Pharmacology (drugs) Flashcards

1
Q

Describe the pharmacology of oxygen

A

Pharmaceutics:

  • Chemistry/Class: Oxygen is a diatomic gas with density and viscosity slightly higher than that of air
  • Preparation: Clear colourless gas
  • Administration + dose: Delivered as inhaled gas through a range of delivery devices; delivered IV (via oxygenated blood, eg ECMO); or given externally (hyperbaric oxygen)
  • Indication: supplementation (eg. In hypoxia), prophylaxis (pre-anaesthetic induction), antidote (CO toxicity), therapeutics (antibiotic in deep anaerobic infections - via hyperbaric; decrease volume of air-filled body cavities by de-nitrogenation - ie Ptx/pneumocephalus; management of decompression sickness)

Pharmacokinetics:

  • Absorption: most pulmonary absorption (250ml/min with 21% FiO2 at rest), some cutaneous absorption <1mL/min
  • Distribution: bound to Hb and dissolved in plasma - distributes to all body tissues
  • Metabolism: metabolised in all tissues. Mainly by cytochrome c mitochondrial enzymes. Zero-order kinetics, roughly 200mL/min. Main metabolites are CO2 and H2O, cleared via lungs and kidney
  • Excretion: exhaled as CO2, or combined with H2O to produce HCO3- and eliminated in urine

Pharmacodynamics:

  • Mechanism of action: Essential component of ATP production
  • Onset/Offset: minutes
  • Organ effects + adverse effects:
    • Airway - oxygen-associated airway irritation (drying out membranes,
    • Respiratory - improved delivery to gas exchange membrane in supplementation. Decreases respiratory drive in all individuals & may result in a fatal decrease in those dependent on hypoxic drive. Adverse effect - absorption atelectasis. Toxicity can also occur - free radical formation, which can cause pneumonitis/worsening ARDS due to lipid peroxidation of the alveolar capillary membrane
    • CVS - Hyperoxia can cause decreased CO, PVR, PAP + cause coronary vasoconstriction with prolonged administration
  • Other - note fire risk (esp in ALS with defib)
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2
Q

Pharmacology of B-agonist bronchodilators

A

Chemistry: similar in structure to NE + adrenaline. Terminal amine group is modified to confer β2-selectivity
Preparation: Inhaled via MDI, or nebulised. Salbutamol available in IV + PO (liquid)
Dose/indication:

SABAs:
* Symptom relief of asthma + COPD
* Prevention of exercise-induced bronchoconstriction
* Note: IV salbutamol used in threatened/preterm labour - relaxes uterine smooth muscle via uterine β2 receptors

LABAs:
* Maintenance treatment of asthma in patients receiving inhaled or oral corticosteroids (LABA rarely/never used as monotherapy)
* COPD

Kinetics
Absorption: salbutamol 10% inhaled absorption when nebulised
Distribution:
SABAs: protein binding 10% salbutamol (Vd 1.3L/kg); terbutaline 25%
LABAs: salmeterol 96%, formoterol ~64%, indacaterol 95%, 60% olodaterol
Metabolism:
SABA: salbutamol & terbutaline: hepatic to inactive sulfate (salbutamol high HER); levalbuterol metabolised in GIT
LABA: salmeterol & indacaterol hepatic - hydroxylated; formoterol & olodaterol hepatic - glucuronidation
Excretion: mostly excreted in urine; salmeterol & indacaterol in faeces; olodaterol both. Elimination half life of salbutamol ~2h

Dynamics
MoA - Activation of Gs protein coupled receptor pathway (adenylate cyclase –> cAMP –> PKA –> phosphorylative events) - leading to bronchial smooth muscle relaxation
* Lowers intracellular Ca2+ concentration
* Acute inhibition of PLC-IP3 pathway and its mobilisation of cellular Ca2+
Act as functional antagonists (reverse bronchoconstriction irrespective of the contractile agent
Effects/adverse
* Resp: bronchodilation
* CVS: sometimes induces tachycardia in high doses
* Endo: Hypokalaemia (effect on Na/K ATPase), hyperlactaemia
* Other: insomnia, muscle cramps

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3
Q

Pharmacology of antimuscarinic bronchodilators

A

Chemistry - Atropine + scopolamine are naturally occurring - esters formed by combination of aromatic acid, tropic acid + complex organic bases. All other antimuscarinics are derived from these
* ○ Ipratropium and tiotropium are quaternary ammonium compounds

Preparation - ipratropium - solution or powder for inhalation; tiotropium powder only
Dose/Indication - COPD, asthma
Kinetics
* ○ Absorption - Ipratropium/tiotropium (quaternary muscarinic receptor antagonists) not well absorbed via GIT. <1% inhaled drug id absorbed through bronchial mucosa
* ○ Distribution - Ipratropium Vd = 2.4-4.6L/kg, 20% protein bound
* ○ Metabolism - ipra –> 60% metabolised to inactive ester hydrolysis products; 40% in urine unchanged
* ○ Excretion - urine + faeces; 2 hrs half life

Dynamics
* MoA
○ Competitive antagonists of Ach binding to muscarinic cholinergic receptors - block the effects of endogenous ACh at muscarinic receptors (bronchodilator effect is M3)
○ Ipratropium is non selective (therefore also inhibits M2 receptors at presynaptic neurons, which provides ACh- mediated inhibition of ACh release - ie. It stops negative feedback, resulting in further ACh release into the synapse. This might work to oppose the muscarinic blockade at the postsynaptic neuron (conversely, tiotropium has lower affinity for M2)
○ prevents increase in cGMP (normal causes bronchoconstriction)
* Effects/adverse effects
○ Resp: bronchodilation, increased viscosity of airway secretions
○ CNS - drowsiness, dizziness, confusion
○ CVS - tachycardia
○ GI - constipation
○ Other - dry mouth

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4
Q

Pharmacology of theophylline/aminophylline

A

Class: Methylxanthines
Chemistry - (theophylline + aminophylline) are methylxanthines similar in structure to common dietary xanthines
○ Aminophylline is a complex of theophylline and ethylenediamine
○ Chemically similar to caffeine
Preparation: PO/PR/IV formulations; Theophylline available in PO form only
Dose/Indication: Acute severe asthma, not responding to other therapies
○ Aminophylline: Loading IV 5mg/kg (rate <25mg/min); maintenance IV 0.5mg/kg/hr (in patients not previously treated with theophylline)
○ Theophylline used in maintenance treatment rarely. Initial 300mg daily
Kinetics
○ Absorption: Rapidly absorbed. Aminophylline has high PO bioavailability (88-96%)
○ Distribution: 50-60% protein bound (albumin), Vd = ~0.5L
○ Metabolism - metabolised in liver - demethylation + hydroxylation; forms active metabolites
○ Excretion - saturation of metabolic pathways occurs near therapeutic range - may have zero-order + first order kinetics. Under first-order, half-life is 8hrs
Dynamics
MoA - unclear but several proposed MoA. Onset 1-2hrs PO; 30mins if IV
—- Inhibition of phosphodiesterases - theophylline is a non-selective PDE inhibitor (but inhibition is minimal within the ‘therapeutic range’). PDE inhibition likely explains bronchodilator effect of theophylline, but does not account for clinical benefit in asthma seen at the low concentrations it is used in
—- Adenosine receptor antagonism - may reduce inflammation by blocking A2B Receptor on mast cells (activated by adenosine in asthmatics). This mechanism accounts for serious side effects (blockage of cardiac + central A1 receptors)
□ May promote apoptosis of eosinophils + neutrophils (by A2A antagonism) + T lymphocytes (PDE inhibition)
—- Histone deacetylase (HDAC2) activation enhances anti-inflammatory effects of corticosteroids. This happens at the low concs used in asthma
—- Non-bronchodilator effects - the clinical benefits from theophylline use occur at plasma concs low enough to explained by bronchodilator action. Increasing evidence that theophylline has anti-inflammatory effects in asthma
Effect/side effects
§ CNS: headache, nausea, vomiting (due to inhibition of PDE4); at high concs, may have seizures from central A1 receptor antagonism
§ CVS: in high concentrations, cardiac arrhythmias may occur due to PDE3 inhibition & antagonism of cardiac A1 receptors
§ GI: Increased acid secretion (PDE inhibition), abdo discomfort
§ Renal: diuresis (Adenosine A1 inhibition)
Other
○ Large variations in clearance - dosage needs to be individualised by measurement of plasma concentrations
○ Plasma monitoring important. Target theophylline conc 5-10mg/L
○ May have a role in prevention of progression of COPD due to anti-inflammatory effects

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5
Q

Pharmacology of Nitric Oxide

A

Pharmaceutics
- Class/chemistry: selective pulmonary vasodilator. Inorganic gas
- Preparation: In aluminium cylinders containing 100/800ppm of NO & N2. Pure NO is toxic and corrosive
- Administration/dose: 5-20ppm dosing - injected into patient limb of inspiratory circuit or via continuous flow
- Indication: pulmonary hypertension

Pharmacokinetics
- Absorption: Highly lipid soluble and diffuses freely across all membranes
- Distribution: VOD potentially very large
- Metabolism: Following inhalation, NO combines with oxyhaemoglobin that is 60-100% saturated, producing methaemoglobin and nitrate. During the first 8hrs of NO exposure, methaemoglobin concentrations increase
- Excretion: NO has a half-life of <5s. Main metabolite is nitrate (70%) which is renally excreted

Pharmacodynamics
- Mechanism of action/adverse effects - NO diffuses into vascular smooth muscle and stimulates guanylate cyclase which catalyses the formation of cGMP, which activates a phosphorylation cascade which leads to smooth muscle relaxation and vasodilation
○ Resp - inhibits hypoxic pulmonary vasoconstriction & preferentially increases blood flow through well-ventilated areas of lung
§ Toxicity - exposure to 500-2000ppm results in methaemaglobinaemia and pulmonary oedema. Contamination by NO2 can lead to pneumonitis and pulmonary oedema
○ CVS - NO is avidly bound to Hb and inactivated before reaching the systemic circulation

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6
Q

Pharmacology of Epoprostenol

A

Pharmaceutics
- Class/chemistry: Inhaled pulmonary vasodilator. Epoprostenol is the synthetic analogue of naturally occurring prostacyclin (PGI2)
- Preparation: as vials containing 500 micrograms of freeze-dried epoprostenol sodium - to be diluted in sodium chloride
- Administration/dose: Can be IV, but usually nebulised as a solution with a glycine buffer
- Indication:
—- pulmonary hypertension –>IV 2ng/kg/min up to 25-40ng/kg/min (titrated to effect; significant variability); neb 10-50ng/kg/min
—- pre-eclampsia
—- Haemolytic-uraemic syndrome
—- anticoagulant during RRT & cardiopulmonary bypass –> 5ng/kg/min

Pharmacokinetics
- Absorption: rapidly absorbed into pulmonary circulation via the lungs
- Distribution: 0.35L/kg
- Metabolism: Degrades spontaneously as well as enzymatically into about sixteen major and minor metabolites
- Excretion: Half life ~ 6 minutes; vasodilation is short lived while platelet inhibition lasts up to 2 hrs

Pharmacodynamics
- Mechanism of action - stimulates adenylate cyclase–> increase in cAMP –> activates PKA –> phophorylates + inhibits MLCK –> smooth muscle relaxation + vasodilation. Increased cAMP in platelets leads to inhibition of platelet phospholipase and COX, and ultimately of platelet aggregation
○ Resp: decrease in PVR and interferes with hypoxic pulmonary vasoconstriction
○ CVS: Relaxation of vascular smooth muscle, leading to decrease in systemic vascular resistance
○ CNS: Cerebral vasodilation - increased cerebral blood flow
○ Haem: powerful platelet inhibitor - bleeding time may double with higher doses
- Other: extends filter life during RRT

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7
Q

Milrinone

A

Pharmaceutics
* Class: Ionotrope
* Chemistry: Bypyridine molecule
* Preparation/Administration: Clear, colourless solution for injection in 10-20mL glass ampoules (1mg/mL)
* Indication + Dose:
* Severe treatment-resistance congestive cardiac failure
* Low cardiac output states following cardiac surgery (loading dose 50mic/kg over 10min; infusion between 0.375-0.75mic/kg/min titrated to response)

Pharmacokinetics:
* Absorption: -
* Distribution: Vd = 0.3-0.4L/kg; 70-80% protein bound
* Metabolism: 12% glucuronidated in liver; Mostly cleared renally - unchanged
* Excretion: Mostly cleared renally - unchanged; half life 2.3hrs in patients with heart failure, longer in renal dysfunction

Pharmacodynamics:
* Mechanism of action: Selective inhibition of type III cAMP PDE in cardiac + vascular muscle (PDE responsible for cAMP catabolism) –> increased intracellular Ca –> increased contractility in cardiac; decreased vascular contraction
* Effects/Adverse:
* CVS: positive ionotropic effect –> CI increases by 25-30%, decreased SVR + MAP. May increase AV nodal conductance (may lead to increase in ventricular response in pts with atrial flutter or AF)
* Renal: u/o + GFR may increase due to increased CO
* Special notes:
- Decrease infusion rate in renal failure

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8
Q

Pharmacology of amiodarone

A

Pharmaceutics
* Class/chemistry - Iodinated benzofuran derivative (Class 3 antiarrhythmic)
* Preparation- PO tablets 100mg or 200mg; IV 30 or 50mg/ml amiodarone hydrochloride
* Administration - PO or IV
* Dose - Initial loading dose 5mg/kg in 250mL 5% dextrose. Maintenance 15mg/kg/day. PO dose initially 200mg TDS, which is reduced to 100-200mg daily after 1/52
* Indication - tachydysrhythmias resistant to other treatment + related to WPW syndrome

Pharmacokinetics
* Absorption - bioavailability of 22-86% (Smith) or 35-65% (Katzung)
* Distribution - 96-98% protein-bound in plasma; VD is 1.3-65.8L/kg, according to dose
* Metabolism - largely in liver, to desethyl-amiodarone (has anti-arrhythmic properties and is cumulative)
* Excretion - 1-5% in urine, mostly in bile + faeces

Pharmacodynamics
Mechanism of Action - prolongs cardiac action potential & delays refractory period.
* - partial antagonism of alpha- and beta- agonists by reducing number of receptors or by inhibiting the coupling of receptors to the regulatory subunit of the adenylate cyclase system
* - Delays K+ efflux, depresses Na+ influx & depresses Ca2+ influx
* - Onset of action - within 1hr IV, PO 2-3days-weeks
* - Duration after discontinuation can be weeks to months. Half-life (elimination half-life has slow (3-10days) and rapid (weeks) components)
Link above to organ systems
* - CVS - marked prolongation of the action potential duration (and QT injterval on the ECG) by blockade of intracellular K.
○ Sinus rhythm is slowed secondary to reduction in the slow diastolic depolarisation in nodal cells. Automaticity is depressed and AV nodal conduction is slowed by 25%
○ May get hypotension post IV admin - may be due to action of the vehicle
○ Toxicity: may get bradycardia/complete HB resistant to atropine, Ad & NAd
* - Metabolic - Can get LFT abnormalities & TFT (inhibition of triiodothyronine & enhancement of reverse triiodothyronine production & is a potential source of inorganic iodine. This can result in hypo or hyperthyroidism)
* - Resp - fatal pulmonary fibrosis occurs in 1%
* - Ophthalm - corneal microdeposits. Can cause halo at peripheries & rarely optic neuritis
* - Skin - deposits result in photodermatitis & grey-blue skin discolouration in malar regions

Other:
- Specific to drug - contraindicated in porphyria

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9
Q

Pharmacology of digoxin

A

Pharmaceutics
* Class/chemistry - Cardiac glycoside. Contains steroid nucleus, Series of sugars at C3 + Lactone ring at C17
* Preparation - Tablets - 62.5mic, 125mic, 250mic, or elixir 50mic/ml; or injection 250mic/mL
* Administration - PO or IV. Should be by slow injection
* Doses - loading dose10-20mic/kg Q6H until desired effect achieved. Then maintenance at 10-20mic/kg daily in divided doses
* Indication - use in AF + Flutter, heart failure, prevention of supraventricular dysrhythmias post thoracotomy

Pharmacokinetics
* Absorption - 65-80% absorbed from PO administration
* Distribution - once in the blood, widely distributed to all organ systems (inc CNS). Heart to serum con is 70:1. Vd = 6-7L/kg
* Metabolism - not extensively metabolised (~16%) in stomach or intestine - mostly excreted unchanged by kidneys
* Excretion - Excretion from kidneys proportional to creatinine clearance (50-70% unchanged). Half life: 36-48hrs

Pharmacodynamics
Mechanism of action -
* - Direct action - binds to and inhibits the action of Na+/K+ ATPase in sarcolemma cell membrane. This causes increased intracellular Na+ & decreased intracellular K+. Na+ displaces bound Ca+, and increased Ca+ results in positive ionotropic action. Decreased K+ leads to slowed AV conduction & decreased pacemaker cell action
* - Indirectly modifies autonomic activity and increases efferent vagal activity

Link above to organ systems
* - CVS - Main action is to increase the force of contraction. HR slowed due to depression of SA node discharge, slowed AV node conduction, increase in the AV nodal refractory period and indirect vagal effect. Rapid IV administration may cause vasoconstriction, leading to hypertension and decreased coronary blood flow. ECG changes - prolonged PR, ST depression, T wave flattening & shortened QT
—– (toxicity) - any dysrhythmia - esp junctional brady, ventricular bigemini, 2nd/3rd degree HB. Reverse tick on ECG
* - Renal - mild intrinsic diuretic effect
* - GI - (toxicity): anorexia, nausea, vomiting, diarrhoea, abdo pain
* - Neuro - (toxicity): headache, drowsiness, confusion, visual disturbances, muscular weakness, coma

Onset of action - PO 1-2hrs; IV 5-60min
Duration - 3-4 days

Other
* - Toxicity - Therapeutic range is 0.6-1.0nmol/L (=0.25 ng/mL) digoxin-specific antibody fragments can treat toxicity. They form complexes with dig molecules then are excreted in urine.
○ Indications for treatment: life-threatening arrhythmia, cardiac arrest, K>5.0
○ Consider treatment when: end organ dysfunction, mod-severe GI symptoms, serum dig >12ng/mL (25nmol/L), significant features of dig toxicity with serum dig > 4nmol/L
○ Formulation - 40mg reconstituted in 4mL. Response in ~20min (0-60)
* - Other specifics
○ Increased risk of dysrhythmias with concurrent sux/pancuronium or B-agonists
○ Increased likelihood of toxicity with: low K, Hyper Na, Hyper Ca, Low Mg, acid-base disturbance, hypoxaemia and renal failure
○ Increased plasma dig levels with coadmin of verapamil, nifedipine, amiodarone, diazepam
○ Cannot be removed by dialysis

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10
Q

Frusemide

A

Pharmaceutics
* Class/chemistry: Loop diuretic; sulfonamide derivative
* Preparation/administration:
- Oral tablets 20, 40mg, 500mg
- IV: vial of clear colourless solution 10mg/mL - can be given as an infusion
* Indication/Dose:
- Oedema - cardiac/hepatic/renal source - 10-1000mg IV daily. Infusion should not exceed 4mg/mL as ototoxicity may result
- Raised ICP
- HTN
- Symptomatic hypercalcaemia

Pharmacokinetics
* Absorption - Bioavailability 40-70%
* Distribution - 96% protein bound; Vd = 0.1L/kg
* Metabolism - Glucuronidation by kidney (50%) - 25% activity of parent; 50% unchanged
* Excretion - 50% excreted unchanged - active secretion via OAT in PCT; Half life up to 2h; but effect lasts 6H

Pharmacodynamics
* Mechanism of action - Inhibition of NKCC transporter in thick ascending limb. Increases Na, K, Cl delivery to distal nephron –> decreases osmotic gradient between duct and inner medulla, preventing water reabsorption in the collecting duct, resulting in diuresis
* Effects +/- side effects
- CVS - hypotension (from hypovolaemia) + unclear mechanism of direct vaso/venodilation
- Renal - Diuresis within mins if given IV, within 1hr if given PO
- Metabolic/electrolytes:
○ Hypokalaemia
○ Hypochloraemic metabolic alkalosis
○ Hypomagnesaemia, hypophosphataemia
○ Acidification of urine
- Other - ototoxicity
* Special points:
- Drug not removed by dialysis
- Enhances effects of ND-NMBA (probably due to hypokalaemia)

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11
Q

Pharmacology of paracetamol

A

Pharmaceutics
* Class/chemistry: Non-opioid analgesic. Para-aminophen derivative
* Preparation: PO tablets + syrup, PR suppository, IV infusion. Multiple fixed dose combinations with other analgesics
* Indication/dose
* Analgesia
* Antipyrexia

Pharmacokinetics
* Absorption: Rapidly absorbed from upper GI. Bioavailability 63-89% due to first pass metabolism
* Distribution: 0-5% protein bound with Vd = 0.7-1l/kg. Non-ionised + lipid solubule, crosses BBB
* Metabolism: In liver - 80-90% metabolised to glucuronide & sulfate & 10% to Cyt P450 to highly reactive intermediate metabolite (NAPQI) which is inactivated by conjugation with glutathione
* Excretion: Half life = 2-4hrs. Metabolites are renally excreted

Pharmacodynamics
* MoA: Multiple modes of action
* COX-1 + COX-2 inhibition
* Inhibits PG synthesis in CNS (antipyretic effect)
* Enhances inhibitory serotonergic pathways
* Acts peripherally to block impulse generation within bradykinin-sensitive chemoreceptors responsible for nociceptive afferents
* Effects/Side effects
* CVS: vasodilation when given IV
* CNS: analgesia
* Metabolic: potentiates ADH
* Haem: dose-dependent effect on platelets (reduced aggregation via platelet COX-1 inhibition and subsequent decrease in thromboxane A2 synthesis)
* Other: Paracetamol can be dialysed off
- in toxic doses, generally >15g, glutathione is depleted, leading to NAPQI binding to hepatic cell membranes, leading to centrilobular necrosis
- NAC can provides cysteine for glutathione synthesis
–> Complication is fulminant liver failure at ~2-7 days
- Methionine added to paracetamol preparations to reduce liver damage

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12
Q

Ibuprofen

A

Pharmaceutics:
* Class/chemistry: NSAID. Aryl-propionic acid derivative
* Preparation: PO tablets, PR suppositories, Topical gels. pKa = 4.91
*Indications/dose
* Analgesia - RA + OA, MSK disorders, soft tissue injuries, gout, renal + biliary colic, dysmenrrhoea, migraine
* Antipyretic

Pharmacokinetics
* Absorption: Bioavailability = 80%
* Distribution >90% protein bound; Vd = 0.14l/kg. Can cross placenta
* Metabolism: Hepatic metabolism via oxidation
* Excretion: Renally excreted; half-life 2 hours

Pharmacodynamics:
* Mechanism of action: Non-specific inhibitor of COX (prevents formation of prostaglandins, thromboxanes, prostacyclin). PGs are involved in the sensitisation of peripheral pain receptors to noxious stimuli
* Organ effects:
* Resp: bronchoconstriction in 20% of asthmatics
* GI: dyspepsia, nausea, gastric ulceration/bleeding
* Haem: reduces platelet aggregation
* Renal: prolonged use - papillary necrosis + interstitial fibrosis. ARF can be precipitated when NSAIDs are administered to patients who have renal perfusion dependant on PG production (eg. When high levels of circulating vasoconstrictors or hypovolaemia)
* Other:
* May cause premature closing of ductus arteriosus in fetus during 3rd trimester of pregnancy
* NSAIDs antagonise antihypertensive effects of ACEIs (inhibition of vasodilatory PG synthesis)

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13
Q

Pharmacology of tramadol

A

Pharmaceutics
* Class/chemistry: Synthetic opioid of the aminocyclohexanol group. Racemic mixture of two enantiomers
* Preparation: PO 50/100/150/200/300/400mg tablets; IV 50mg/mL
* Indication/dose: Analgesia - moderate to severe pain

Pharmacokinetics
* Absorption: High bioavailability (68-100%)
* Distribution: 20% protein bound; Vd = 4l/kg. 80% crosses placenta
* Metabolism: 85% demethylated in liver. One active metabolite (O-desmethyltramadol)
* Excretion: 90% renally excreted; 10% in faeces. Half life 4-6hrs

Pharmacodynamics
* MoA: Non-selective agonist at mu- kappa- and delta- opioid receptors (relatively higher affinity for mu). Also inhibits neuronal reuptake of NE + enhances 5-HT release
* Effects/Side effects
* CNS: analgesic potency equivalent to pethidine. Only 30% reversed by naloxone. SEs include nausea, dizziness, sedation, diaphoresis
* Other: Should be avoided in ESKD

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14
Q

Pharmacology of morphine

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Naturally occurring phenanthrene derivative
* Preparation/ Administration: Available in oral formulations of various strengths, syrup of various strengths, 15/30mg suppositories, clear colourless solution for injection 10/15/30mg/mL of morphine sulfate. Preservative free formulation needed for epidural/spinal injection. Weak base (pKa 8). Routes: PO, IV, IM, S/c. 23% ionised at pH 7.4
* Indication/dose: Dose generally titrated to effect. Initial dose 0.1-0.2mg/kg s/c or 0.05-0.1mg/kg IV
* Pre-mediation
* Pain relief in terminal care
* Treatment of ACS/LV failure

Pharmacokinetics
* Absorption: BA 30% (extensive FPM)
* Distribution: 20-40% PB; VD ~ 4L/kg
* Metabolism: Liver - Morphine-3glucuronide(60%-arousal), morphine-6-glucuronide (5-10% analgesic-13x more potent than parent), normorphine
* Excretion: Urine, small percentage of metabolites in faeces. Half-life ~4hrs, accumulation of M6G in renal failure. Maximal CSHT 20min (regardless of duration of infusion)

Pharmacodynamics
* MoA: Agonist at MOP & KOP. GiPCR –> intracellular Ca+ conc –> increases K+ conductance and hyperpolarisation of excitable cell membranes. Onset: 5-10min, 30min PO; Peak: 20min; Duration: 3-5hrs IV
* Effects/Side effects:
* CVS: may cause some histamine release - decreases SVR, may cause orthostatic hypotension
* Resp: respiratory depression, may cause bronchoconstriction in high doses
* CNS: potent analgesic. Euphoria
* GI: decreases GI motility, increases CBD pressure (spasm of sphincter of Oddi). N/v/constipation
* Renal: increases tone of ureters, bladder - retention
* pruritis may occur from eipdural/spinal admin
* Other: Caution in hepatic/renal failure. Dependence is an issue

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15
Q

Pharmacology of codeine

A

Pharmaceutics
* Class/chemistry Opioid analgesic. Naturally occurring phenanthrene (methylated morphine derivative)
* Preparation: Available PO 15/30/60mg tablets. IM. Solution 60mg/mL for injection
* Indication/dose: Initial dose 30-60mg Q4h
* Mild-mod pain
* Diarrhoea
* Antitussive

Pharmacokinetics
* Absorption: BA 50% (little FPM). Absorption faster after IM
* Distribution: PB 7%; VD 4L/kg
* Metabolism: Hepatic:
* glucuronidation (10-20%) - C-6-G
* N-demethylation (10-20%) - norcodeine
* O-demethylation (5-15%) - morphine
* Some genetic variability. ‘Fast’ metabolisers produce more morphine
* Excretion: Renal. 17% excreted unchanged. Half-life ~3hrs

Pharmacodynamics
* MoA: Low affinity for opioid receptors. Morphine contributes analgesic effects. Antitussive effects due to specific high-affinity codeine receptors. Onset: 15-30min PO; peak: 60min; Duration: 4-6hrs
* Effects/Side effects:
* CVS: significant hypotension (histamine release) if given IV - therefore this route avoided.
* Resp: antitussive effect. Respiratory depression
* CNS: 10x less potent
* GI: inhibits GI motility

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16
Q

Pharmacology of methadone

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Diphenylheptane derivative. pKa 9.2; 1% unionised at pH 7.4
* Preparation: Many formulations - tablets, liquid, IV. Usually taken PO
* Indication/dose: Dosing regimen highly individualised - based on percentage of daily baseline oral morphine dose
* - Opioid use disorder
* - Opioid withdrawal
* - Chronic pain

Pharmacokinetics
* Absorption: PO BA 75% (low FPM)
* Distribution: 90% PB; Volume of distribution wide ranging
* Metabolism: Liver - multiple inactive metabolites
* Excretion: 40% excreted unchanged in urine (enhanced in acidic conditions). In high doses, renal clearance becomes important

Pharmacodynamics
* MoA: Agonist at MOP & may have activity at NOP(unclear if partial agonist vs antagonist). May be an antagonist at NMDAR - this thought to be especially beneficial in treatment of certain neuropathic pain otherwise resistant to typical opioids. Onset: 10-15min; Peak 30-60min; Long duration of action
* Effects/Side effects: Similar to other MOP agonists - however long duration of action
* CNS: benefits in tolerance and addiction

17
Q

Pharmacology of oxycodone

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Semi-synthetic phenanthrene
* Preparation: Available PO (immediate + slow release; in combination with naloxone) + IV (10mg/mL & 50mg/mL). pKa 8.5
* Indication/dose:
* Moderate-severe pain, initial dose 5mg PO Q4hr

Pharmacokinetics
* Absorption: BA 80%
* Distribution: 45% PB; VD 2.5L/kg. Penetrates placenta, and is found in breast milk
* Metabolism: Hepatic. 3A4 –> noroxycodone; 2D6 –> oxymorphone (both active)
* Excretion: Renal. Half-life 3hrs

Pharmacodynamics
* MoA: Agonist at MOP, KOP, DOP. GiPCR. Onset: 10-15min PO; Peak 30-60min; Duration: 3-6hrs
* Effects/Side effects
* CVS: minimal
* Resp: respiratory depression, antitussive
* CNS: drowsiness, relief of anxiety, euphoria
* GI: decreases GI motility. N/v/c
* Renal: urinary retention

18
Q

Pharmacology of hydromorphone

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Semi-synthetic penanthrene. pKa 8.6
* Preparation: PO, IV, PR
* Indication/dose:
* Mod-severe pain 2-4mg Q4-6hrs
* Palliative care

Pharmacokinetics
* Absorption: BA: 50%
* Distribution: 15% PB; VD = 4L/kg
* Metabolism: Hepatic to inactive metabolites
* Excretion: Excreted in urine

Pharmacodynamics
* MoA: Agonist at MOP. May act on DOP + KOP. Onset: <15min PO, peak <30min PO; Duration 4-6hrs
* Effects/Side effects: Similar to other MOP agonists
* CNS: 5x more potent than morphine, analgesia, euphoria, sedation, miosis
* GI: reduced GI motility

19
Q

Pharmacology of buprenorphine

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Semi-synthetic phenanthrene. pKa 8.5
* Preparation: Clear colourless solution containing 300mic/mL, 200/400microg tablets and various strengths of transdermal patches
* Indication/dose:
* Mod-severe pain - 0.3-0.6mg Q6-8hrly IV or 0.2-0.4mg s/l

Pharmacokinetics
* Absorption: 15% BA via PO route (extensive FPM) –> given s/l (44-94%). 40-90% IM
* Distribution: 96% PB. VD = 3L/kg
* Metabolism: N-dealkylation in liver to norbuprenorphine (active)
* Excretion: Predominantly via faeces as unchanged buprenorphine, remainder excreted in urine. Elimination half life - 5hrs

Pharmacodynamics
* MoA: Partial agonist at MOP. Affinity for KOP (but low intrinsic activity here). Dissociates slowly from receptor - reason for prolonged analgesic effect. Onset: <15min S/l, <30min t/d; Peak 60-90min, hrs t/d; Duration: up to 72hrs s/l or 96hrs t/d
* Effects/Side effects
* CVS: HR, SBP decrease
* Resp: respiratory depressant + antitussive
* CNS: 25x more potent than morphine. Decreases cerebral glucose metabolism by 30%
* Other: Naloxone does not completely reverse respiratory depression, but doxapram will. Partial agonism precipitates abstinence syndromes in opioid-dependent subjects

20
Q

Pharmacology of fentanyl

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Tertiary amine (synthetic phenylpiperidine derivative)
* pKa 8.4, 9% unionised at pH7.4.
* Preparation: Available PO, IV, S/L, IN, TD.
* Indication/dose: Dose titrated to effect
* analgesia during GA
* premedication
* Palliative care

Pharmacokinetics
* Absorption: BA 33%
* Distribution: 90% PB; VD ~4L/kg. Octanol:water partition coefficient 717
* Metabolism: Liver - N-dealkylation –> norfentanyl, then further hydroxylation to hydroxypropionyl derivatives. CYP 3A4 plays predominant role in metabolism. Metabolites not pharmacologically active
* Excretion: 10% of drug excreted in urine. Elimination half-life ~2hrs. Maximum CSHT of 300min.

Pharmacodynamics
* MoA: Highly selective MOP agonist (GiPCR) –> inhibition of AC –> reduced cAMP, closure of voltage-gated Ca channels. Onset: <1-2min; Peak: 3-5min; Duration: 30-60min
* Effects/Side effects:
* CVS: bradycardia (vagal); CO, MAP, SVR, PVR unaffected. Obtunds CV response to laryngoscopy and intubation
* Resp: potent respiratory depressant - decreases RR & tidal volume. Minimal histamine release
* CNS: 50-80x more potent than morphine
* GI: decreases GI motility & gastric acid secretion
* Other: Secondary peak in plasma fentanyl concentration due to elution from muscle

21
Q

Pharmacology of Alfentanil

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Synthetic phenylpiperidine derivative. pKa 6.5; 90% unionised at pH7.4
* Preparation: Colourless solution containing 500ug or 5mg/mL.
* Indication/dose:
* Adjunct for intubation - 25-100mic/kg
* Pain during anaesthesia

Pharmacokinetics
* Absorption: Administered IV only
* Distribution: PB 90%. VD - 0.6L/kg. Highly lipophilic. Quickly crosses BBB
* Metabolism: Rapidly metabolised by CYP 3A4 –>noralfentanil (minimally active)
* Excretion: Renally excreted. Elimination half-life 1.5hrs

Pharmacodynamics
* MoA: MOP agonist. Onset: <1min; Peak <2min; Duration: <15min
* Effects/Side effects: Similar to other MOP agonists - however short duration of action
* CNS: ~10-20x more potent than fentanyl

22
Q

Pharmacology of Remifentanil

A

Pharmaceutics
* Class/chemistry: Opioid analgesia. Synthetic phenylpiperidine derivative. pKa 7.1; 68% unionised at pH7.4
* Preparation: White lipophilised powder to be reconstituted. 1/2/5mg vials. IV only
* Indication/dose: Titrated to response. 0.0125-1mic/kg/min infusion or 1mic/kg bolus dose over 30s
* Analgesia in GA
* Analgesia during labour
* Analgesia/sedation during ‘awake’ fibreoptic

Pharmacokinetics
* Absorption: Given IV only
* Distribution: 70% PB. VD (ss)= 0.3L/kg
* Metabolism: Rapidly hydrolysed by non-specific plasma and tissue esterases –> remifentanil acid (4600x less potent)
* Excretion: CSHT - fixed 4-5min. Elimination half life 10min

Pharmacodynamics
* MoA: Pure MOP agnoist; Peak effect 1-3min
* Effects/Side effects:
* CVS: decreases MAP + HR
* Resp: Potent respiratory depressant. May get chest wall rigidity similar to fentanyl
* CNS: analgesic potency similar to fentanyl. Centrally mediated vagal activity, miosis
* GI: decreased GI motility. Relatively low n+v

23
Q

Pharmacology of pethidine

A

Pharmaceutics
* Class/chemistry: Opioid analgesic. Synthetic phenylpiperidine derivative
* Preparation: Tablets + IV
* Indication/dose: Starting PO dose 50-150mg Q4h; IV/IM 25-100mg
* Premedication
* Mod-severe pain
* Anti-spasmodic

Pharmacokinetics
* Absorption: BA 100% IM or 45-75% PO
* Distribution: ~50% PB; VD ~ 4L/kg
* Metabolism: N-demethylation to norpethidine (50% potency of pethidine) - may accumulate in renal failure
* Excretion: Renal. Elimination half life up to 7hrs

Pharmacodynamics
* MoA: MOP + KOP; Onset: 15min; duration 2-3hr
* Effects/Side effects
* CVS: orthostatic hypotension. Mild quinidine effect –> tachycardia
* Resp: Potent respiratory depressant. Minor antitussive activity
* CNS: 1/10 as potent analgesic as morphine. Causes more euphoria + less n+v than equipotent morphine dose
* GI: less increase in CBD pressure, less constipation than morphine
* Other: May precipitate severe HTN in pts on MAOIs. Effectively inhibits post anaesthetic shivering

24
Q

Pharmacology of gabapentin

A

Pharmaceutics
* Class/chemistry: Anticonvulsant, analgesic. Acetic acid derivative that is structurally related to GABA
* Preparation: PO formulations
* Indication/dose: Can be titrated on initiation
* post-herpetic neuralgia
* painful diabetic neuropathy
* partial seizures with or without secondary generalisation
* neuropathic pain - dose up to 1800mg/day

Pharmacokinetics
* Absorption: Well absorbed, BA 60%
* Distribution: VD = 0.8L/kg, not bound to plasma proteins
* Metabolism: Not metabolised
* Excretion: Excreted unchanged in urine. Needs adjustment in renal impairment. Half life 5-7hrs

Pharmacodynamics
* MoA: Binds to α2δ subunit of voltage gated Ca+ channels. Disrupts regulatory functions of α2δ - prevents delivery of calcium channels to cell membrane & reduced activation of channels by this subunit. This decreases NT release. It may also reduce NMDA response to glutamate, reduce MAO release, stimulate enzyme conversion of glutamate to GABA & increase synaptic release of GABA
* Effects/Side effects
* CNS: analgesic + anticonvulsant properties. May have dizziness, nausea, nystagmus, tremor, somnolence

25
Q

Pharmacology of pregabalin

A

Pharmaceutics
* Class/chemistry: Anticonvulsant, analgesic, anxiolytic. GABA analogue
* Preparation: PO formulations
* Indication/dose: Initial 150mg/day
* peripheral and central neuropathic pain
* partial seizures
* GAD

Pharmacokinetics
* Absorption: Rapidly absorbed, BA >90%
* Distribution: VD = 0.5L/kg, not bound to plasma proteins
* Metabolism: Minimal
* Excretion: 98% of dose excreted unchanged. Half life 6hrs

Pharmacodynamics
* MoA: Same as gabapentin
* Effects/Side effects:
* CNS: analgesic, anticonvulsant, anxiolysis. Dizziness + somnloence may occur

26
Q

Paracetamol pharmacodynamics and toxicity

A

PHARMACOLOGICAL EFFECT

Mechanism of action:
- Weak inhibitor of cyclooxygenase (COX) 1 & 2 –> prevention of prostaglandin (PG) production
○ Proposed COX-3/COX-1 splice variant responsible for central effects, however this enzyme has no role in PG synthesis in humans
- Activation of descending serotonergic pathway
- Enhances endocannabinoids via active metabolite AM404 (endocannabinoid reuptake inhibitor; COX, NO + TNF-a inhibitor)

Toxicity:
- Toxic dose
○ Acute single ingestion: ≥10g or ≥ 200mg/kg (whichever is less)
○ Repeated supratherapeutic ingestion:
§ ≥10g or ≥ 200mg/kg (whichever is less) over a single 24hr period
§ ≥12g or ≥ 300mg/kg (whichever is less) over a single 48hr period
§ ≥ a daily therapeutic dose per day for more than 48hrs in someone who also has abdo pain/nausea/vomiting
- Mechanism of toxicity:
○ Hepatic metabolism:
§ 90% conjugated with sulfate/glucuronide via UDP-glucuronyl transferase (UGT) and sulfotransferase (SULT)
§ 2% excreted unchanged
§ Rest is oxidised to by CYP450 enzymes to NAPQI (toxic metabolite)
○ In therapeutic doses, NAPQI is conjugated with glutathione –> non-toxic compounds excreted in urine
○ In toxic doses, glucuronidation + sulfation pathways are saturated, shunting metabolism to pathway producing NAPQI
○ When hepatic glutathione is depleted, NAPQI reacts with cellular proteins –> cell injury
○ Some incidence of AKI - pathophysiology thought similar to hepatic injury (CYP450 enzymes in kidney) –> results in ATN
- Conditions enhancing hepatotoxicity
○ Chronic alcohol use disorders - increased risk for hepatotoxicity following ingestion of repeated, supratherapeutic doses of acetaminophen (EtoH = CYP inducer)
§ Note: acute EtOH co-ingestion not associated with increased risk (?saturation of CYP enzymes)
§ Note2: cirrhosis not associated with increased risk (low activity of CYP therefore less paracetamol metabolism)
○ Malnutrition/fasting state (hepatic glucuronidation dependent on CHO reserves)
○ Older age (>40)
○ Smoking (tobacco contains CYP inducers)

Management of toxicity
- Resuscitation
- Gastrointestinal decontamination - give activated charcoal (50g) if ingestion <2hrs of toxic dose, <4hr of ≥30g
- N-acetylcysteine = antidote
○ Paracetamol nomogram used to determine whether to commence NAC
§ Serum paracetamol level vs time. Above nomogram = commence treatment (only for acute ingestion of immediate release)
○ Mechanism of action:
§ Provide cysteines for glutathione synthesis
§ May bind directly to NAPQI
- Monitoring:
○ LFTs, INR, BSL, VBG