Creation of reactive, polar functional groups - Oxidation: usually by CyP450 system - Reduction and hydrolysis

Production of polar compounds for renal elimination Either the drug or its phase 1 metabolite - Conjugation reactions - Glucuronidation, sulfonation, acetylation, methyl

PHY Flashcards by (Anonymous)

Pharmacokinetics

Pharmacodynamics

Pharmacokinetics: what the body does to the drug

Pharmacodynamics: what the drug does to the body

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Clearance

Volume of plasma cleared of a drug per unit time

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Half-life

Time taken for drug concentration to decline to half its original value.

Depends on volume of distribution and clearance

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Volume of Distribution

Volume into which a drug appears to distribute.

High for lipid-soluble drugs

Low for water soluble drugs

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First Order Kinetics

Clearance of drug is always proportional to plasma concentration.

Most drugs are in this category

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Zero Order Kinetics

Clearance of drug not always proportional to plasma concentration.

Saturation of metabolism → constant rate of elimination regardless of plasma levels.

E.g. phenytoin, salicylates, ethanol

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Bioavailability

Percentage of the dose of a drug which reaches the systemic circulation.

100% for IV administration

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Multiple Dosing

If a drug given at intervals the concentration will reach a steady state in ~ 5 half-lives.

Loading dose: ↓ time needed to reach a steady state.

Useful if long or short half life.

Phenytoin, digoxin, amiodarone, theophylline

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Therapeutic Drug Monitoring

Indicated when lack of drug efficacy, possibility of poor compliance, suspected toxicity, or prevention of toxicity.

􏰀 Aminoglycosides (essential)
􏰀 Vancomycin (essential)
􏰀 Li (essential)
􏰀 Phenytoin
􏰀 Carbamazepine
􏰀 Digoxin
􏰀 Ciclosporin
􏰀 Theophylline

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First Pass Metabolism

Metabolism and inactivation of a drug before it reaches the systemic circulation.

i.e. pre-systemic elimination

Occurs in gut wall and liver

E.g. propranolol, verapamil, morphine, nitrates

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Pathways of Drug Metabolism and Elimination

Excrete unchanged by the kidney (e.g. furosemide)

Phase 1 metabolism then renal excretion

Phase 2 metabolism then renal excretion

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Phase 1 Metabolism

Creation of reactive, polar functional groups

Oxidation: usually by CyP450 system
Reduction and hydrolysis

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Phase 2 Metabolism

Production of polar compounds for renal elimination

Either the drug or its phase 1 metabolite

Conjugation reactions
Glucuronidation, sulfonation, acetylation, methyl

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Cytochrome P450 System

Most important system of phase 1 metabolism

> 11 subtypes

CyP3A4

Most important subtype
≥ 30% of drugs: CCBs, β-B, statins, benzos

CyP2D6
- Second most important
- ≥20% of drugs: antidepressants, some β-B,
opiates

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List of pro-drugs.

L-Dopa → dopamine

Enalapril → enalaprilat

Ezetimibe → ez-glucuronide

Methyldopa → α-methylnorepinephrine

Azathioprine → 6-mercaptopurine (by XO)

Carbimazole → methimazole

Cyclophosphamide

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Adverse drug reactions (ADR)

Type A

Common, predictable reactions
Dose-related (but may occur @ therapeutic doses)
Consequence of known pharmacology of the drug

Type B

Rare, idiosyncratic reactions
Usually not dose-related
E.g. allergies and pharmacogenetic variations

Long-Term ADR

Dependence, addiction
Withdrawal phenomena
Adaptive changes: e.g. tardive dyskinesia

Delayed ADR

Carcinogenesis
Teratogenesis

4 types of allergies

Type 1: anaphylaxis
- Penicillins, contrast media

Type 2: cytotoxic antibodies

E.g. causing haemolysis
Penicillins, cephalosporins, oral hypoglycemics
Methyldopa

Type 3: immune complexes

Serum sickness-like reaction
Penicillins, sulphonamides

Type 4: cell-mediated

Contact dermatitis
Topical abx
Antihistamine cream

ADR caused by the following?

Carbamazepine
Cyclophosphamide
Chlorpropamide
SSRIs
TCAs

SIADH

ADR caused by the following?

Spironolactone
Digoxin
Verapamil
Cimetidine
Metronidazole

Gynaecomastia

ADR caused by the following?

Bleomycin
Busulfan
Amiodarone
Nitrofurantoin
Sulfasalazine
Methotrexate
Methysergide

Pulmonary Fibrosis

ADR caused by the following?

Isonazid
Vincristine
Amiodarone
Nitrofurantoin
Penicillamine

Peripheral Neuropathy

Drugs that increase QTc

Fluoroquinolones: cipro
Venlafaxine
Neuroleptics: phenothiazines, haldol
Macrolides
Anti-arrhythmics 1a/III: quinidine, amiodarone, sotalol
TCAs
Histamine antagonists

ADR caused by the following?

Clavulanic acid: may be delayed
Fluclox: may be delayed
Erythromycin
Sulfonylureas (glibenclamide)
OCP
Tricyclics
Chlorpromazine, prochlorperazine

Cholestasis: decrease in bile flow

Which drugs cause hepatocellular damage?

Paracetamol
Valproate, phenytoin, carbamazepine
Halothane
Methotrexate
Statins
Rifampicin, isoniazid, pyrazinamide

Drugs that cause bone marrow toxicity

Pancytopenia /aplastic anaemia: - Cytotoxics - Phenytoin - Chloramphenicol - Penicillamine - Phenothiazines - Methyldopa Neutropenia: - Carbamazepine - Carbimazole - Clozapine - Sulfasalazine Thrombocytopenia: - Valproate - Salicylates - Chloroquine

Extrapyramidal side effects are caused by? Parkinsonism Acute dystonia Akathisia Tardive dyskinesia

Typical antipsychotics Rarely: metoclopramide, prochlorperazine Esp. in young women Dyskinesias and dystonias are common with anti- parkinsonian drugs. Mechanism: - D2 block in the nigrostriatal pathway - Excess AChM (hence effect of anti-AChM)

Parkinsonism

- Occurs w/i months - Commoner in the elderly - Bradykinesia tremor, rigidity Treatment: - Procyclidine (anti-AChM)

Acute Dystonia

- Occurs w/i hrs-days of starting drugs - Commoner in young males - Involuntary sustained muscle spasm - E.g. lock jaw, spasmodic torticollis, oculogyric crisis Treatment: - Procyclidine

Akathisia

- Occurs w/i days-months - Subjective feeling of inner restlessness Treatment: - Propranolol (crosses BBB)

Tardive dyskinesia

Rhythmic involuntary movements of head, limbs and trunk. - Chewing, grimacing - Protruding, darting tongue - Occur in 20% of those on long-term neuroleptics (yrs) Treatment: - Switch → atypical neuroleptic - Clozapine may help - (procyclidine worsens symptoms)

Indirect drug interactions

Diuretics and steroids → Increase risk of digoxin toxicity via low K+ NSAIDs + warfarin → Increased risk of GI bleed Abx + warfarin → Increase bleeding risk (Abx kill GI microflora that make vit K)

P450 Inducers Mnemonic: CRAP GPS

- Carbamazepine - Rifampicin - Alcohol (chronic) - Phenytoin - Griseofulvin - Phenobarbital - St. John’s Wort

Important Drugs Metabolised by P450

- Ciclosporin - Oral contraceptive pill - Warfarin - Epileptic drugs: phenytoin, CBZ - Statins - Theophylline

P450 Inhibitors Google SICKFACE .COM

- Grapefruit juice - Sodium valproate - Isoniazid - Cimetidine - Ketoconazole - Fluconazole - Alcohol (binge) - Ciprofloxacin - Erythromycin/Clarithromycin - Chloramphenicol - Omeprazole - Metronidazole

Extrapyramidal side effects list

Akinesia - finding it hard to start a movement Akathisia - finding it hard to keep still, and with ‘an inner feeling of restlessness’ Dyskinesia – unusual movements or twitches (usually of the face) that may keep on repeating themselves Oculogyric crisis – unusual eye movements, most commonly with the eyes turning upwards Parkinsonism – some of the symptoms look like someone with Parkinson’s disease e.g. tremor or stiffness