bronchodilators

β2 adrenoceptor Short-Acting (4-6 hours); Bronchodilator: dilates bronchial smooth muscle Given by inhaler or nebuliser for Tremor and some tachycardia.
agonists Salbutamol and by direct action on β2 adrenergic receptors. treatment of acute asthma. Overuse in asthma therapy can lead
Terbutaline → Antagonise bronchial smooth muscle spasm to tolerance (correct use of
induced by inflammatory mediators. Given i.v. in status asthmaticus. anti-inflammatory medication
Long-Acting (~12 hours); → Inhibit the release of inflammatory mediators minimises need for β agonists.
Salmeterol, Formoterol by mast cells. → Drug interactions; β blockers
(competitive inhibition),
antiglaucomals (acts at muscarinic
receptors) may cause bronchospasm

Muscarinic Ipratropium Bromide Bronchodilator: antagonises bronchial Used mainly in asthma produced Side effects; dizziness, GI, dry
receptor constriction caused by parasympathetic by irritant stimuli. (Inhaled or mouth
antagonists stimulation. Onset of action is slow → 30 - 60 min nebuliser).
for maximum effect. Used in combination with a
short or long acting β2 agonist

Xanthines Theophylline Theophylline inhibits phosphodiesterase (which
metabolises cAMP) leading to increased
intracellular cAMP which could inhibit
inflammatory cell activation and produce
bronchodilation. (Mechanism not fully
understood).
Used only when β2 agonists are
ineffective (due to side effects of
xanthines).
>Poor therapeutic index (small
range between minimum effective
and minimum toxic dose).
>CNS stimulation; improvement in
mental and motor tasks, tremor,
nervousness, sleep interference
>Cardiac stimulation; positive
inotropic and chronotropic effects =
 cardiac arrhythmias
>Diuresis: increased GFR
>GIT symptoms; nausea, vomiting,
anorexia
>Drug interactions (due to inhibited
metabolism = drug build up); oral
contraceptives, erythromycin,
calcium channel blockers,
cimetidine

Drug Class Examples Mechanism of Action Therapeutic Use Adverse Effects

Anti-Inflammatory Drugs

Glucocorticoids Beclomethasone, Mechanisms;
Budesonide, Fluticasone >Inhibition of platelet activating factor (PAF)
(twice as potent as other >Inhibition of allergen-induced influx of
two) inflammatory cells in the lung
>Inhibition of the activation of macrophages and
mediator release from eosinophils
>Reduction in cytokine formation
>Reduction in the synthesis of IL-3
>Inhibit the induction of COX-2 and the formation
of arachidonic acid
>Given prophylactically to
inhibit late phase asthma
response.
>Given continuously to reduce
bronchial hyper-activity.
>Inhaled = main preventative
asthma therapy
Given in combination with a
long-acting β2 agonist
>Oral Thrush and Hoarseness (rinse
mouth after use)
>Growth suppression in children
(untreated asthma also causes this)
>Systemic Effects; bruising, dermal
thinning, adrenal suppression, and
altered bone metabolism leading to
osteoporosis
→ Side Effects more likely in oral
glucocorticoids (prednisolone)

Sites of action in eicosanoid biosynthesis;

 Actions in Asthma;

Leukotriene Montelukast, Zafirlukast Leukotrienes are potent broncho-constrictors and >Prophylaxis for asthma. GIT, headache, rare psychiatric
receptor amplify the inflammation process. Therefore >Blocks antigen and exercise effects in children
antagonists inhibiting the receptors relaxes the bronchial induced asthma.
smooth muscle. >Can reduce the need for
(Competitive antagonists of LTC4, LTD4, LTE4) steroids
>Useful in aspirin-sensitive
asthma
 Good for reducing frequency but
not necessarily severity.

Leukotriene Zileutin Blocks formation of LTB4 as well as LTC4, LTD4, Used in antigen, exercise, and Nausea, drowsiness, and
synthesis and LTE4 by inhibiting 5-lipoxygenase. aspirin induced asthma. constipation.
inhibitors

Mast Cell Sodium Cromoglycate and Prevents allergen-induced mediator release from Given prophylactically by Not all asthmatics respond.
Stabilising Nedocromil Sodium mast cells. Do not act as bronchodilators. inhalation or nebuliser.
Agents Effective in antigen, exercise,
and irritant induced asthma.
Most often given to children.

Allergen Depends on allergen >Standard therapies aim to suppress inflammation Mild swelling at site of injection
Immunotherapy but do not address the initiating event in allergic Sneezing, bronchospasm, and in
asthma more severe cases, anaphylaxis with
>Involves treating IgE mediated disease with hypotension and collapse.
increasing doses of an allergen (e.g. dust mite) in
order to decrease patient sensitivity to that Side effects usually occur within 30
allergen. min, therefore resuscitation
equipment must be available
(adrenaline, oxygen with mask and
mask ventilator).

Anti-IgE Omalizumab Omalizumab: Monoclonal antibodies targeted Not a bronchodilator and should Injection reactions (redness,
Therapy against IgE → binds to IgE, stopping it from not be used in an acute asthma stinging, bruising)
Reslizumab, binding to receptors on mast cells and basophils → attack. Anaphylaxis in 0.1% of patients.
Mepolizumab, allergic response prevented at a very early stage.
Benralizumab
Reslizumab, Mepolizumab, Benralizumab:
Target IL-5 to prevent activation of eosinophil
production.

Novel/Experimental Therapies
Cytokine Strategies include
Modulators ● Drugs that inhibit cytokine synthesis (e.g. glucocorticoids) → may prove most useful
● Blocking antibodies to cytokines or their receptors
● Soluble receptors to mop up secreted cytokines
● Receptor antagonists

Peptides → Interaction of a T cell receptor and a peptide protein complex can lead to inactivation of the T cell’s capacity to respond to subsequent peptide or
allergen challenges.
→ results in reduced responsiveness to allergens and the asthmatic response
→ E.g. Cat Peptide Allergen Desensitisation (cat PAD) to treat cat-induced allergies including asthma

DNA vaccines DNA vaccine can be made by splicing the genes encoding allergen DNA (e.g. mite) into plasmid DNA
When the DNA vaccine is injected into an animal a strong immune response is induced, protecting the animal from sensitisation to allergens
● Enhances TH1 mediated response: suppresses allergic response
● Decreases TH2 mediated allergic response

TB Treatment
First line therapy

Drug Mechanism of Action ADME Resistance Adverse Effects

Rifampicin Rifamycins are macrocyclic antibiotics. t1/2 = 2-5 hours. Food decreases the Cmax Mutations in the rpoB gene Infrequent;
They bind in a pocket of bacterial RNA polymerase by 1/3rd and therefore should be taken (encodes β subunit of bacterial GIT (vomiting,
β subunit → inhibition of chain formation in RNA on an empty stomach. RNA polymerase). diarrhoea, nausea),
synthesis by blocking the activity of DNA Metabolised by microsomal β-esterases Efflux pump rash, fever, drug
dependent RNA polymerase. (Only in prokaryotic and cholinesterases. induction/mutations also interactions (with HIV
cells). Induces CYPs resulting in decreased t1/2 confer rifampicin resistance. medications)
for compounds metabolised by CYPs.
Active against most gram + bacteria. One of the Excreted through liver into bile.
most active anti-TB agents known.

Isoniazid A pro-drug that must be activated by the catalase Activated by bacterial enzymes then Mutations or deletion of Not common;
peroxidase-enzyme encoded by the katG gene in m. metabolised by a liver KatG. Efflux pump induction >Hepatotoxicity
tuberculosis. N-acetyltransferase (acetylation). also seen. >Peripheral neuropathy
 Creates a range of reactive species → inhibit (paresthesias, muscle
multiple targets including mycolic acid synthesis, aches, muscular
lipid peroxidation, DNA, and NAD metabolism. weakness, ataxia)
Targets cell-wall constituents → bacteriostatic for >Allergic skin reaction,
resting bacteria and bactericidal for dividing >CNS (restlessness,
bacteria. muscle twitch, and
psychiatric disorders)

Pyrazinamide Mechanism not completely understood. Metabolised by microsomal deamidase Most common are mutations Rare;
Thought to enter m. tuberculosis via passive to POA and subsequently hydroxylated in pyrazinamidase that lead to > Anorexia
diffusion and is then converted to the active to 5-hydroxy-POA, which is then reduced affinity for > Nausea and Vomiting
metabolite pyrazinoic acid (POA) by excreted by the kidneys. pyrazinamide. >Photosensitisation of
nicotinamidase/pyrazinamidase (PZase). the skin
Clearance reduced in renal failure. Efflux pumps also play a role. >Dysuria
>Malaise
t1/2 is 2-10 hours, but varies considerably >Fever
 Affects fatty acid synthase (nicotinamide analogue) with weight and gender. Inhibits urate
→ affects cell wall synthesis. excretion, leading to;
>hyperuricemia → can
It is inactive at neutral pH, but kills bacteria under lead to acute gout.
acidic conditions → effective against bacteria inside
of macrophages. Injury to the liver is the
most serious side
effect. Hepatic toxicity
is rare, except in
patients with
pre-existing liver
disease (no longer an
issue with combination
therapy).

Ethambutol Mechanism not completely known. ~ 80% of the drug is not metabolised at Most common are mutations Uncommon;
all and is renally excreted. leading to increased >Optic Neuritis (visual
Inhibition of cell wall synthesis via inhibition of production of arabinosyl disturbances, colour
arabinosyl transferases (EmbA, EmbB, EmbC) → Dosing frequency should be reduced in transferase which blindness)
bacteriostatic. renal failure. overwhelms the inhibitory >Peripheral
EmbA and EmbB polymerise into arabinan and then effect of ethambutol. Neuropathy
arabinogalactan, whilst EmbC is needed for the t1/2 = 3 hours >Rash
production of the glycolipid lipoarabinomannan. Change in binding site and >Fever
enhance efflux pumps also >Increased urate
play a role. concentration → gout
>Pruritus
>Joint pain
>GI upset
>Abdominal pain
 >Malaise
>Headache
>Dizziness
>Confusion
>Disorientation
>Hallucinations

Second line drugs → used when there is tolerance or insensitivity towards first line therapy. Most have significantly greater toxicity.

Class Examples Mechanism of Action Key Adverse Effects

Group A: Levofloxacin, Inhibition of DNA gyrase by binding to catalytic sites on the A QTc prolongation (delayed ventricular
Fluroquinolones moxifloxacin, gatifloxacin subunits of DNA gyrase → prevents catalysis of the formation of repolarisation), therefore monitoring necessary
negative supercoils in the double-stranded DNA of bacteria. when combined with other agents of same
effect.

Group B: Kanamycin, amikacin, Inhibition of protein synthesis via 3 mechanisms; Nephrotoxicity, ototoxicity, electrolyte
Aminoglycosides capreomycin, streptomycin imbalance.
(second-line (rarely used) Avoid combination of aminoglycosides with
injectables) other potentially nephrotoxic agents and use
with caution in patients with diabetes mellitus
or renal disease.

Group C: core second-line agents

Thioamides Ethionamide and Inhibition of cell wall synthesis → via inhibition of enoyl acyl Nausea and vomiting (if persistent, may indicate
prothionamide. carrier protein reductase (InhA) which inhibits synthesis of drug-induced hepatitis or pancreatitis).
mycolic acid (key cell wall component). Hypothyroidism.
Thyroid stimulating hormone levels need to be
monitored.
Oxazolidinones Cycloserine, terizidone, Inhibition of protein synthesis → via binding ay the P site a the CNS effects (psychosis, confusion, depression)
linezolid, clofazimine ribosomal 50S subunit. → terizidone and cycloserine
Peripheral neuropathy → linezolid
Myelosuppression → linezolid
Ocular toxicity → linezolid
QTc prolongation → clofazimine
Skin and Conjunctival pigmentation →
clofazimine

Group D: add-on agents

Bedaquiline Binds to subunit c of mycobacterial ATP synthase and inhibits its QTc prolongation, arthralgia, hepatitis,
activity → loss of energy production. headache

Resistance can be an issue due to mutations in

the subunit c target site, and efflux pump
induction.

Nitroimidazoles Delamanid and Pretomanid Delamanid is a pro-drug which gets activated by the enzyme QTc prolongation, nausea, vomiting, dizziness.
deazaflavin dependent nitroreductase. The enzyme intermediate
metabolite which is formed inhibits mycolic acid production.

Para-aminosalicylic acid (PAS) Inhibition of DNA precursor synthesis. GIT Toxicity

PAS is a prodrug that requires activation via the folate biosynthetic
pathway.
PAS acid binds pteridine synthetase (a key component in the first
step of folate synthesis) with greater affinity than PABA (the
natural acid that binds pteridine synthetase).
This inhibits the synthesis of folic acid → inhibition of DNA
synthesis → slowed cell growth and multiplication.
(Bacteriostatic).
Need to monitor thyroid stimulating hormone
levels.
Four mechanisms of resistance;
>Overexpression of Efflux pump (TAP)
>Diminished bioactivation of PAS (altered
substrate binding pocket)
>Overexpression of DfrA or RibD → inhibition
 neglected.
>Inactivation of thymidylate synthase →
decreased catalytic demand on DHFR

Categories of TB:

Multi-drug resistant TB (MDR-TB): TB disease in

which the TB bacterium is resistant to both isoniazid and
rifampin (the two strongest anti-TB medications).

Extensively Drug Resistant TB (XDR-TB):

● Pre-XDR-TB: TB caused by m. tuberculosis

strains that fulfill the definition of MDR-TB and
which are also resistant to any
fluoroquinolone.
● XDR-TB: TB caused by m. tuberculosis strains
that fulfill the definition of MDR-TB and which
are also resistant to any fluoroquinolone and at least one additional second-line injectable drug (amikacin,
capreomycin, or kanamycin) (WHO, 2021).
○ Three drug regimen of bedaquiline, pretomanid, and high-dose linezolid for adult patients with XDR, treatment
intolerant, or non-responsive MDR pulmonary TB.