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Basic science notes


CLINICAL PHARMACOLOGY NOTES
Bioavailability
refers to absorption of the drug. Increased gastric emptying and
induction of liver enzymes increases first pass metabolism and reduced
bioavailability.
Potency refers to the amount of drug usually needed to produce an effect, such as
relief of pain or reduction of blood pressure. For instance, if 5 milligrams of drug A
relieves pain as effectively as 10 milligrams of drug B, drug A is twice as potent as
drug B.
Efficacy refers to the potential maximum therapeutic response that a drug can
produce. Frusemide eliminates more salt than hydrochlorothiazide, hence it has higher
efficacy than hydrochlorothiazide.
The difference in speed of acetylation is due to the amount (or activity) of the
enzyme N-acetyltransferase available. Fast acetylation is a trait which is autosomal
dominant inherited.
Drugs with zero order kinetics

Alcohol
Phenytoin
Fluoxetine
LIVER ENZYME INDUCERS (PCBRAS)
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol
Sulphonylureas
LIVER ENZYME INHIBITORS (OAAK DEVICCES)
Omeprazole
Amiodarone
Allopurinol
Ketoconazole
Disulfram
Erythromycin
Valproate
Isoniazid
Ciprofloxacin
Cimetidine
Ethanol
Sulphonamides

Drug induced lupus:
procainamide
isoniazid
chlorpromazine
penicillamine
sulfasalazine
hydralazine
methyldopa
quinidine
Drugs which can cause gynaecomastia are :
digoxin
oestrogens
spironolactone
cimetidine
verapamil
nifedipine
Drugs causing galactorrhoea are:
Oral contraceptive pills
Phenothiazines such as chlorpropramide and thioridazine
Metoclopramide
Bromocriptine
The drugs most commonly implicated in SIADH are:
cyclophosphamide
chlorpromamide
carbamazepine
clofibrate
thiazide diuretics
vincristine
vinblastine
phenothiazines
tricyclic antidepressants
SSRIs
Drugs producing hypercalcemia include:
lithium,
alkaline antacids
DES,
Thiazides
estrogens
progesterone
MISCELLANEOUS DRUGS

Common side effects of Selective Serotonin Reuptake Inhibitors (SSRIs) are
nausea, vomiting, diarrhoea, appetite and weight loss, sexual dysfunction and
deranged liver function tests. Similarly, the common side effects of fluoxetine are
:anxiety or nervousness; decreased appetite; diarrhoea; drowsiness; headache;
increased sweating; nausea; tiredness or weakness; trembling or shaking; insomnia.

Amiodarone
blocks conversion of T4 to T3 and affects pituitary thyroid axis.
The following changes in thyroid function tests occur within 3 months of starting
amiodarone and are not indicative of thyroid disease:
increase in TSH up to 20mU/L
increase in T4 to upper limit of normal
decreased T3 levels.
Anticholinergic syndrome occurs following overdose with drugs that have
anticholinergic activity.
Examples of these are tricyclic antidepressants, antihistamines and atropine. Features include flushed skin, urinary retention, tachycardia, mydriasis (dilated pupils) and agitation. Physostigmine, a reversible inhibitor of acteylcholinesterase, is effective in treating anticholinergic symptoms but there is a significant risk of cardiac toxicity (bradycardia, AV conduction defects and asystole) with the drug.
Bisphosphonates
acts at the cellular level. They act directly or indirectly on the
osteoclasts. The effect can be on the formation of osteoclasts and/or on their activity.
A decrease in osteoclast number can occur either through direct action on osteoclast
precursors, or indirectly by stimulating the osteoblasts to produce an inhibitor of
osteoclast formation. Osteoclast inactivation is associated with bisphosphonate uptake
from the bone surface.
β-interferon
is a long term treatment (as opposed to steroids for acute relapses) which
is of benefit only in the relapsing remitting form (about 40% of MS patients have this
form), and slows progression of disability and reduces demyelinating lesions.
Aspirin toxicity causes symptoms of nausea, vomiting, headache, confusion and
tinnitus or hearing difficulties.
Major side effects of carbimazole are: agranulocytosis, thrombocytopaenia, acute
hepatic necrosis, cholestatic hepatitis, lupus-like syndrome and vasculitis. It may
cause neutropenia in 1 in 800 patients.
Clozapine induced agranulocytosis
occurs in about 1% to 10% of patient who take
clozapine. Patients who have experienced agranulocytosis with prior treatment of
clozapine should not receive clozapine again.
Hyperkalaemia, hirsutism, tremors, hypertension, nausea and vomiting, headache,
gum hypertrophy, parasthesiae and hypomagnesaemia are side effects of ciclosporin.
Disulfiram (antabuse) acts by causing raised acetaldehyde levels. This causes
unpleasant effects. Metronidazole and disulfram synergism may lead to psychosis.
Digoxin is slowly absorbed, hence peak effects can be delayed for up to half a day
after an overdose. Visual disturbance, nausea and vomiting, tachy and
bradyarrhythmias can occur with an overdose. Activated charcoal decreases
absorption.
Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding
portion of the tumor necrosis factor receptor (TNFR) linked to a human IgG1. The
receptor binds to TNF, it is not a monoclonal antibody. It is licensed for juvenile
rheumatoid arthritis and juvenile idiopathic arthritis. Side effects are septic arthritis,
demyelination, pancytopenia, aplastic anaemia and congestive heart failure. .
Infliximab is a monoclonal anti-TNF antibody.
Ezetimibe acts by prevent cholesterol absorption from the small intestine. Typically it
reduces LDL-cholesterol by approximately 20%, triglycerides by up to 5% and raises
HDL-cholesterol by approximately 5%.
Ezetimibe is currently licensed for use in combination with a statin in patients who
fail to reach desired lipid profiles or as monotherapy in patients intolerant to a statin.
Thiazides block Na+ and Cl- reabsorption in the distal tubule. There is usually
passive Na+ and Cl- co transport. With this blocked, natriuresis occur. The distal
convoluted tubule accounts for 5% of total sodium chloride reabsorption. Thiazides
elevate LDL cholesterol, reduce urinary calcium excretion and can cause impotence.
Hypercalciuria can be treated with thiazides.
Thiazides can cause thrombocytopaenia, hypokalaemia (blocking NaCl channels), and
hyperuricaemia.
Frusemide acts on the thick portion of the ascending loop of Henle. It inhibits Na+
and Cl- reabsorption there via Na+, K+, -ATPase-dependent pump. Owing to the
large NaCl absorptive capacity of the loop of Henle, agents that act at this site
produce a diuretic effect much greater than that seen with other diuretic groups.
Insulin glargine is a long-acting insulin analogue, there is a smooth, prolonged
absorption profile with no peaks. As such, it is a long-acting agent, suitable for
providing a basal level of insulin which mimics the normal physiological state.
Its smooth profile reduces the risk of hypoglycaemia, and when given at night, provides good control of the fasting blood glucose.
Lofexidine a centrally acting alpha-2 adrenergic agonist, was launched specifically
for symptomatic relief in patients undergoing opiate withdrawal programmes. In open
studies in small groups of methadone dependent patients, lofexidine treatment enabled
successful detoxification (defined as remaining drug free for 10 days after the last
methadone dose) in greater than 65% of patients.
Mesalazine can cause neutropenia. It works in IBD by release in the terminal ileum.
Mesalazine is given in the acute attacks in Crohn's disease. Sulfasalazine
(sulphapyridine and 5-amino-salicylic acid) is used in rheumatoid arthritis.
Penicillamine is a DMARD which can is used in Rheumatoid arthritis, Juvenile
chronic arthritis and as a copper binder in Wilson’s hepatolenticular degeneration. It
is also used in PBC, chronic active hepatitis and cystinuria. It can cause aplastic
anaemia and thrombocytopenia, proteinuria and loss of taste.
Penicillamine is associated with drug-induced lupus, Goodpasture’s syndrome,
myasthenia, myositis and Stevens-Johnson syndrome.
Orlistat is an inhibitor of gastrointestinal lipases, leading to reduced fat absorption. It
is licensed for patients with BMI > 28 with associated risk factors, a weight
management programme should be in place. Use is not recommended for more than 2
years.
Quetiapine is indicated for the management of the manifestations of schizophrenia.
The commonest side effects (>5%) are excessive sedation, dizziness, dry mouth,
postural hypotension, and elevated ALT.
Theophylline is metabolised in the liver. Plasma theophylline levels are increased in
heart failure, cirrhosis of the liver, viral infections, elderly patients, and by drugs that
inhibit metabolism of theophylline. The plasma levels of theophylline are decreased in
smokers, chronic alcoholism and by drugs that induce liver metabolism.

Metformin
a biguanide. Its mode of action is thought to be multifactoral and includes
delayed uptake of glucose from the intestinal tract, increased peripheral glucose
utilisation mediated by increased insulin sensitivity and inhibition of increased
hepatic and renal gluconeogenesis
.
In metformin overdose, main symptoms of toxicity include gastrointestinal upset due
to a severe lactic acidosis. Hypoglycaemia is not often seen in metformin overdose. If
lactic acidosis occurs following overdose, mortality can be high. Management is
gastric decontamination and use of activated charcoal if appropriate, and correction of
acidosis with 8.4% sodium bicarbonate. Haemodialysis can be considered in severe
cases.
Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile
characterized by estrogen agonist activity in some tissues with estrogen antagonist
activity in other tissues. The first widely used SERM, tamoxifen, has estrogen
antagonist activity in breast tissue but shows estrogen-like activity in other tissues.
Raloxifene is another SERM in clinical use, and it was developed to avoid some of
the undesirable estrogen agonist actions of other SERMs to improve the drug safety
profile. Raloxifene has been introduced for clinical use in treatment and prevention of
postmenopausal osteoporosis.
Sumatriptan is a 5HT1 agonist and may be useful in the treatment of acute migraine
attacks. is available in injectable, intranasal, and oral formulations. Ergotamine
tartrate is also effective in acute migraine. Propanolol, valproate, NSAIDs,
amitriptyline, pizotifen and gabapentin are effective as prophylactic drugs in
migraine.
IMMUNOSUPPRESANTS

Immunosuppresants: Corticosteroids act on cytosolic rather than cell membrane
receptors. Both mycophenolate and azathioprine
Approximately 1 in 300 Caucasians have thiopurine methyl transferase (TPMT)
deficiency. TPMT is the enzyme that metabolises 6-mercaptopurine and its deficiency
results in high risk of azathioprine toxicity.
Azathioprine is used when steroid withdrawal causes recurrent relapse. Bone marrow
suppression (low white cell count) and pancreatitis are side effects of azathioprine
Methotrexate: Binding of methotrexate to dihydrofolate reductase reduces nucleotide
synthesis as well as amino acids serine and methionine. Folinic acid rescue is usually
given after methotrexate therapy (e.g. 24 hours) to reduce myelosuppression side
effects.
Methotrexate is associated with interstitial pneumonitis. This is rare but a serious
complication. Chest radiography reveals a diffuse interstitial or mixed interstitial and
alveolar infiltrate, with a predilection for the lower lung fields.
Common side effects of gold are mouth ulceration, leucopenia, proteinuria and skin
rashes.
Hydroxychloroquine can cause renal toxicity.
Sulphasalazine causes nausea and vomiting, leucopenia and deranged liver function.
Allopurinol specifically inhibits xanthine oxidase and prevents metabolism of
azathioprine to mercaptopurine. This action causes increased toxicity of
azathioprine.
TOXICITY / ADVERSE EFFECTS

Common symptoms of lithium toxicity (can occur at levels greater than 1.1 mmol/l)
are nausea and vomiting, diarrhoea, disorientation, tremors and ataxia.
Lithium can cause hypercalcaemia and hypothyroidism along with a goitre, fine
tremor, weight gain, diabetes insipidus and cardiac arrhythmias.
Gammahydroxybutyric acid causes hypernatraemia, metabolic acidosis,
hypokalaemia, hyperglycaemia.
Hypotension/shock, glucose >8.3 mmol/l, white cell count > 15, haemetemesis and
decreased consciousness are features of severe iron poisoning.
The primary symptoms of mercury poisoning are vague psychiatric ones. Short-time
memory can deteriorate. Organic mercury can cross the blood-brain barrier and cause
irreversible nervous system and brain damage, e.g., loss of motor control, numbness
in limbs, blindness, and inability to speak.
Methaemoglobinaemia can be caused either by a genetic defect in red cell
metabolism or haemoglobin structure, or acquired by a variety of drugs and toxins.
Common drugs dapsone, nitrates, prilocaine, antimalarials, sulphonamides and dyes.
Domestic causes of acquired methaemoglobinaemia include ingestion of food and
water high in nitrites and nitrates exposure to aniline dyes in dyed blankets, laundry
markings, freshly dyed shoes, red wax crayons and cleaning solution.
Standard pulse oximeters give spuriously low readings in the presence of excess
methaemoglobin. Methylene blue is indicated in any patient with symptoms and/or
signs of hypoxia (mental changes, tachycardia, dyspnoea, chest pain). It is
contraindicated in G6PD deficiency. High flow oxygen should be administered.
Carbon monoxide poisoning is produced by the incomplete combustion of carbon
containing fuels such as gas, coal, oil, wood and coke. Headache is the most common
symptom (90%) followed by nausea & vomitting, vertigo, alteration in consciousness
and weakness. The cherry red skin colour occurs when COHb concentration exceeds
20% but it is rarely seen in life. Pulse oximetry gives falsely high oxygen saturation
sand it is not recommended.
Phenytoin toxicity can cause:
sedation
slurred speech
nystagmus
ataxia
vertigo
Long term side effects of phenytoin are:
gingival hypertrophy
hirsutism
acne
coarseness of facial features
Common drugs which can precipitate a porphyria attack are:
Barbiturates
Sulfonamides
chloroquine
steroids
Barbiturate withdrawal in an habitual abuser a well recognised cause of fits.
Benzodiazepine elevates the level of an inhibitory neurotransmitter, GABA, therefore
it serves as a tranquilizer. Barbiturates are prescribed as anticonvulsants, sedatives,
and general anesthetics. Commonly abused barbiturates include amobarbital
(Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). These drugs depress
the respiratory and nervous system functions. Symptoms of withdrawal syndrome
appear 12-20 hours after the last dose; they include anxiety, irritability, elevated heart
and respiration rate, muscle pain, nausea, tremors, hallucinations, confusion, and
seizures.
Chronic cocaine use can result in erectile dysfunction, ejaculatory dysfunction,
hypersomnia, excitement, emotional instability, restlessness, irritability, apprehension,
inability to sit still, teeth grinding, cold sweats, tremors, twitching of small muscles
Severe anxiety and paranoid hallucinations, mania, and psychosis can also occur with
cocaine use.
Features of acute MDMA (ecstasy) toxicity include agitation, tachycardia,
hypertension, dilated pupils, sweating, hyperthermia, disseminated intravascular
coagulation (DIC), rhabdomyolysis and acute renal failure.
Theophylline poisoning results in profound Hypokalaemia, SVT and VT, vomiting,
agitation and convulsions. Activated charcoal is the method of choice for elimination.
Diazepam may be used to control convulsions and Propanolol may help tachycardia
and reversal of hyperglycaemia (however, beware of using it in asthma).
Agents not adsorbed by activated charcoal include:
metals (lithium, iron)
hydrocarbons and solvents
alcohols
Neuroleptic malignant syndrome is characterized by fever, muscular rigidity, labile
blood pressure, altered mental status, decreased conscious level and autonomic
dysfunction. Although potent neuroleptics (eg, haloperidol, fluphenazine) are more
frequently associated with NMS, all antipsychotic agents may precipitate the
syndrome. For example, these agents are prochlorperazine, promethazine , clozapine ,
risperidone .
Dystonic reactions usually subsides within 24 hours following cessation of treatment
and can be treated with procyclidine 5-10 mg i.m.
They are well-recognized with dopamine receptor antagonists (neuroleptics). Phenothiazines, prochloperazine, haloperidol and metclopramide are examples of drugs which can cause dystonic reactions. Oculogyric Crisis is one of the acute dystonic reactions. It is the most common of
the ocular dystonic reactions (which include blepharospasm, periorbital twitches, and
protracted staring episodes).
Priapism as a side effect is associated with phenothiazines (chlorpromazine),
haloperidol, trazodone and alpha blockers (prazosin).
MORPHINE EQUIVALENT DOSES

100 mg of MST has the equivalent dose of 25 ug/hr of fentanyl over a day.
A 24 hour diamorphine dose should be 1/3 of the 24 hour morphine dose.
The breakthrough dose of short acting morphine such as oramorph should be 1/6th of
the total 24 hour dose of morphine.
The equivalent dose of oral oxycodone 0.833 is to diamorphine SC 1.3 (about 2/3).

PREGNANCY

Trimethoprim is a folate antagonist and can increases the risk of neural tube defects.
There is relative contraindication for ciprofloxacin in pregnancy due to the possible
teratogenic effect. Augmentin, cefaclor, nitrofurantoin and metronidazole are safe in
pregnancy.
Carbimazole crosses the placenta and can cause nail/finger abnormalities.
Propylthiouracil is commonly used in pregnancy instead of carbimazole due to the
risks of neonatal hypothyroidism with carbimazole.
Warfarin in the first trimester can cause fetal hypoplasia of the nose and limbs. After
this period warfarin is associated with neurological damage – mental retardation,
microcephaly, optic atrophy and blindness. There is an option to convert from heparin
to warfarin in the third trimester, but the patient will have to be re-converted back to
heparin before delivery.

Source: http://www.indchaptrcpi.org/online_exam/uploadPdf/Clin%20Pharm%20Notes.pdf

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