General Pharmacology part 2 Flashcards
Avd of a drug, definition
It is the total plasma required to accommodate the administered drug in the whole body at plasma concentration
Avd = (Dose*f)/conc
Loading dose
It is the high dose of drug given for drugs with high volume of distribution to maintain a specific plasma concentration
Loading dose = (avd*conc)/f
Factors which affect avd of a drug
- Lipid solubility
- Fat content (hence gender and age)
- Plasma protein binding
- Specific tissue binding
Digoxin accumulates in which organ
Skeletal muscle
Therefore avd is calculated based on lean body mass
Dialysis is not effective in removing toxicity in which cases
- Increased avd
- High plasma protein binding capacity
- Which are irreversible binders
Examples of drugs whose toxicity cannot be treated by dialysis
O) Opioid and organophosphates
A) Amphetamine
B) Benzodiazepines and beta blockers
C) Ca channel blockers
D) Digoxin
Antidote of benzodiazepines and beta blockers
For benzodiazepines it is flumazenil
For beta blockers it is glucagon (source of cAMP)
Antidotes of amphetamines, digoxin and Ca channel blockers
Antidote of amphetamine- ammonium chloride
Antidote of digoxin- digiband
For Ca channel blockers it is Ca gluconate
Antidote for opioids and organophosphates
Antidote for opioids is naloxone
Antidote for organophosphates is atropine
Free drugs that bind to albumin
C. Most CNS drugs like antipsychotics, anti epileptics, benzodiazepines
A. Antibiotics (sulfonamides and penicillin)
N. NSAIDs
W. Warfarin
A. Aspirin
S. Some other examples are also there
Hence warfarin blocks aspirin and vice versa
Drugs that bind to alpha 1 acid glycoprotein
- Opioids
- TCA Tricyclic antidepressants
- Anti-arrhythmics (lidocaine, amiodarone, beta blockers)
Conditions in which albumin decreases leading to toxicity of such drugs
Nephrotic syndrome
Liver cirrhosis
Chronic kidney disease
Conditions in which there is an increase in alpha 1 acid glycoprotein which leads to decreased efficacy of such drugs
Rheumatoid arthritis
Inflammatory bowel disease
Myocardial infarction
Examples of prodrugs
Levodopa All ACE inhibitors except captopril and lisinopril Clopidogrel Famciclovir (antiviral) Carbimazole (anti thyroid)
Primary purpose of phase 2 of drug metabolism
The purpose is to make the drug by conjugation:
- Water soluble
- Ionised
Functions of phase 1 of drug metabolism
- Usually drug inactivation
- For some drug, it is activation
- In the latter part of phase 1 , the water solubility in increased (though by a small amount) by addition of a functional group to the drug
Phase 1 reactions of drug metabolism
O. Oxidation R. Reduction C. Cyclisation H. Hydrolysis A. Aliphatic or aromatic hydroxylation D. Deamination
Phase 2 (conjugation) reactions of drug metabolism
G. Glucuronation, glycination , glutathionation
A. Acetylation
M. Methylation
S. Sulfation
Most common reactions of phase 1 and phase 2 of drug metabolism
For phase 1: oxidation
For phase 2: glucuronidation
Which reactions in drug metabolism are microsomal and which are not
All reactions of phase 1 (mediated by cytochrome p450) and glucuronidation of phase 2 reactions is microsomal
Rest are non-microsomal
What does P450 in CYP450 stand for
The P stands for pigment and the 450 for the wavelength of light absorbed by the pigment
Nomenclature of cytochrome p450. Example CYP1A2
The 1 stands for the family. The A stands for the subfamily.
The 2 stands for the G number
Various cytochromes
- CYP1A2: TTT
- CYP2B6: CM
- CYP2C9: PW
- CYP2C19: OC
- CYP2D6: BOAT
- CYP2E1: EE
- CYP3A4
Drugs which are metabolised by CYP1A2
Tamoxifen
Tacrine
Theophylline
Drugs which are metabolised by CYP 2B6
Cyclophosphamide
Methadone
Drugs which are metabolised by CYP2C9
Phenytoin
warfarin
Drugs which are metabolised by CYP2C19
Omeprazole
It activated clopidogrel
Note:
Omeprazole (used for treating MI) inhibits clopidogrel (used for treating peptic ulcer)
Drugs which are metabolised by CYP2D6
Beta blockers antidepressants (TCA, SSRI)
antipsychotics
opioids-tramadol
Activates Tamoxifen
Drugs which are metabolised by CYP2E1
Ethanol
Enflurane
Drugs which are metabolised by CYP3A4 or
Substrates for P-gp
The most common for drug metabolism
Metabolises more than 50% of all drugs
Eg., protease inhibitor, statins, amiodarone, cisapride, oestrogen, mifeprestone, erythromycin
Atazanavir and irinotecan contradicted in Criggler Najjar syndrome. Why?
These drugs are highly toxic drugs and contradicted in Criggler Najjar syndrome there is a deficiency of glucuronyl transferase
Conjugation of drugs
Types
- Glucuronidation: BAISO
- Glutathionation: IF
- Glycination: N
- Acetylation: SHIPD
- Methylation: MM
- Steroids: S
Drugs which are conjugated via glucuronidation
Benzodiazepines Azatanavir Irinotecan statins oestrogen
Why is conjugated oestrogen is not excreted
Estrogen glucuronide When it reaches the colon the bacteria secretes glucuronidase which unconjugates the estrogen
This causing enterohepatic circulation
Antibiotics cause OCP failure. Why?
The antibiotics kill the bacteria which secretes glucuronidase inhibits enterohepatic circulation.
The oestrogen levels fall causing OCP failure
Drugs metabolised by glutathionation
Ifosfamide
Fosfomycin
Drugs metabolised by glycination
Niacin
Drugs metabolised by acetylation
What is their side effect
Sulphonamides Hydralazine Isoniazid Procainamide Dapsone Side effect is SLE (systemic lupus erthematosus)
Drugs metabolised by methylation
6-mercaptopurine
Methyldopa
MM
Steroids are conjugated by
Sulfation
Drugs which are microsomal enzyme inducers
G. Griseofulvin R. Rifampin (imp) A. Alcohol (chronic) B. Benzpyrene P. Phenytoin, phenobarbital, primidone C. Carbamazepine Can cause OCP failure
Drugs which can cause folic acid deficiency when taken for a long time
Most anti-epileptics like phenytoin, phenobarbital, primidone,carbamazepine cause folic acid deficiency especially when taken for a long time.
These are microsomal enzyme inducers
Substances other than drugs which cause microsomal enzyme induction
DDT
A plant called St. John’s wort
Examples of microsomal enzyme inhibitors are
Q. Quinidine I. Isoniazid (sometimes inducer, sometimes inhibitor) C. Cimetidine K. Ketoconazole V. Valproate E. Erythromycin G. Grape fruit juice D. DEC
Application of microsomal enzyme inhibitors
When ketoconazole (a microsomal enzyme inhibitor) is given with terpenadine (QT elongation), the usually asymptomatic drug causes torsades and death
Application of microsomal enzyme inducers
When a young girl on OCP is given rifampicin for tuberculosis, it may cause pregnancy
Phases of clinical trials
- Human pharmacology and toxicity study
- Therapeutic exploratory trial
- Therapeutic confirmatory trial
- Post marketing surveillance
(5. Pharmacoepidemiology - Microdosing )
Adverse effects of drugs
- Side effects
- Secondary effects
- Toxic effects
- Intolerance
- Idiosyncrasy
- Allergy
- Photosensitivity
- Dependence and addiction
- Withdrawal reactions
- Teratogenicity
- Mutagenicity and carcinogenicity
- Drug induced diseases
