Pharm Flashcards
Bioavailability (f)?
proportion of administered drug which reaches the systemic circulation.
Determined by extent of absorption and amount of drug that is subject to pre-systemic metabolism.
f = AUC oral/AUC IV
Dose rate = ?
Elimination (Clearance) rate
Plasma concentration of a drug at steady state = ?
Clearance (CL)
What is first pass metabolism?
The extent of metabolism occurring after the drug is absorbed but before it reaches the systemic circulation.
Many drugs undergo 1st pass met in liver/gut wall.
When does steady state occur?
What is the time to reach steady state dependent on?
When amount of drug administered is equal to the amount of drug eliminated in the same period = 4.5. half lives
Time to reach steady state is dependent on the half life of the drug.
Time to reach steady state is dependent on the dose. T/F
False.
Dependent on half life.
Formula for half life?
t1/2 = Vdx07/Cl
What is first order kinetics?
The same time is taken to remove half the drug independent of the dose e.g. 10 mg vs. 10 g
Formula for desired concentration (Css)
Css = maintenance dose rate/ CL
Why do we give a loading dose? Formula for loading dose?
Dose given with the aim of immediately achieving steady state concentrations (quicker therapeutic range).
Loading dose = [target concentration) x VD (L)
Formula for clearance
CL = Vd x 0.7 / t1/2
What is zero order elimination?
a constant amount of drug is eliminated per unit of time (linear line in opposite direction, [drug]/time) e.g. EtOH
What is saturable metabolism? Examples of drugs.
Drug concentrations rise disproportionately (non linear) compared with dose. EtOH Aspirin Clonidine Fluoxetine Methotrexate Paroxetine Phenytoin Verapamil Propafenone
Clockwise hysteresis loop curve. What explains the concentration effect/response loop?
Rapid tolerance to a drug develops. Response for a given plasma concentration is initially high but decreases as the tolerance develops. E.g. cocaine, pseudoephedrine
Anti-clockwise hysteresis loop curve. What explains the concentration effect/response loop?
There is a delay in the distribution of the drug from plasma to its site of action
What is the extraction ratio (ER)? Examples of high extraction drugs vs. low?
The fraction of drug removed in a single pass the organ (liver/renal) of elimination.
ER = 1 - [concentration out/concentration in]
CL = ER x blood flow
Bioavailability = fraction absorbed x (1- ER)
Low extraction drugs:
Diazepam
Warfarin
High extraction: morphine bb ccb ergot alkaloids nitrates perhexiline prazsin tcas
In patients with liver disease, what is the higher concentrations and greater effects of drugs due to?
Increased bioavailability.
Bioavailability = fraction absorbed x (1-ER)
What physiological changes occur in the elderly causing impacts of hepatic drug metabolism?
Decrease in blood flow 20-50%
Marked fall in cyp P450 activities and drugs
Vd - decreased lean mass and increased body mass
What is potency?
Measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
Highly potent drug e.g. fentanyl, alprazolam evokes a larger response at low concentration.
It is the first curve on the graph to have an effect
The clearance of drugs that are weak acids or bases are affected by changes in urine pH. What happens to the clearance of the basic/acid drug if:
Urine made more acidic
Urine made more alkaline
Urine made more acidic:
Basic drug CL increased
Acidic drug CL decreased
Urine made more alkaline:
Basic drug CL decreased
Acidic drug CL increased
TCA toxicity:
Clinical
ECG
Tx
Clinical: Coma Sedation Hypotension - as alpha 1 receptors blocked Seizures Dilated pupils Tachycardia
ECG:
Monomorphic VT as Na channels in phase 0 of action potential is blocked
Prolonged QRS > 120 ms
RAD
Tx:
NAHCO3 1 mmol/kg
Aim is serum alkalinisation as it binds TCA and excretes
Anticholinergic (anti-muscarinic)toxicity: Drugs, Clinical, Ix, Tx?
Pure Anticholinergics: Atropine Benztropine Benzhexol Anticholinergic plants e.g. Brugmansia sp Angel's Trumpet
Drugs with anticholinergic effects:
TCA
Antihistamines
Anti-psychotics
Clinical: Peripheral: Dry mouth Dry skin Mydriasis Tachycardia Urinary retention GI ileus (decreased bowel sounds) Hyperthermia
Central: Hallucinations Delirium agitation aggression Sedation Seizures
Tx: Physostigmine 2 mg IV Repeat if partial response DO not use in drugs with partial anticholinergic effects AE: Seizures and arrhythmias
Cholinergic toxicity: Drugs, Clinical, Ix, Tx?
Acetylcholine esterase inhibitors e.g. donepezil, rivastigmine, neostigmine (MG), organophosphorous pesticides, chemical warfare nerve agents
Acetylcholine receptor agonists e.g. nicotine, mushrooms
Clinical:
CNS excitation - delirium, coma, seizures
Neuromuscular excitation - fasiculations, weakness and paralysis
Autonomic - salivation, lacrimation, diaphoresis, flushing, miosis
Resp - bronchorrhea, broncoconstriction
CVS- bradycardia, HT, arrhythmias
Metabolic - hypokalaemia, hyperglucaemia, metabolic acidosis
GI - abdo pain, vomiting and diarrhea
Tx:
Atropine 1.2-3mg (used in bradycardia, anticholinergic). Continue until target end point achieved. May require up to 100 mg.
Targets: Chest clear, no wheeze HR > 80 bpm SBP > 80 mmHg Pupils no longer constricted dry axillae
Methaemoglobinaemia. Causes, Clinical, Ix, Tx?
Occurs when ferrous iron in blood is oxidized to ferric form.
Causes:
Local anaes e.g. articaine, benzocaine, lignocaine, prilocaine, procaine
Abx- sulfamethoxazole, clofazimine, dapsone
Anti-malarials - chloroquine, primaquine
Prodrugs or sources of nitric oxide - Na nitrite (laxatives), Na nitrate, Na nitroprusside, GTN and amyl nitrite
Clinical:
Relate to concentration
20%
NMS: Causes, Clinical, Ix, Diagnostic criteria, Tx?
Due to dopamine receptor blocking drug or withdrawn from doapine therapy e.g. levodopa and bromocriptine in PD. Almost all antipsychotics have been associated with NMS.
Presentation:
Tetrad
- hyperthermia
- EPS, lead pipe rigidity, bradykinesia or akinesia, dystonias, abnormal movements and posture, dysphagia, tremor
- Autonomic effects - tachy, HT, labilae BP, diaphoresis, tachpneoa
- CNS: drowsiness, confusion, coma, muism, incontinence
Ix: CK ++ Leucocytosis Low Fe Metabolic acidosis EEG: diffuse slowing consistent with metabolic encephalopathy
Diagnostic criteria:
DSM IV consist of i) severe muscle rigidity, ii) elevated temperature, iii) diaphoresis, incontinence, dec GCS etc
Tx: bromocriptine 2.5 mg PO. Increase up to 5 mg as needed. Resp support IVF Cooling
Serotonin toxicity: Causes, Clinical, Diagnostic criteria, Tx?
Causes:
Serotonin re-uptake inhibitors
e.g. escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, opoioids, herbal
(st John’s wart)
MAOI e.g. phenelzine, moclebemide, linezolid, methylene blue
Serotonin releasing drugs e.g. amphetamines
Others: Lithium, tryptophan
Clinical:
Triad
- neuromuscular excitation e.g. hyperreflexia, clonus, ocular clonus, myoclonus, shivering, tremor, hypertonia or rigidity
- Autonominc - hypethermia, diaphoresis, flushing, mydriasis, tachycardia
- CNS - agitation, anxiety, confusion
Tx:
Cyproheptadine 12 mg
Sedation with bezos
Sympathomimetic syndrome. Drugs, Presentation, Tx?
Catecholamines e.g. adrenaline, dopamine
Indirect sympathomimetics e.g. pseudoephedrine
Amphetmines, cocaine
Xanthines e.g. theophylline, caggeine
MAOIs e.g. moclobemide
NA reuptake inhibitors e.g. duloxetine, venlafaxine, reboxetine
Presentation:
CVS e.g tachy etc
CNS e.g. excitation, seizures, euphoria
NM- hyperreflexia, tremor, rhabdo
Autonomic - hyperthermia, diaphoerisis, flushing, pallor
metabolic effects- hypoK, hyperGly, acidosis
GI e.g, N/V
Tx:
GTN infusion or
Phentolamine or
Sodium nitroprusside
Drugs implicated in DRESS
Aromatase anti-epileptics o Carbamazepine o Phenytoin o Lamotrigine o Phenobarbital Minocycline allopurinol Dapsone Abacavir Nevirapine
Carbamazepine and oxcarbezine. Which HLA testing recommended prior to commencing?
HLA-B*1502
Allopurinol. Which HLA test is recommended?
HLA-B*5801
Abacavir. Which HLA test is mandatory?
HLA-B*5701
What is Pharmacokinetics? ADME
What the body does to the drugs. Absorption Distribution Metabolism Elimination
What is pharmacodynamics?
What the drug does to the body
A drug is highly protein bound to albumin. Pt develops nephrotic syndrome. What is the pharmacokinetic effect of hypoalbuminaemia?
Increased free drug level
Most common adverse effect of interferon?
Neuropsychiatric disturbance followed by flu like symptoms
which drug used in combination with an SSRI may result in more severe adverse outcomes of serotonin syndrome?
MAOI e.g. moclobemide, phenelzine
- carries the greatest risk
Bevacizumab. Target site? Indication?
VEGF monoclonal Ab
Metastatic colorectal Ca
MOA of Levodopa with carbidopa or benserazide?
Levodopa is converted to dopamine in the brain and peripheral tissues, and replenishes depleted striatal dopamine.
It is given with a peripheral dopa decarboxylase inhibitor (benserazide or carbidopa) to reduce peripheral dopamine production and also reduce adverse effects (eg nausea, vomiting, hypotension).
Ropinirole MOA. AE?
Doapmine agonist
Impulse control disorders
MOA of Nimodipine?
Dihydro CCB.
Crosses BBB to prevent cerebral vasospasm i.e. aneurysms
Non selective BB?
Carvidilol
Propanolol
Sotalol
Timolol (glaucoma) - reduce intra-occular pressure
The concentration of Drug A is reduced when drug B is added and increased when Drug B is removed. What is the mechanism for this interaction?
Protein binding displacement
The main drugs involved in drug binding are albumin and alpha-acid glycoprotein.
Only free drug is active, metabolized and renally excreted.
Plasma protein levels correlate with the degree of protein binding and levels of bound drug only.
Measured drug levels include protein bound and free.
Protein binding is only significant if drug is highly protein bound and there is a large change in plasma protein levels
In methyl Alcohol poisoning, what are the effects due to?
Systemic effects of formaldehyde are due to its metabolic conversion to formate -> metabolic acidosis, circ shock, resp insuff, acute renal failure.
Formaldehyde
- skin, eye and resp irritant
- inhaled vapours cause narrowing of the bronchi and accumulation of fluids in the lungs
- erosive injury to GIT, esp pharynx, epiglottis, oesophagus and stomach
What is the difference between efficacy and potency?
Efficacy = max response achieved by a drug
Potency = measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
Which analgesics are renally excreted?
Oxycodone and active metabolite oxymorphone
Tramadol
Gabapentin
Pregabalin
Morphine - renally excreted glucuronide metabolites
Codeine
Which analgesics are hepatic cleared?
Buprenorphine
Fentanyl
What electrolyte disturbance does Lithium induce?
HyperNa
Litium induces nephrogenic DI
Which drugs cause hyponatraemia and SIADH?
Carbemazepine
Valproate
Sertraline
Quetiapine
Salicylate poisoning:
Presentation
Ix
Vomiting Air hunger Tininitus Confusion Palpitations
Ix: HyperNa HAGMA Mild hypoglycaemia Ketones in UA
MOA Cinecalcet?
Reduces PTH levels by increasing sensitivity of ca receptors on PTH glands
Protein binding.
Do changes in protein binding affect drug effect?
In most cases, protein binding displacement due to another highly protein bound drug, does not result in an increased drug effect.
The fraction of an unbound drug in plasma is..
usually not affected by drug concentration
dependent on the affinity of the drug for the binding protein
What are the 3 binding proteins and their respective actions?
Albumin - binds acidic drugs e.g. warfarin. Has 6 binding sites, 2 for drugs.
Alpha acid glycoprotein - binds basic drugs e.g. disopyramide, lignocaine. Has one binding site.
Lipoprotein - bind lipid drugs e.g. amphotericin B, cyclosporin.
What happens if the unbound fraction in plasma of warfarin is increased?
the unbound fraction at steady state would increase.
clotting synthesis rates would not be altered.
Total warfarin clearance would double.
Unbound warfarin clearance would not change.
What happens is the unbound fraction of phenytoin in renal failure patients is increased from 0.1 to 0.2?
The therapeutic range in terms of unbound drug should double.
The therapeutic range in terms of total drug should be reduced from 10-20mg/L to 5-10 mg/L.
Linear pharmokinetics means?
steady state drug concentration is proportional to the dose
Which process are saturable and can result in non-linear pharmcokinetics?
drug metabolism
protein binding
renal tubular secretion
Saturation of a drug metabolising enzyme occurs when?
the drug concentration is above the Km.
Km is the measure of the affinity of the substrate for the enzyme.
Saturation of protein binding occurs when?
The drug concentration approaches the concentration of the protein binding sites.
Alcohol pharmacokinetics.
A blood EtoH concentration of 0.05% about one standard drink will maintain steady state.
Blood concentrations causing impaired driving performance means alcohol metabolism is saturated.
Common electrolyte abnormality associated with bactrim?
Hyperkalaemia
Hyponatraemia
How is Dabigatran excreted?
Renal excretion.
CI if egfr
Zero order kinetics
First order
Saturable
Zero order kinetics
- elimination is constant e.g. EtOh
First order
- amount cleared dependent on amount in body
- each t1/2, 50% cleared
Saturable
- change in dosing regime = large change in drug level
- use small dose changes and monitoring e.g. phenytoin, aspirin, theophylline, clonidine
Dosing in elderly. Pharmacokinetic change?
Decreased Vd - due to decreased lean body mass, decrease H2O and increased fat
Decreased clearance - due to decreased renal and heaptic function
decreased PB due to decreased albumin
Polypharmacy = drug interactions
Dosing in elderly. Pharmacodynamic changes?
Impaired homeostatic response - senistivity to effect e.g. orthostatic hyoptension
Alterations in receptor function -> less rpedicatable effect
Idiosyncratic reactions more common
Co-morbidities -> more CI
Polypharmacy - pharmacodynamics drug interactions e.g. aspirin and warfarin
Pharmacokinetic changes in pregnancy
Clearance increased - increased CO and haptic and renal blood flow. Hormones -> enyme induction
Increased Vd by 20%
Decreased protein binding therfore lower measured drg levels but free levels are unchanged
Pharmocodynamic issues in pregnancy?
All drugs cross placenta to some extent
All drugs diffuse into breast milk
Agonist.
Full vs. partial
Enhances target receptors usual actions e.g. slabutamol
Full agonsit = elicits max response with suff high dose
Partial agonist = unbale to elicit max response despite max dose
Antagonsit.
Competitive vs. non-competitive
Inhibits target receptor’s usual action
Competitve antagonsit binds reversibly to receptor. Max effect still achievable with higher doses of agonist
Non-competitive antagonist (selfish)
- binds irreversibly to receptor
- max effect not achievable with agonsit
Why does hydralazine, procainamide, isoniazid cause drug induced lupus?
slow acetylation
