Pharmacology Flashcards
CYP3A4 inducers
D - Dexamethasone R - Rifampicin J - St John’s Wort A - Chronic Alcohol P - Phenytoin and Carbimazole
Inducer = increase rate of another drug’s metabolism
CYP3A4 inhibitors
G - Grapefruit juice R - Ritonavir A - Azoles C - CCBs E - Erythromycin/ Clarithromycin O - Omemprazole C - Cimetidine
Inhibitor = inhibits metabolism of another drug (i.e. co-prescribed medication level can rise)
How many half lives does it take to reach steady state?
5 half lives (97%)
Formula for half life of a drug?
T1/2 = 0.693 x Vd/Cl
What is the formula for maintenance infusion rate of a drug?
DR = CL x Css
DR = maintenance dose rate (mg/hr) CL = Clearance (L/hour) CSS = steady state drug concentration (mg/L)
What is the formula for the loading dose of a drug?
Loading dose = Vd x target plasma concentration
What is the formula for volume of distribution?
Vd = amount of drug in body (A) / plasma drug concentration (C)
What is the formula for bioavailability?
Non-IV AUC / IV AUC
Pharmacokinetics
What the body does to the drug
Describes the relationship between the dose and the unbound drug concentration at the site of action and the time course of drug concentration in the body
Pharmacodynamics
What the drug does to the body
Describes the relationship between the unbound drug concentration at the receptor and the drug response (i.e. therapeutic effect)
Drug disposition
Absorption, distribution, metabolism, excretion
Parameters in pharmacokinetics
Clearance (CL) - efficacy of elimination of a drug from the body
Volume of distribution (V) - relationship between drug concentration in the blood and drug in the tissue at the site of action
Half life
Definition of Clearance
The volume of blood cleared per unit time
Determines the maintenance dose rate required to achieve target plasma concentration at steady state
Formula for extraction ratio
Extraction ratio = 1 - (concentration out / concentration in)
Definition of steady state
Situation at which the rate of drug administration is equal to the rate of drug elimination
At steady state: elimination = maintenance dose rate
Definition of elimination
Amount of drug eliminated per unit time ‘mg/hr’
Directly proportional to the plasma drug concentration
Directly proportional to the clearance
Statin muscle related adverse events
Risk is substantially increased when taking statins metabolised by CYP3A4 e.g. Lovastatin, Simvastatin and Atorvastatin
Less risk with Pravastatin
Taking other drugs that INHIBIT CYP3A4 increase risk
Risk is greater at higher doses
SLO1B1 gene
Onset usually weeks to months after initiation
Reduced capacity to metabolise codeine related to which cytochrome?
Reduced activity of P450 2D6
Thiopurine methyltransferase (TPMT) homozygous deficient patients
Azathioprine, mercatopurine and thioguanine are all pro drugs that are inactivated by TPMT
Low TPMT activity = high 6GTN levels = severe myelosuppression (need dose reduction)
High TMPT activity = low 6GTN levels = less therapeutic efficacy
Typical dose dependent (type A) adverse drug reaction to Cholinesterase inhibitors?
Bradycardia
Clinically significant interactions with grapefruit juice
Amiodarone, atorvastatin, cyclosporine, felodipine, simvastatin, tacrolimus
Factors increasing risk of muscle disorders with simvastatin and atorvastatin
CYP3A4 inhibitors
Disease states: DM, hypothyroidism, renal and hepatic disease
Advanced age
High dose
Medicines inhibiting metabolism by other means e.g. gemfibrozil
Zero order kinetics
Alcohol
Aspirin
Phenytoin
Theophylline
Hepatic clearance
hepatic clearance = Hepatic blood flow x extraction ratio
High hepatic extraction ratio: morphine, GTN, propranolol, CCB, haloperidol, antidepressants
Low hepatic extraction ratio: NSAIDs, diazepam, carbamazepine, phenytoin, warfarin
What has the greatest impact on drug metabolism in old age.
Reduced hepatic blood flow
Causes of impact of drug metabolism in old age?
Clearance
- CrCl declines 1% per year but serum Cr may be normal
- 40% reduction in blood flow, 30% reduction in liver mass
- age selective impairment of phase I > phase II
Vd
- decreased lean body mass, decreased body water, increased body fat (Vd decreased for water soluble drugs)
Half life: usually longer
Pharmacodynamics
- blunted homeostatic response
- impaired receptor systems e.g. cholinergic
Drugs and pregnancy
Increased HBF and RBF due to increased CO
Increased Vd
Decreased protein bindin
Isotretinoin: greatest risk in 1st trimester
Doxycycline: greatest risk in 3rd trimester
Inhibition p- glycoprotein leads to?
An increase in blood drug concentration
P-glycoprotein is an efflux pump
P-glycoprotein substrates
Digoxin Antineoplastic drugs ( docetaxel, vincristine) Calcineurin inhibitors (cyclosporin, tacrolimus) Macrolides (clarithromycin) CCB (amlodipine) Protease inhibitors Rivaroxaban Ticagrelor Loperamide Steroids
P-glycoprotein inhibitors
Macrolides (clarithromycin, erythromycin) Verapamil Amiodarone Ritonovir Antifungals (e.g. itraconazole) Ticagrelor
P-glycoprotein inducers
Rifampicin
St John’s Wort
Carbamazepine
Phenytoin
Stimulators receptors of alcohol
GABA-A
5-HT3
NMDA
Stimulators receptor of benzodiazepines
GABA-A
Stimulatory receptors of Cocaine
Binds to Dopamine transporter
Blocks dopamine re-uptake from synapse
Stimulatory receptor of heroin
Mu-opioid receptors
Methamphetamine
Binds to dopamine transporter
Blocks dopamine re-uptake from synapse
Stimulatory receptor of nicotine
Nicotine can - stimulates dopamine release
Hysteresis
Positive hysteresis: clockwise = tachyphylaxis
Negative hysteresis: anti-clockwise = drug distribution to site of action
Adverse drug reactions
SSRIs - platelet dysfunction Gentamicin - ototoxicity Omeprazole - interstitial nephritis Sitagliptin - pancreatitis Atypical antipsychotics - metabolic syndrome Anti convulsants - suicidality
Type A ADR
Dose related
Frequent
Usually occurs in preclinical / trial phase
No immunological basis
Type B ADR
Dose relationship unclear
Infrequent
Occurs post marketing
Immunological basis e.g. anaphylactic
Severe skin reactions: DRESS
Drug Reaction Eosinophilia and Systemic Symptoms
Fever, rash organ involvement (liver, kidney then lungs)atypical lymphocytosis,
Lymphadenopathy, HHV-6 / EBV / CMV reactivation 3-8 weeks following initiation
Stevens-Johnson Syndrome vs Toxic epidermal necrosis
SJS: 1-10% skin detachment
TEN: >30% skin detachment
SJS-TEN overlap: 10-30% skin detachment
Acute generalised Exanthematous pustulosis
Widespread erythema followed by sterile pustules, fever, neutrophilia
Drug-gene pairs
Azathioprine and TPMT
Warfarin and VKOR
Cetuximab and KRAS
Codeine and CYP2D6
What drug will minimise cardiac toxicity in amitriptyline overdose?
Sodium bicarbonate - redistribution of unionised drug away from toxic component
MIC Type 1
Concentration dependent killing and prolonged persistent effects
Aminoglycosides, daptomycin, fluroquinolones
Goal of therapy = maximise concentrations
PK/PD parameter: peak/MIC; 24h AUC/ MIC
MIC Type II
Time dependent killing and minimal persistent effects
Carbapenems, cephalosporins, erythromycin, linezolid, penicillins
Goal of therapy = maximise duration of exposure
PK/PD parameter: T>MIC
MIC Type III
Time dependent killing and moderate to prolonged persistent effects
Azithromycin, clindamycin, tetracyclines, vancomycin
Goal of therapy = maximise amount of drug
PK/PD parameter: 24h AUC/MIC
Antioxidant required for conversion of paracetamol metabolite NAPQI to non-toxic substances?
Glutathione
MOA lumacaftor / Ivacaftor
Lumacaftor: improves the processing and conformational stability of F508del CFTR, enabling more of the mature CFTR protein to be successfully transported to the cell surface
Ivacaftor: CFTR potentiator that facilitates increased chloride transport by potentiaiting the channel open probability of the CFTR protein at the cell surface
Improves lung function by 3% inpatients homozygous for the F508del- CFTR mutation
Tenofovir - patterns of kidney injury
Proximal tubular dysfunction, AKI, CKD
Leads to increased creatinine, proteinuria, glycosuria, hypophosphatemia, acute tubular necrosis
Drugs that cause pulmonary fibrosis
Antineoplastic agents (Bleomycin, busulfan, cyclophosphamide) Nitrofurantoin Amiodarone Flecanide Penicillamine
Mechanism by which dobutamine increases cardiac output
Activation of beta adrenergic receptors
Ionotropes
Agents that increase myocardial contractility (inotropy)
E.g. adrenaline (beta receptors), dobutamine ( beta 1 and 2 receptors), isoprenaline, ephedrine
Vasopressors
Agents that cause vasoconstriction = increased systemic and/or pulmonary vascular resistance
E.g. noradrenaline (alpha receptors), vasodilatory, metaraminol, vasopressin, methylene blue
Entresto (Sacubitril / Valsartan)
Angiotensin receptor-neprilysin inhibitor (ARNI)
Designed to block harmful effects of RAAS activation while raising levels of several endogenous vasoactive peptides (inc BNP, bradykinin and adrenomedullin) which are typically degraded by neprilysin
Medications that cause hyponatremia
Diuretics (esp indapamide and HCT)
SSRIs (e.g. fluoxetine, sertraline)
SNRIs (e.g. venlafaxine)
Carbamazepine
THC MOA
Partial agonist activity at the cannabinoid receptor CB1 (located in CNS)
Results in a decrease in the concentration of the secondary messenger molecule cAMP through inhibition of adenylate cyclise
Carbamazepine MOA
Prevents repetitive neuronal discharges by blocking voltage-dependent and use-dependent sodium channels
HLAB*1502 allele = increased risk of SJS
Steady state plasma concentration may not be achieved for 2-4 weeks because of autoinduction of metabolism
Aprepitant MOA
Antagonise substance P / neurokinin-1 receptors
Augments antiemetic activity of 5-HT3 receptor antagonists
Inhibits acute and delayed phases of chemotherapy induced emesis
Serotonin Syndrome
Hunter Criteria
Onset 24hrs
Must have taken a serotonergic agent and meet ONE of the following conditions :
- spontaneous clonus
- inducible clonus PLUS agitation or diaphoresis
- ocular clonus PLUS agitation or diaphoresis
- tremor PLUS hyperreflexia
- hypertonia + temp >38 + ocular clonus or inducible clonus
Drug-drug interactions
- Tamoxifen and Paroxetine (CYP2D6 inhibitor)
- Azathioprine and allopurinol (TMPT)
- Simvastatin and Erythromycin (P450 3A4)
- Omeprazole and Clopidogrel (omeprazole inhibits CYP2C19, reducing metabolism of clopidogrel)
Glucagon indications
Beta blocker overdose with cardio genie shock or profound bradycardia unresponsive to atropine
CCB overdose with heartblock unresponsive to calcium
Flumazenil
Competitive antagonist at benzodiazepine receptors
Use in bento overdose
DO NOT USE in mixed overdose with proconvulsant drugs (TCAs, antihistamines, amphetamines)
Anticholinergic (antimuscarinic) toxidrome
Pure anticholinergic agents: atropine, benztropine, benzhexol
Drugs with anticyclone effects: TCAs, antihistamines, antipsychotics
Peripheral anticholinergic effects: dry skin, dry mouth, mydriasis, urinary retention, GI ileus
Central anticholinergic effects: hallucinations, delirium, agitation, agression
Antidotal therapy = physostigmine
Location and action of alpha 1 receptors
Peripheral, renal and coronary circulation
Vasoconstriction
Location and action of beta 1 receptors
Heart
Increase contractility and HR
Location and action of beta 2 receptors
Lungs; peripheral and coronary circulation
Vasodilation, bronchodilation
Location and action of dopaminergic receptors
Mesenteric, renal, coronary arteries
Vasodilation
Aramine receptor and mechanism
Works solely on the alpha-adrenergic system
Peripheral vasoconstriction
Isoprenaline receptors and mechanism
Works solely on the beta-adrenergic system
Inotrophy and chronotrophy (causes tachycardia)
Neuroleptic malignant syndrome
Onset: days to weeks Neuromuscular findings: bradyreflexia, severe muscle rigidity, normal pupils Causative agents: dopamine antagonists Treatment: bromocriptine Resolution: days to weeks
Malignant hyperthermia
Caused by mutation of the ryanodine receptor (type 1) Criteria - respiratory acidosis - Arrhythmia (tachycardia, VT, VF) - Metabolic acidosis - muscle rigidity - muscle breakdown ( CK >20,000; cola coloured urine, excess myoglobin, hyperK) - increased temp - family history - reversal with dantrolene
Paracetamol overdose
Cytochrome P450 2E1 and 3A4 convert paracetamol to highly reactive intermediary metabolite NAPQI
Normally NAPQI is detoxified by conjugation with glutathione
In overdose, sulfate and glutathione pathways become saturated -> more paracetamol shunted to P450 system to produce NAPQI -> hepatocellular supply of glutathione become depleted
Therefore NAPQI remains in its toxic form in the liver
Agonist vs antagonist
Agonist - enhances target receptor’s usual action
Full agonist - able to elicit maximal response with higher doses
Partial agonist - unable to elicit maximal response despite higher dose
Antagonist - inhibits target receptor’s usual action
Competitive antagonist - reversible binding; maximal dose CAN be reached with higher dose of agonist
Non-competitive agonist - non-reversible binding. Maximum effect CANNOT be achieved with higher dose of agonist
Phase I clinical trial
Focus on pharmacology - mode of delivery, dose finding, dosing schedule
May include healthy participants
Phase II clinical trial
Focus on safety
Also pharmacology and efficacy
Usually subjects with disease, n<100
Phase III clinical trial
Focus on efficacy
Subjects with disease
n: 100-1000s
Done after preliminary evidence suggests effectiveness of the drug
Phase IV clinical trial
Focus on long-term safety
Post marketing surveillance
E.g. use of registries
Carbamazepine and contraception
Carbamazepine can reduce efficacy of oral and implantable hormonal contraceptives by inducing cytochrome P450 enzymes, which increase clearance of sex hormones
Anticholinergic toxicity
Signs: delirium, tachycardia, dry, flushed skin, dilated pupils (mydriasis), myoclonus, increased temp, urinary retention
Agents: TCAs, atropine, benztropine, antihistamines
Cholinergic toxicity
Signs: confusion, CNS depression, weakness, salivation, lacrimation, incontinence, GI cramping, emesis, diaphoresis, muscle fasiculations, miosis, hypotension, seizures
