1. Lithium is used to treat and prevent mania and bipolar disorder. It works by inhibiting neurotransmitter release in the brain. 2. It is excreted unchanged in the urine, so renal impairment increases the risk of toxicity. The dose must be carefully monitored and reduced in renal impairment. 3. Toxicity can occur even at therapeutic levels and includes tremors, ataxia, confusion, seizures, and cardiac issues. Hemodialysis is required to treat severe toxicity.

1. Dialyzable drugs
By Dr. Dinesh Kumar G
Pharm. D

2. Factors Influencing Dialyzability
• Molecular weight – Smaller molecular weight substances will pass through the dialysis
membrane more easily than larger molecular weights.
• Protein Binding – Drugs with a high degree of protein binding will have a small plasma
concentration of unbound drug available for dialysis, making them poorly dialyzable or requiring
multiple sessions.
• Volume of Distribution – Drugs with large volumes of distribution usually due to lipid solubility
and low plasma protein binding are poorly dialyzable.
• Plasma clearance – Although plasma clearance may be beneficial, increasing plasma clearance
will decrease dialysis clearance.
• Dialysis Flow Rates – Greater degrees of dialysis can be achieved with faster dialysate flow rates
if the dialysate drug concentrations is low. As the concentration of drug is increased in the
dialysate the flow rate needs to be lowered.

3. BLISTMED
B - Barbiturates
L - Lithium
I - Isoniazid
S - Salicylates
T - Theophylline/Caffeine (both are methylxanthines)
M - Methanol, metformin
E - Ethylene glycol
D - Depakote, dabigatran
Others - Carbamazepine

4. Phenobarbitone
CLINICAL USE: Anti-epileptic agent
DOSE IN NORMAL RENAL FUNCTION
• 1-3 mg/kg/day in divided doses
• Oral: 60–180mg at night
• Status epilepticus: 10mg/kg, max 1g IV
PHARMACOKINETICS
• Molecular weight (daltons) - 232.2 (254.2 as sodium salt)
• % Protein binding - 45–60
• % Excreted unchanged in urine - 25
• Volume of distribution (L/kg) - 1
• Half-life – normal/ESRF (hrs) - 75–120/Unchanged

5. Phenobarbitone
DOSE IN RENAL IMPAIRMENT GFR (mL/min)
• 20–50 Dose as in normal renal function
• 10–20 Dose as in normal renal function, but avoid very large doses
• <10 Reduce dose by 25–50% and avoid very large single doses
DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES
• CAPD Dialysed. Dose as in GFR<10mL/ min
• HD Dialysed. Dose as in GFR<10mL/ min

6. Phenobarbitone
ADMINISTRATION
• Route - IV, oral
• Rate of administration - Not more than 100mg/minute
• Comments - For IV administration, dilute 1 in 10 with water for injection
• Aim for plasma concentration of 15– 40mg/L (65–170 µmol/L) for optimum response
• May cause excessive sedation and increased osteomalacia in ERF

9. BARBITURATES
MECHANISM OF
ACTION
1.Bind to GABAA receptors
2.↑ duration of Cl
-
channel opening; ↑ Cl
-
influx
3.Membrane hyperpolarization; ↓ neuronal excitability
INDICATIONS Anxiety, Preoperative sedation, Convulsions
ROA PO, IV, IM
SIDE EFFECTS
•Headache, somnolence, confusion
•CNS depression, hallucinations, vertigo
•Nausea, vomiting, diarrhea
•Asthenia, ataxia
•Tolerance, dependence, and withdrawal symptoms
CONTRAINDICATIONS
•Concomitant use with other CNS depressants
•Hypotension, laryngospasm, bronchospasm
ASSESSMENT AND
MONITORING
CLIENT EDUCATION
Vital signs - include orthostatic hypotension assessment
•Weight, LOC
•Laboratory values: CBC, hepatic, renal, cardiac function
•Side effects - report to provider and intervene if necessary
Phenobarbital for long-term anticonvulsant therapy - monitor serum folate levels
• Avoid hazardous activities like driving until response is known
• Provide safety measures like raising side-rails and ensuring adequate lighting
• Can reduce the efficacy of oral contraceptives
• Make position changes slowly to reduce effects of orthostatic hypotension
• Promptly report flu-like symptoms or a rash which could indicate Stevens-Johnson syndrome

19. Lithium
CLINICAL USE
Treatment and prophylaxis of mania, manic depressive illness, and recurrent depression
Aggressive or self-mutilating behaviour
DOSE IN NORMAL RENAL FUNCTION It is generally started at 600 mg/day and gradually
increased to yield therapeutic plasma levels; mostly 600–1200 mg/day is required.
Toxicity—
a. Therapeutic Levels: 0.6 to 1.2 mEq/L
b. Mild-Moderate Symptoms: 1.5 to 2.5 mEq/L
c. Potentially Lethal: 3 to 4 mEq/L.

20. Lithium
PHARMACOKINETICS
Molecular weight (daltons) – 73.9
% Protein binding – 0
% Excreted unchanged in urine – 95
Volume of distribution (L/kg) – 0.5–0.9
Half-life – normal/ESRF (hrs) – 12–24/40–50
DOSE IN RENAL IMPAIRMENT GFR (mL/min)
<10 – Avoid if possible, or reduce dose and monitor plasma concentration carefully

21. Lithium
• Doses are adjusted to achieve lithium plasma concentrations of 0.4–1.0mmol/L (lower
end of range for maintenance therapy in elderly patients) in samples taken 12 hours after
the preceding dose. It takes 4–7 days to reach steady state
• Long-term treatment may result in permanent changes in kidney histology and
impairment of renal function. High serum concentration of lithium, including episodes of
acute lithium toxicity, may aggravate these changes. The minimum clinically effective
dose of lithium should always be used.
• Lithium generally should not be used in patients with severe renal disease because of
increased risk of toxicity.
• Up to one-third of patients on lithium may develop polyuria, usually due to lithium
blocking the effect of ADH. This reaction is reversible on withdrawal of lithium therapy.

22. Lithium
Adverse effects. Toxicity occurs at levels only marginally higher than therapeutic levels.
1. Nausea, vomiting and mild diarrhea occur initially, can be minimized by starting at lower
doses.
2. Thirst and polyuria are experienced by most, some fluid retention may occur initially, but
clears later.
3. Fine tremors are noted even at therapeutic concentrations.
4. CNS toxicity manifests as plasma concentration rises producing coarse tremors,
giddiness, ataxia, motor incoordination, nystagmus, mental confusion, slurred speech,
hyperreflexia. Overdose symptoms are regularly seen at plasma concentration above 2
mEq/L. In acute intoxication these symptoms progress to muscle twitching, drowsiness,
delirium, coma and convulsions. Vomiting, severe diarrhea, albuminuria, hypotension
and cardiac arrhythmias are the other features.

23. Toxicity Treatment
1. Activated charcoal does not adsorb lithium very well and must not be administered.
2. Whole bowel irrigation with polyethylene glycol electrolyte lavage solution at a rate of
2 L/hr for 5 hours has been shown to be very useful in the early stages.
3. Hemodialysis: The indications for hemodialysis in lithium intoxication are inexact;
some authors recommend hemodialysis for any patient with a level above 3.5 mEq/L.
Other authors recommend hemodialysis for all patients with more than prodromal
symptoms and slightly increased 12-hour serum lithium concentration. Lithium
clearance during hemodialysis is approximately 100–120 ml/min, thus four hours of
hemodialysis is equivalent to 24-hour clearance of 16–20 ml/min. Renal lithium
clearance is 20 to 30% of creatinine clearance, thus those with renal impairment
(calculated creatinine clearance less than 60 ml/min) are generally candidates for
hemodialysis. Once begun, hemodialysis should be carried out as long as necessary to
reduce the serum lithium concentration to less than 1 mEq/L after redistribution.

24. 4. Continuous arteriovenous hemodiafiltration (CAVH), if available, is more efficacious
than hemodialysis.
5. Administration of sodium polystyrene sulfonate can help reduce absorption of lithium.
Dose—
i. Adults: 60 ml of suspension (15 gm resin) given orally four times a day; 120 to 200 ml of
suspension (30 to 50 gm resin) given rectally as retention enema following a cleansing
enema.
ii. Children and Infants: Dose is based on exchange ratio of about 1 mEq of potassium per
1 gram of resin or approximately 1 gram/kg/dose every 6 hours orally, or every 2 to 6 hours
rectally.
6. Supportive measures: artificial ventilation, anticonvulsants, and correction of
hypotension, dehydration, and hypovolaemia

25. Lithium
5. On long-term use, some patients develop renal diabetes insipidus. Most patients gain
some body weight. Goiter has been reported in about 4%. This is due to interference with
release of thyroid hormone → fall in circulating T3, T4 levels → TSH secretion from
pituitary → enlargement and stimulation of thyroid. Enough hormone is usually produced
due to feedback stimulation so that patients remain euthyroid. However, few become
hypothyroid. Lithium induced goiter and hypothyroidism does not warrant discontinuation
of therapy; can be easily managed by thyroid hormone supplementation.
6. Lithium is contraindicated during pregnancy: fetal goiter and other congenital
abnormalities, especially cardiac, can occur; the newborn is often hypotonic.
7. At therapeutic levels, Li+ can cause reduction of T-wave amplitude. At higher levels, SA
node and A-V conduction may be depressed, but arrhythmias are infrequent. Lithium is
contraindicated in sick sinus syndrome. Lithium can cause dermatitis and worsen acne.

26. Lithium
1. Acute mania
2. Prophylaxis in bipolar disorder
3. Lithium is being sporadically used in many other recurrent neuropsychiatric illness,
cluster headache and as adjuvant to antidepressants in resistant nonbipolar major
depression.
4. Cancer chemotherapy induced leukopenia and agranulocytosis: Lithium may hasten the
recovery of leukocyte count.
5. Inappropriate ADH secretion syndrome: Lithium tends to counteract water retention but
is not dependable.

27. LITHIUM
CLASS Mood stabilizer; antimanic agent
MECHANISM OF
ACTION
•Inhibition of norepinephrine and dopamine release in the brain
•Increase of serotonin production in the brain
•Alteration of Na
+
/ K
+
ion transport (brain, muscle cells)
INDICATIONS Bipolar disorder
ROA PO
SIDE EFFECTS
•Nausea, vomiting, diarrhoea, Muscle weakness, hyperreflexia, ataxia, Slurred speech
•Seizures, Nephrogenic diabetes insipidus (polyuria, polydipsia), Serotonin syndrome
CONTRA
INDICATIONS AND
CAUTIONS
•Boxed warning: toxicity
•Pregnancy, breastfeeding
•Children < 12 years
•Cardiac / renal / hepatic impairment
•Schizophrenia, brain trauma, brain organ syndrome
•NSAIDs, ACE inhibitors, diuretics
•Dehydration, hyponatremia
•Thyroid disease
ASSESSMENT AND
MONITORING
CLIENT
EDUCATION
Mental status, Medication history
• Baseline labs: BUN, creatinine, electrolytes, TSH, liver function, thyroid function, negative
pregnancy test
• Do not crush or chew, Do not stop even if feeling better, Take with meals or milk
• Regular monitoring of lithium levels required
• Keep fluid and sodium balance consistent
• Report signs or symptoms of toxicity

28. Methanol
• Methyl alcohol is added to industrial rectified spirit to render it unfit for drinking. It is
only of toxicological importance. Mixing of methylated spirit with alcoholic beverages or
its inadvertent ingestion results in methanol poisoning. Methanol is metabolized to
formaldehyde and formic acid by alcohol and aldehyde dehydrogenases respectively, but
the rate is 1/7th that of ethanol. Methanol also is a CNS depressant, but less inebriating
than ethanol. Toxic effects of methanol are largely due to formic acid, since its further
metabolism is slow and folate dependent. A blood level of >50 mg/dl methanol is
associated with severe poisoning. Even 15 ml of methanol has caused blindness and 30 ml
has caused death; fatal dose is regarded to be 75–100 ml.
• Manifestations of methanol poisoning are vomiting, headache, epigastric pain,
uneasiness, drunkenness, disorientation, tachypnoea, dyspnea, bradycardia and
hypotension. Delirium and seizures may occur, and the patient may suddenly pass into
coma. Acidosis is prominent and entirely due to production of formic acid. The specific
toxicity of formic acid is retinal damage. Blurring of vision, congestion of optic disc
followed by blindness always precede death which is due to respiratory failure.

30. Treatment
1. Keep the patient in a quiet, dark room; protect the eyes from light.
2. Gastric lavage with sod. bicarbonate if the patient is brought within 2 hours of ingesting
methanol. Supportive measures to maintain ventilation and BP should be instituted.
3. Combat acidosis by I.V Sod. bicarbonate infusion. This is the most important measure;
prevents retinal damage and other symptoms; large quantities may be needed.
4. Ethanol is preferentially metabolized by alcohol dehydrogenase over methanol. At a
concentration of 100 mg/dl in blood it saturates alcohol dehydrogenase and retards methanol
metabolism. This helps by reducing the rate of generation of formaldehyde and formic acid.
Ethanol (10% in water) is administered through a nasogastric tube; loading dose of 0.7 ml/kg is
followed by 0.15 ml/kg/hour. Because pharmacokinetics of alcohol changes over time and no i.v.
formulation is available, maintenance of a fixed concentration is difficult. Alcohol blood level
needs to be repeatedly measured. Moreover, the enzyme saturating concentration of ethanol
itself produces intoxication and can cause hypoglycemia. Use of ethanol for this purpose is
tricky. Treatment has to be continued for several days because the sojourn of methanol in body is
long.

31. 5. Pot. chloride infusion is needed only when hypokalemia occurs due to alkali therapy.
6. Hemodialysis: clears methanol as well as formate and hastens recovery.
7. Fomepizole (4-methylpyrazole) is a specific inhibitor of alcohol dehydrogenase and the
drug of choice for methanol poisoning by retarding its metabolism. A loading dose of
15 mg/kg i.v. followed by 10 mg/kg every 12 hours till serum methanol falls below
20 mg/dl, has been found effective and safe. It has several advantages over ethanol, viz.
longer t½ and lack of inebriating action, but is not available commercially in India.
8. Folate therapy: Calcium leucovorin 50 mg injected 6 hourly has been shown to reduce
blood formate levels by enhancing its oxidation. This is a promising adjuvant approach

32. Thank You