Neurologic Disorders and COVID-19
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# Overview

# Pathophysiology of the Complications in the Nervous System

# Mechanism of targetting the Nervous System

# Complications in the Central Nervous System

### Cerebrovascular Accident/Stroke
- Hemorrhagic
- Ischaemic

### Acute Encephalitis

### Viral Meningitis

### Epileptic Seizures

### Encephalopathy

### Headache

# Complications in the Peripheral Nervous system

### Guillain-Barre syndrome

### Anosmia

### Acute Myelitis

### Miller Fischer Sydrome

### Polyneuritis Cranialis

# Complications due to medication interaction

### 1. Statin induced myotoxicity
- Myalgia, myopathies, rhabdomyolysis

### 2. 2nd and 3rd degree atrioventricular block
- Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)

### 3. Prolong QTc interval
- Chloroquine/Hydroxychloroquine
- Azithromycin

### 4. Myelotoxicity
- Ribavirin

### 5. Prolonged PR interval
- Atazanavir

### 6. Myelosuppression

# COVID-19 Experimental Treatments with Interaction Potential

## 1. Remdesivir (GS5734)
- Adults 40 kg: Daily IV dose over 30 min.
Day 1: 200 mg, Day 210: 100 mg
- Paed <40 kg: Daily IV dose over 30 min.  Day 1: 5 mg/kg, Day 210: 2.5 mg/kg
- NCT04302766
- NCT04292899
- Inhibits: CYP3A4, OATP1B1/3, BSEP, MRP4, and NTCP
- Induces: CYP1A2 and CYP2B6
- Unlikely clinically significant (all in vitro data)
- Concurrent use with hydroxychloroquine- decreases the antiviral activity of remdesivir.

## 2. Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)
- 400mg/100mg twice daily for 14 days
- Crushing tablet  absorption  45%133.
- Use oral liquid (42.4% alcohol and 15.3% propylene glycol)
- Use compatible feeding tubes (PVC or silicone)
- Avoid metronidazole and disulfiram
- Absorbed in jejunum: NG ok; NJ may  effect
- NCT04276688
- ChiCTR2000029539
- Lopinavir extensively metabolized by CYP3A
- Inhibitor of CYP3A4 (potent), Pgp, BCPR, and OATP1B1
can increase concentration of drugs metabolized or substrates of these pathways
- can increase concentration of drugs metabolized or substrates of these pathways
- Inducer of CYP2C9, CYP2C19, and glucuronidation
- Can prolong PR interval.
- Rare reports of 2nd and 3rd-degree atrioventricular block in patients with underlying risk factors

## 3. Chloroquine/Hydroxychloroquine
- 200 mg three times a day for 10 days
- NCT04261517
- ChiCTR2000029609
- Metabolised by CYP2C8, CYP3A4, CYP2D6
- Inhibited by CYP2D6 and Pgp
- Can prolong QTc interval, consider ECG monitoring where appropriate
- Concurrent use of HCQS with antibiotic azithromycin causes chest pain, congestive heart failure.
- Antacids decrease the absorption of hydroxychloroquine.
- Neostigmine, pyridostigmine antagonize the action of hydroxychloroquine.

## 4. Interferon beta
- NCT04276688
- Interferons have been reported to reduce CYP450 drug metabolism
- Care with narrow therapeutic index drugs dependent on CYP450 clearance

## 5. Ribavirin
- Do not crush  known teratogen.
- Contact hospital pharmacy for solution compounded from capsules or (SAS) product availability
- NCT04276688
- Not metabolized by CYP450 unlikely to contribute to CYP interactions.
- Inhibits inosine monophosphate dehydrogenase:
- Can interfere with azathioprine metabolism possibly leading to accumulation of 6methylthioinosine monophosphate (6MTIMP), which has been associated with myelotoxicity

## 6. Favipiravir
- ChiCTR2000029600 (favipiravir plus interferon)
- ChiCTR2000029544 (favipiravir plus baloxavir marboxil)
- Metabolised by aldehyde oxidase in the cytosol of the liver.
- Inhibits:
CYP2C8 (strong)
OAT1, OAT3 (mod)
CYP1A2 (weak) , CYP2C9 (weak) , CYP2C19 (weak) , CYP2CD6 (weak) , CYP2E1 (weak) , CYP3A4 (weak)
Aldehyde oxidase Inhibitors increase the concentration of favipiravir. The drugs include selective estrogen receptor modulators(SERMs), H2 receptor antagonists like cimetidine, calcium channel blockers, anti-arrythmic drugs like propafenone, tricyclic antidepressants.
- CYP2C8 (strong)
- OAT1, OAT3 (mod)
- CYP1A2 (weak) , CYP2C9 (weak) , CYP2C19 (weak) , CYP2CD6 (weak) , CYP2E1 (weak) , CYP3A4 (weak)
- Aldehyde oxidase Inhibitors increase the concentration of favipiravir. The drugs include selective estrogen receptor modulators(SERMs), H2 receptor antagonists like cimetidine, calcium channel blockers, anti-arrythmic drugs like propafenone, tricyclic antidepressants.
- Low-risk QT prolongation

## 7. Atazanavir
- Requires pH <4.
- Avoid antacids 2 h before and 1 hour after.
- Food  bioavailability
- Absorbed in jejunum: NG ok; NJ may  effect
- Metabolised by: CYP3A4 (extensively)
- Inhibits: CYP3A4, UGT1A1, OATP1B1 (strong), CYP2C8 (weak)
- Absorption depends on low pH; drugs increasing pH will decrease atazanavir concentration
- Dose-related prolongation in PR interval.
- Care with drugs increasing QT interval or in patients with preexisting risk factors.

## 8. Nitazoxanide (prodrug) (active metabolite: tizoxanide)
- Maybe dispersible or crushed check the brand
- Take with food  increases bioavailability by 50%.
- Nil effects on CYP450 enzymes
- Tizoxanide highly protein-bound (>99.9%)
- Will compete for binding sites; monitor drugs highly protein-bound with a narrow therapeutic index (such as  warfarin)

## 9. Tocilizumab (IL6 monoclonal antibody)

### Pharmacokinetics and Dosing:
- NCT04310228
- NCT04306705
- Nil significant drug interactions.
- COVID19 increases IL6 expression. Tocilizumab reduces IL6 expression. IL6 increases CYP3A4, CYP26C19, CYP2C9, CYP1A2. When tocilizumab is used to treat COVID19, the effect on drugs affected by these CYP enzymes is unknown.

## 10. Dexamthasone

### Pharmacokinetics and Dosing:
- Oral or Intravenous- 6mg/day for 10 days
- Given in patients who are mechanically ventilated.
- Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial
- Interacts with many drugs like oral contraceptive pills, digoxin, blood thinners ( clopidogrel, warfarin, dabigatran )

## 11. Ivermectin:
- It is not FDA approved for use in SARS-CoV2

### Pharmacokinetics:
- Metabolised by liver microsomes by Cyt P450-3A4

### Research Trial:
- A study by a National Breast Cancer Foundation Fellowship, Australia (ECF-17-007) for KMW and an National Health and Medical Research Council (NHMRC), Australia Senior Prinicple Research Fellow (SPRF) (APP1103050) for DAJ, found Ivermectin to be effective in treating SARs-CoV2.

### Interactions:
- Ivermectin increases the side effects of blood thinners.
- Grapefruit juice increases the concentration of ivermectin.
- Avoid or limit alcohol use in patients taking ivermectin.