Y01. Pharmacopeia: Respiratory Pharmacology

PAST QUESTIONS – F11. Respiratory Pharmacology and Therapeutic Gases (Click to Open)

SYLLABUS (Fourth Edition, 2023)

LEVEL 1	LEVEL 2	LEVEL 3
Oxygen	Bronchodilators	Corticosteroids
	Anti-muscarinic agents – ipratropium, theophylline (aminophylline)	– Inhaled – Intravenous – Oral
	Beta agonists – Salbutamol	Exogenous Surfactant
		Pulmonary Vasodilators
		Nitric Oxide
		Prostacyclin

N.B. The Syllabus tables used in out Pharmacopeia seem incomplete, but that is intentional because we have only included groups/classes/drugs which are mentioned directly in the syllabus or have been asked before in the exams.

TRAINEE EXPECTATIONS

Trainees are expected to understand a drug’s pharmacology in the context of normal physiology, extremes of age (i.e., neonates, paediatrics, and the elderly), obesity, pregnancy (including foetal implications) and critical illness. An understanding of potential toxicity and relevant antidotes is also expected. Agents may be listed in more than one section when they are used for different indications.
This is not an exhaustive list of all drugs relevant to or important in ICU practice. Each drug or classes of drugs have been assigned a details of understanding level outlined below. This is a guide to the minimum level of knowledge expected for that drug.
For classes of drugs where examples are not specified, it is suggested a prototypical drug from the class be studied, as well as the relevant variations within the class exploring the major differences that exist between the agents in that class.

LEVELS OF UNDERSTANDING

Level 1	Level 2	Level 3
For these drugs, a detailed knowledge and comprehension of:	For these drugs a detailed knowledge of:	For these drugs a detailed knowledge of:
Class, Indications, and dose
Mechanism of Action
Pharmacodynamics and Adverse effects
Pharmacokinetics	Important pharmacokinetic differences or considerations when using in ICU
Pharmaceutics

CICMWrecks Tables (Click to Open)

MASTER TABLE (excluding Corticosteroids)
INDIVIDUAL TABLES	Asthma Drugs
	Salbutamol
	Salbutamol vs. Ipratropium
	Oxygen
	Aminophylline
	Inhaled Pulmonary Vasodilators
	Inhaled Nitric Oxide
	Corticosteroids

MASTER TABLE (excluding Corticosteroids)

Pharmacopeia - Resp

	OXYGEN	SALBUTAMOL	IPRATROPIUM	AMINOPHYLLINE / THEOPHYLLINE	NITRIC OXIDE	PROSTACYCLIN	EXOGENOUS SURFACTANT
GROUP	MEDICAL GAS	BRONCHODILATORS - BETA AGONISTS	BRONCHODILATORS - ANTIMUSCARINIC	BRONCHODILATORS - METHYLXANTHINES	PULMONARY VASODILATORS	PULMONARY VASODILATORS	Exogenous Surfactant
CICM Level of Understanding	Level 1	Level 2	Level 2	Level 2	Level 3	Level 3	Level 3

INTRODUCTION	Oxygen is a colourless, odourless, tasteless gas present in the atmosphere at a concentration of approximately 21%.	short-acting, selective beta2-adrenergic receptor agonist used in the treatment of asthma and COPD.	quaternary ammonium derivative of atropine that acts as an anticholinergic agent.		Endothelium Derived Relaxing Factor Produced by NO synthase from arginine in O2 - and NADPH dependent fashion.	Epoprostenol (Inhaled or continuous infusion) Iloprost (inhaled) PGI2 is a the main arachidonic acid metabolite in vascular endothelium
USES	1. Treatment and prevention of hypoxia 2. Treatment of carbon monoxide poisoning 3. Pneumotosis coli 4. Anaerobic infection 5. Cluster headaches 6. Resoprtion of pneumothoraxes	(i) the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, reversible obstructive airway disease, and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor, and/or (ii) the acute prophylaxis against exercise-induced bronchospasm and other stimuli known to induce bronchospasm	in combination with inhaled beta-agonist systemic corticosteroids for the management of severe exacerbations of asthma flares requiring treatment bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and emphysema Studied for Rhinorrhoea and Sialorrhea	1. Asthma 2. COPD 3. Used to reduce frequency of central apnoea in premature neonates 4. Heart failure	Selective pulmonary vasodilator in pulmonary hypertension Hypoxic respiratory failure associated with pulmonary hypertension in neonates RV dysfunction after cardiac surgery, ARDS	1. Pulmonary hypertension 2. Refractory hypoxia 3. Anticoagulation including CRRT and limb ischaemia 4. Pre-eclampsia


PHARMACEUTICS (PC)
PC: Chemical	Medical oxygen is produced via fractional distillation of atmospheric air or using an oxygen concentrator, which absorbs nitrogen. • Critical pressure of 50bar • Critical temperature of -119’C • Boiling point -182’C • MW of 32	Synthetic sympathomimetic amine racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta2-receptor than the S-isomer and the S-isomer has been associated with toxicity	Synthetic quaternary ammonium compound derived from atropine	Aminophylline is a Methylxanthine derivative 80% theophylline and 20% ethylenediamine (no therapeutic effects)	Manufactured as a byproduct in nitric acid synthesis. In vivo it is synthesized from L-arginine in a process catalyzed by nitric oxide synthase	Epoprostenol: PGI2 is reconstituted in a highly viscous and basic glycine diluent (causes tracheitis)
PC: Presentation	It is presented as a liquid or compressed gas (Clear, colourless, odourless) • Stored in black cylinders with white shoulders at 137bar • Variable size cylinders (from B which is 170L to G which is 8000L) • Available as wall oxygen in hospitals	- Clear colourless solution containing 50-500mcg/ml after dilution for IV infusion - Metered dose inhaler (100mcg) and dry powder (200-400mcg) for inhalation - Clear colourless solution containing 2.5-5mg/ml for nebulization - Oral preparation (syrup or tablets)	Isotonic solution containing 0.25mg/ml for nebulization (100-500mcg Q6hr) or as a MDI of 200mcg/dose (1-2 puffs Q6) Maximum effect achieved in 1.5-2 hours and lasts 4-6 hours	Oral and IV preparations	In aluminium cylinders containing 100/800 ppm of NO and nitrogen The cylinders may contain either 353 L at standard temperature and pressure (sTP) of NO in nitrogen or 1963 L at sTP. Pure NO is toxic and corrosive. No can also be supplied via stainless steel medical gas piping	Can be delivered as a continuous IV infusion or continuous nebulizer


PHARMACODYNAMICS (PD)
PD: Main Action	participate in oxidative phosphorylation, which produces the ATP required for cellular function	β2 agonist	Competitive inhibition of cholinergic receptors	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes	pulmonary vasodilation	pulmonary vasodilation
PD: Mode of Action	It moves down the oxygen cascade from a partial pressure of 159mmHg in atmospheric gas to approximately 105mmHg in the alveoli (dependent on PACO2 as per the alveolar gas equation), then to the mitochondria, where the PO2 may be as low as 2-3mmHg. Note the Pasteur point (1-2mmHg) is the minimum mitochondrial PO2 required for oxidative phosphorylation to proceed.	β2 agonist - GsPCR: Adenylate cyclase activated, cAMP On cell membranes: ↑Na+/K+ ATPase activity and hyperpolarisation Mild β1 agonist effects	- Competitive inhibition of cholinergic receptors in bronchial smooth muscle leading to inhibition of the bronchoconstrictor effect and vagal efferent impulses - M3 are receptors for bronchial smooth muscle contraction and mucous production - Inhibition of M3-R leads to decreased IP3/DAG and therefore decreased calcium required for bronchoconstriction	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes, which hydrolyse cAMP and possible cGMP leading to increases in their levels. This potentiates the effects of Beta-2 receptors. In addition it interferes with translocation of calcium into smooth muscle and stabilizes mast cells by antagonizing the actions of adenosine	NO interacts with haem containing compounds - Interacts with haem group in Guanylyl cyclase → increased cGMP - Phosphorylation of proteins leading to reduced cytosolic Ca2+ → reduced Contraction When inhaled, pulmonary vasodilation occurs and an increase in the partial pressure of arterial oxygen results. Dilation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor	Agonist at IP receptor - GsPCR receptor - → Increased cAMP via adenylyl cyclase - → Smooth muscle relaxation and inhibits smooth muscle growth
PD: Route & Doses	Oxygen can be delivered via variable intake devices (nasal prongs, Hudson masks), or in fixed amounts via venturi masks or endotracheal tubes.	Inh/Neb/IV	Inh/Neb	PO/IV Doses: Loading dose 5.7 mg/kg IV Maintenance dose: Continuous infusion - Adults <60yrs: 0.5 mg/kg/hr (max 1,125mg/day) - Adults >60yrs: 0.38 mg/kg/hr (max 500mg/day) - 0.25mg/kg/hr (max 500mg/day): Reduced dose with Cardiac decompensation / cor pulmonale/ Sepsis with MOF Dosing should be adjusted based on serum levels	Inh Dosing is generally between 10 and 40ppm	Inh
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS - If used for hypoxaemia, all cardiovascular parameters are expected to improve - However, administration of 100% for prolonged periods of time will decrease HR (effects on chemoreceptors), decrease diastolic blood pressure, slightly reduce cardiac output and cause coronary vasoconstriction - It causes a decrease in pulmonary vascular resistance Resp - 100% oxygen will lead to a mild respiratory depression - Nitrogen is eliminated from the lungs within 2-3min, leading to atelectasis CNS - 100% O2 leads to cerebrovascular vasoconstriction and a decrease in CNS blood flow	CVS: - At high doses, especially IV, B1 effects cause increased inotropy and chronotropy - At lower doses, B2 effects predominate and may cause a decreased SVR due to skeletal muscle vasodilation - May precipitate arrhythmias, particularly in the presence of hypokalaemia Resp: - Bronchodilation, leading to increased FEV1 - Interferes with hypoxic pulmonary vasoconstriction and may precipitate shunt leading to hypoxia Metabolic/Other: - Na/K/ATPase is stimulated and transports K into cells leading to hypokalaemia - Increased blood glucose - Beta adrenergic activity leads to increased production of lactate - Tremor Uterus: - Relaxes gravid uterus - 10% crosses the placenta and causes fetal tachycardia	CVS - Cardiovascular effects are minimal after inhaled - M2 effects may lead to tachycardia, increased CO and increased BP particularly when given IV Resp - Bronchodilation - May cause a small decreased mucous production GIT - Dry mouth - Decreased gastric secretions when given orally CNS - Unable to cross BBB	Resp - Bronchodilation - Increased sensitivity of the respiratory center to CO2 - Increased diaphragmatic contraction - In its IV form it impairs hypoxic pulmonary vasoconstriction and therefore requires oxygen therapy CVS - Mild positive inotropic and chronotropic effects and causes coronary and peripheral vasodilation - Lowers threshold for arrhythmias, particularly ventricular Renal - Increases renal blood flow and GFR - Decreased sodium reabsorption leading to a natriuretic and diuretic effect and may precipitate hypokalaemia Metabolic/Other - Hypokalaemia - SIADH	CVS: potent vasodilator that mediates the hypotension and significant vascular leak characteristic of septic shock. Inhaled No is a selective pulmonary vasodilator, since it is avidly bound to haemoglobin and thereby inactivated before reaching the systemic circulation. NO released from the vascular endothelium inhibits platelet aggregation and attenuates platelet and white cell adhesion. RS: inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving VQ mismatch CNS: increases the cerebral blood flow and appears to have a physiological role as a neurotransmitter within the autonomic and central nervous systems. GU: may play a role in the regulation of renin production and sodium homeostasis in the kidney. physiological mediator of penile erection. Metabolic/other: NO released from macrophages reacts with superoxide ion to form the free radical peroxynitrite which is toxic to bacteria. Insulin release appears to be modulated by NO.	- Pulmonary vasodilation by agents given via inhalational route → vasodilation of ventilated blood vessels → increased perfusion → improved V/Q matching - Improved V/Q matching → increased paO2 - Pulmonary vasodilation → decreased PVR → Decreased RVSP and improves RV funcion
PD: Side Effects / Toxicity	CNS – visual changes and seizures may occur at 3 atmospheres Ocular – retrolental fibroplasia has been seen in premature babies treated with oxygen, possibly due to vasoconstriction of developing retinal vessels CVS – improvement in haemodynamics if oxygen is being used to correct hypoxaemia. Prolonged administration of 100% FiO2 may cause a reduction in heart rate and cardiac output, and coronary artery vasoconstriction. Respiratory – Potential decrease in respiratory drive (significant in patients who are CO2 retainers and rely on their hypoxic drive to breathe). Absorption atelectasis. Tracheobronchitis. ALI/ARDS due to the production of oxygen free radicals (superoxide, hydroxide, hydrogen peroxide), which cause parenchymal damage and diffuse lung injury.	- Anxiety, tremor, insomnia, restlessness - Hypokalaemia - Arrhythmias - Lactic acidosis and ketosis	Paradoxical bronchospasm headache, dizziness, nausea, dry mouth, shaking (tremors), nervousness, or. cold symptoms such as stuffy nose, sneezing, cough, or sore throat.	1. Co-administration with drugs that inhibit CYP450 (cimetidine, erythromycin, cipro) will elevate plasma levels 2. In high concentrations it antagonizes NMDR 3. Above concentrations of 35mcg/ml enzymes become saturated and its kinetics change from first order to zero order resulting in toxicity. This manifests as cardiac toxicity (arrhythmias), CNS toxicity (seizures) and rhabdo	Exposure to 500–2000 ppm of NO results in methaemoglobinaemia and pulmonary oedema. Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema. Thrombocytopoenia Hypotension	Flushing Headache Nausea Hypotension Diarrhoea


PHARMACOKINETICS (PK)
PK: Absorption	- Freely absorbed across the normal alveolar membrane - Fick’s Law of diffusion	Inhalational / IV BA 10%	Inh Poor bioavailability PO: 30% Inh: 5%	Rapidly absorbed orally with bioavailability of 90%	highly lipid-soluble and diffuses freely across cell membranes	Highly lipid soluble and rapidly absorbed through alveoli

PK: Distribution	Diffuses across the alveolar membrane as per Fick’s Law to enter the blood. Main mode of transportation is bound to haemoglobin, with a small fraction dissolved in blood. Under normal circumstances there is approximately 1.75L of oxygen stored within the body. This may be increased with preoxygenation in anaesthesia or with hyperbaric oxygenation.				Little Systemic distribution after inhalation	Little Systemic distribution after inhalation
Protein binding (PK: Distribution)		Only weak protein binding	Very weak protein binding	50% protein bound	Highly protein bound
Volume of distribution (PK: Distribution)		Vd (IV) 4-5L/kg	Vd 4.6L/kg	Vd 0.5L/Kg

PK: Metabolism	Oxygen is consumed in oxidative phosphorylation, producing ATP, CO2 and H2O.	Converted by liver to inactive metabolite (esterified / oxidative deamination / conjugation with glucuronide)	Metabolized by GIT by CYP450 enzymes.	- Low ER and metabolism is independent of blood flow - Hepatic metabolism to active and inactive metabolites including a 3-methylxanthine derivative that is active - Cigarette smoking increases clearance	- Following inhalation, NO combines with oxyhaemoglobin that is 60–100% saturated, producing methaemoglobin and nitrate. - During the first 8 hours of NO exposure, methaemoglobin concentrations increase. - Nitric oxide also reacts with O2 to produce NO2	Rapidly removed from circulation by hydrolysis to 6-oxo-PGF1 alpha in blood

PK: Excretion	Exhaled as CO2 and water	Excreted urine as 40% free dug and 60% metabolite Small amount in faeces	80-100% urine (unchanged), rest faeces Mostly in faeces if given orally	Approximately 10% excreted in urine unchanged	The main metabolite is nitrate (70%) which is excreted by the Kidneys.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)		T1/2 5hrs	T1/2 1.6hrs	First order kinetics T1/2 is 8 hours	Half-life of <5 seconds.	Plasma half life is 30sec-3min


SPECIAL POINTS	Measurement: 1. Gas - Mass spectrometer - Paramagnetic analyzer - Fuel cell 2. Blood - Clarke electrode - Pulse oximetry	Appears to potentiate NDMR			Benefits of inhalational route - Reduced systemic effects Delivery of drug to ventilated areas → selective vasodilation → improved V/Q	Benefits of inhalational route - Reduced systemic effects Delivery of drug to ventilated areas → selective vasodilation → improved V/Q

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INDIVIDUAL TABLES

ASTHMA DRUGS

Pharmacopeia - Resp

	OXYGEN	SALBUTAMOL	IPRATROPIUM	AMINOPHYLLINE / THEOPHYLLINE	EXOGENOUS SURFACTANT
GROUP	MEDICAL GAS	BRONCHODILATORS - BETA AGONISTS	BRONCHODILATORS - ANTIMUSCARINIC	BRONCHODILATORS - METHYLXANTHINES	Exogenous Surfactant
CICM Level of Understanding	Level 1	Level 2	Level 2	Level 2	Level 3

INTRODUCTION	Oxygen is a colourless, odourless, tasteless gas present in the atmosphere at a concentration of approximately 21%.	short-acting, selective beta2-adrenergic receptor agonist used in the treatment of asthma and COPD.	quaternary ammonium derivative of atropine that acts as an anticholinergic agent.
USES	1. Treatment and prevention of hypoxia 2. Treatment of carbon monoxide poisoning 3. Pneumotosis coli 4. Anaerobic infection 5. Cluster headaches 6. Resoprtion of pneumothoraxes	(i) the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, reversible obstructive airway disease, and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor, and/or (ii) the acute prophylaxis against exercise-induced bronchospasm and other stimuli known to induce bronchospasm	in combination with inhaled beta-agonist systemic corticosteroids for the management of severe exacerbations of asthma flares requiring treatment bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and emphysema Studied for Rhinorrhoea and Sialorrhea	1. Asthma 2. COPD 3. Used to reduce frequency of central apnoea in premature neonates 4. Heart failure


PHARMACEUTICS (PC)
PC: Chemical	Medical oxygen is produced via fractional distillation of atmospheric air or using an oxygen concentrator, which absorbs nitrogen. • Critical pressure of 50bar • Critical temperature of -119’C • Boiling point -182’C • MW of 32	Synthetic sympathomimetic amine racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta2-receptor than the S-isomer and the S-isomer has been associated with toxicity	Synthetic quaternary ammonium compound derived from atropine	Aminophylline is a Methylxanthine derivative 80% theophylline and 20% ethylenediamine (no therapeutic effects)
PC: Presentation	It is presented as a liquid or compressed gas (Clear, colourless, odourless) • Stored in black cylinders with white shoulders at 137bar • Variable size cylinders (from B which is 170L to G which is 8000L) • Available as wall oxygen in hospitals	- Clear colourless solution containing 50-500mcg/ml after dilution for IV infusion - Metered dose inhaler (100mcg) and dry powder (200-400mcg) for inhalation - Clear colourless solution containing 2.5-5mg/ml for nebulization - Oral preparation (syrup or tablets)	Isotonic solution containing 0.25mg/ml for nebulization (100-500mcg Q6hr) or as a MDI of 200mcg/dose (1-2 puffs Q6) Maximum effect achieved in 1.5-2 hours and lasts 4-6 hours	Oral and IV preparations


PHARMACODYNAMICS (PD)
PD: Main Action	participate in oxidative phosphorylation, which produces the ATP required for cellular function	β2 agonist	Competitive inhibition of cholinergic receptors	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes
PD: Mode of Action	It moves down the oxygen cascade from a partial pressure of 159mmHg in atmospheric gas to approximately 105mmHg in the alveoli (dependent on PACO2 as per the alveolar gas equation), then to the mitochondria, where the PO2 may be as low as 2-3mmHg. Note the Pasteur point (1-2mmHg) is the minimum mitochondrial PO2 required for oxidative phosphorylation to proceed.	β2 agonist - GsPCR: Adenylate cyclase activated, cAMP On cell membranes: ↑Na+/K+ ATPase activity and hyperpolarisation Mild β1 agonist effects	- Competitive inhibition of cholinergic receptors in bronchial smooth muscle leading to inhibition of the bronchoconstrictor effect and vagal efferent impulses - M3 are receptors for bronchial smooth muscle contraction and mucous production - Inhibition of M3-R leads to decreased IP3/DAG and therefore decreased calcium required for bronchoconstriction	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes, which hydrolyse cAMP and possible cGMP leading to increases in their levels. This potentiates the effects of Beta-2 receptors. In addition it interferes with translocation of calcium into smooth muscle and stabilizes mast cells by antagonizing the actions of adenosine
PD: Route & Doses	Oxygen can be delivered via variable intake devices (nasal prongs, Hudson masks), or in fixed amounts via venturi masks or endotracheal tubes.	Inh/Neb/IV	Inh/Neb	PO/IV Doses: Loading dose 5.7 mg/kg IV Maintenance dose: Continuous infusion - Adults <60yrs: 0.5 mg/kg/hr (max 1,125mg/day) - Adults >60yrs: 0.38 mg/kg/hr (max 500mg/day) - 0.25mg/kg/hr (max 500mg/day): Reduced dose with Cardiac decompensation / cor pulmonale/ Sepsis with MOF Dosing should be adjusted based on serum levels
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS - If used for hypoxaemia, all cardiovascular parameters are expected to improve - However, administration of 100% for prolonged periods of time will decrease HR (effects on chemoreceptors), decrease diastolic blood pressure, slightly reduce cardiac output and cause coronary vasoconstriction - It causes a decrease in pulmonary vascular resistance Resp - 100% oxygen will lead to a mild respiratory depression - Nitrogen is eliminated from the lungs within 2-3min, leading to atelectasis CNS - 100% O2 leads to cerebrovascular vasoconstriction and a decrease in CNS blood flow	CVS: - At high doses, especially IV, B1 effects cause increased inotropy and chronotropy - At lower doses, B2 effects predominate and may cause a decreased SVR due to skeletal muscle vasodilation - May precipitate arrhythmias, particularly in the presence of hypokalaemia Resp: - Bronchodilation, leading to increased FEV1 - Interferes with hypoxic pulmonary vasoconstriction and may precipitate shunt leading to hypoxia Metabolic/Other: - Na/K/ATPase is stimulated and transports K into cells leading to hypokalaemia - Increased blood glucose - Beta adrenergic activity leads to increased production of lactate - Tremor Uterus: - Relaxes gravid uterus - 10% crosses the placenta and causes fetal tachycardia	CVS - Cardiovascular effects are minimal after inhaled - M2 effects may lead to tachycardia, increased CO and increased BP particularly when given IV Resp - Bronchodilation - May cause a small decreased mucous production GIT - Dry mouth - Decreased gastric secretions when given orally CNS - Unable to cross BBB	Resp - Bronchodilation - Increased sensitivity of the respiratory center to CO2 - Increased diaphragmatic contraction - In its IV form it impairs hypoxic pulmonary vasoconstriction and therefore requires oxygen therapy CVS - Mild positive inotropic and chronotropic effects and causes coronary and peripheral vasodilation - Lowers threshold for arrhythmias, particularly ventricular Renal - Increases renal blood flow and GFR - Decreased sodium reabsorption leading to a natriuretic and diuretic effect and may precipitate hypokalaemia Metabolic/Other - Hypokalaemia - SIADH
PD: Side Effects / Toxicity	CNS – visual changes and seizures may occur at 3 atmospheres Ocular – retrolental fibroplasia has been seen in premature babies treated with oxygen, possibly due to vasoconstriction of developing retinal vessels CVS – improvement in haemodynamics if oxygen is being used to correct hypoxaemia. Prolonged administration of 100% FiO2 may cause a reduction in heart rate and cardiac output, and coronary artery vasoconstriction. Respiratory – Potential decrease in respiratory drive (significant in patients who are CO2 retainers and rely on their hypoxic drive to breathe). Absorption atelectasis. Tracheobronchitis. ALI/ARDS due to the production of oxygen free radicals (superoxide, hydroxide, hydrogen peroxide), which cause parenchymal damage and diffuse lung injury.	- Anxiety, tremor, insomnia, restlessness - Hypokalaemia - Arrhythmias - Lactic acidosis and ketosis	Paradoxical bronchospasm headache, dizziness, nausea, dry mouth, shaking (tremors), nervousness, or. cold symptoms such as stuffy nose, sneezing, cough, or sore throat.	1. Co-administration with drugs that inhibit CYP450 (cimetidine, erythromycin, cipro) will elevate plasma levels 2. In high concentrations it antagonizes NMDR 3. Above concentrations of 35mcg/ml enzymes become saturated and its kinetics change from first order to zero order resulting in toxicity. This manifests as cardiac toxicity (arrhythmias), CNS toxicity (seizures) and rhabdo


PHARMACOKINETICS (PK)
PK: Absorption	- Freely absorbed across the normal alveolar membrane - Fick’s Law of diffusion	Inhalational / IV BA 10%	Inh Poor bioavailability PO: 30% Inh: 5%	Rapidly absorbed orally with bioavailability of 90%

PK: Distribution	Diffuses across the alveolar membrane as per Fick’s Law to enter the blood. Main mode of transportation is bound to haemoglobin, with a small fraction dissolved in blood. Under normal circumstances there is approximately 1.75L of oxygen stored within the body. This may be increased with preoxygenation in anaesthesia or with hyperbaric oxygenation.
Protein binding (PK: Distribution)		Only weak protein binding	Very weak protein binding	50% protein bound
Volume of distribution (PK: Distribution)		Vd (IV) 4-5L/kg	Vd 4.6L/kg	Vd 0.5L/Kg

PK: Metabolism	Oxygen is consumed in oxidative phosphorylation, producing ATP, CO2 and H2O.	Converted by liver to inactive metabolite (esterified / oxidative deamination / conjugation with glucuronide)	Metabolized by GIT by CYP450 enzymes.	- Low ER and metabolism is independent of blood flow - Hepatic metabolism to active and inactive metabolites including a 3-methylxanthine derivative that is active - Cigarette smoking increases clearance

PK: Excretion	Exhaled as CO2 and water	Excreted urine as 40% free dug and 60% metabolite Small amount in faeces	80-100% urine (unchanged), rest faeces Mostly in faeces if given orally	Approximately 10% excreted in urine unchanged
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)		T1/2 5hrs	T1/2 1.6hrs	First order kinetics T1/2 is 8 hours


SPECIAL POINTS	Measurement: 1. Gas - Mass spectrometer - Paramagnetic analyzer - Fuel cell 2. Blood - Clarke electrode - Pulse oximetry	Appears to potentiate NDMR

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SALBUTAMOL

Pharmacopeia - Resp

	SALBUTAMOL	EXOGENOUS SURFACTANT
GROUP	BRONCHODILATORS - BETA AGONISTS	Exogenous Surfactant
CICM Level of Understanding	Level 2	Level 3

INTRODUCTION	short-acting, selective beta2-adrenergic receptor agonist used in the treatment of asthma and COPD.
USES	(i) the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, reversible obstructive airway disease, and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor, and/or (ii) the acute prophylaxis against exercise-induced bronchospasm and other stimuli known to induce bronchospasm


PHARMACEUTICS (PC)
PC: Chemical	Synthetic sympathomimetic amine racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta2-receptor than the S-isomer and the S-isomer has been associated with toxicity
PC: Presentation	- Clear colourless solution containing 50-500mcg/ml after dilution for IV infusion - Metered dose inhaler (100mcg) and dry powder (200-400mcg) for inhalation - Clear colourless solution containing 2.5-5mg/ml for nebulization - Oral preparation (syrup or tablets)


PHARMACODYNAMICS (PD)
PD: Main Action	β2 agonist
PD: Mode of Action	β2 agonist - GsPCR: Adenylate cyclase activated, cAMP On cell membranes: ↑Na+/K+ ATPase activity and hyperpolarisation Mild β1 agonist effects
PD: Route & Doses	Inh/Neb/IV
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS: - At high doses, especially IV, B1 effects cause increased inotropy and chronotropy - At lower doses, B2 effects predominate and may cause a decreased SVR due to skeletal muscle vasodilation - May precipitate arrhythmias, particularly in the presence of hypokalaemia Resp: - Bronchodilation, leading to increased FEV1 - Interferes with hypoxic pulmonary vasoconstriction and may precipitate shunt leading to hypoxia Metabolic/Other: - Na/K/ATPase is stimulated and transports K into cells leading to hypokalaemia - Increased blood glucose - Beta adrenergic activity leads to increased production of lactate - Tremor Uterus: - Relaxes gravid uterus - 10% crosses the placenta and causes fetal tachycardia
PD: Side Effects / Toxicity	- Anxiety, tremor, insomnia, restlessness - Hypokalaemia - Arrhythmias - Lactic acidosis and ketosis


PHARMACOKINETICS (PK)
PK: Absorption	Inhalational / IV BA 10%

PK: Distribution
Protein binding (PK: Distribution)	Only weak protein binding
Volume of distribution (PK: Distribution)	Vd (IV) 4-5L/kg

PK: Metabolism	Converted by liver to inactive metabolite (esterified / oxidative deamination / conjugation with glucuronide)

PK: Excretion	Excreted urine as 40% free dug and 60% metabolite Small amount in faeces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2 5hrs


SPECIAL POINTS	Appears to potentiate NDMR

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SALBUTAMOL vs IPRATROPIUM

Pharmacopeia - Resp

	SALBUTAMOL	IPRATROPIUM	EXOGENOUS SURFACTANT
GROUP	BRONCHODILATORS - BETA AGONISTS	BRONCHODILATORS - ANTIMUSCARINIC	Exogenous Surfactant
CICM Level of Understanding	Level 2	Level 2	Level 3

INTRODUCTION	short-acting, selective beta2-adrenergic receptor agonist used in the treatment of asthma and COPD.	quaternary ammonium derivative of atropine that acts as an anticholinergic agent.
USES	(i) the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, reversible obstructive airway disease, and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor, and/or (ii) the acute prophylaxis against exercise-induced bronchospasm and other stimuli known to induce bronchospasm	in combination with inhaled beta-agonist systemic corticosteroids for the management of severe exacerbations of asthma flares requiring treatment bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and emphysema Studied for Rhinorrhoea and Sialorrhea


PHARMACEUTICS (PC)
PC: Chemical	Synthetic sympathomimetic amine racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta2-receptor than the S-isomer and the S-isomer has been associated with toxicity	Synthetic quaternary ammonium compound derived from atropine
PC: Presentation	- Clear colourless solution containing 50-500mcg/ml after dilution for IV infusion - Metered dose inhaler (100mcg) and dry powder (200-400mcg) for inhalation - Clear colourless solution containing 2.5-5mg/ml for nebulization - Oral preparation (syrup or tablets)	Isotonic solution containing 0.25mg/ml for nebulization (100-500mcg Q6hr) or as a MDI of 200mcg/dose (1-2 puffs Q6) Maximum effect achieved in 1.5-2 hours and lasts 4-6 hours


PHARMACODYNAMICS (PD)
PD: Main Action	β2 agonist	Competitive inhibition of cholinergic receptors
PD: Mode of Action	β2 agonist - GsPCR: Adenylate cyclase activated, cAMP On cell membranes: ↑Na+/K+ ATPase activity and hyperpolarisation Mild β1 agonist effects	- Competitive inhibition of cholinergic receptors in bronchial smooth muscle leading to inhibition of the bronchoconstrictor effect and vagal efferent impulses - M3 are receptors for bronchial smooth muscle contraction and mucous production - Inhibition of M3-R leads to decreased IP3/DAG and therefore decreased calcium required for bronchoconstriction
PD: Route & Doses	Inh/Neb/IV	Inh/Neb
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS: - At high doses, especially IV, B1 effects cause increased inotropy and chronotropy - At lower doses, B2 effects predominate and may cause a decreased SVR due to skeletal muscle vasodilation - May precipitate arrhythmias, particularly in the presence of hypokalaemia Resp: - Bronchodilation, leading to increased FEV1 - Interferes with hypoxic pulmonary vasoconstriction and may precipitate shunt leading to hypoxia Metabolic/Other: - Na/K/ATPase is stimulated and transports K into cells leading to hypokalaemia - Increased blood glucose - Beta adrenergic activity leads to increased production of lactate - Tremor Uterus: - Relaxes gravid uterus - 10% crosses the placenta and causes fetal tachycardia	CVS - Cardiovascular effects are minimal after inhaled - M2 effects may lead to tachycardia, increased CO and increased BP particularly when given IV Resp - Bronchodilation - May cause a small decreased mucous production GIT - Dry mouth - Decreased gastric secretions when given orally CNS - Unable to cross BBB
PD: Side Effects / Toxicity	- Anxiety, tremor, insomnia, restlessness - Hypokalaemia - Arrhythmias - Lactic acidosis and ketosis	Paradoxical bronchospasm headache, dizziness, nausea, dry mouth, shaking (tremors), nervousness, or. cold symptoms such as stuffy nose, sneezing, cough, or sore throat.


PHARMACOKINETICS (PK)
PK: Absorption	Inhalational / IV BA 10%	Inh Poor bioavailability PO: 30% Inh: 5%

PK: Distribution
Protein binding (PK: Distribution)	Only weak protein binding	Very weak protein binding
Volume of distribution (PK: Distribution)	Vd (IV) 4-5L/kg	Vd 4.6L/kg

PK: Metabolism	Converted by liver to inactive metabolite (esterified / oxidative deamination / conjugation with glucuronide)	Metabolized by GIT by CYP450 enzymes.

PK: Excretion	Excreted urine as 40% free dug and 60% metabolite Small amount in faeces	80-100% urine (unchanged), rest faeces Mostly in faeces if given orally
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	T1/2 5hrs	T1/2 1.6hrs


SPECIAL POINTS	Appears to potentiate NDMR

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OXYGEN

Pharmacopeia - Resp

	OXYGEN	EXOGENOUS SURFACTANT
GROUP	MEDICAL GAS	Exogenous Surfactant
CICM Level of Understanding	Level 1	Level 3

INTRODUCTION	Oxygen is a colourless, odourless, tasteless gas present in the atmosphere at a concentration of approximately 21%.
USES	1. Treatment and prevention of hypoxia 2. Treatment of carbon monoxide poisoning 3. Pneumotosis coli 4. Anaerobic infection 5. Cluster headaches 6. Resoprtion of pneumothoraxes


PHARMACEUTICS (PC)
PC: Chemical	Medical oxygen is produced via fractional distillation of atmospheric air or using an oxygen concentrator, which absorbs nitrogen. • Critical pressure of 50bar • Critical temperature of -119’C • Boiling point -182’C • MW of 32
PC: Presentation	It is presented as a liquid or compressed gas (Clear, colourless, odourless) • Stored in black cylinders with white shoulders at 137bar • Variable size cylinders (from B which is 170L to G which is 8000L) • Available as wall oxygen in hospitals


PHARMACODYNAMICS (PD)
PD: Main Action	participate in oxidative phosphorylation, which produces the ATP required for cellular function
PD: Mode of Action	It moves down the oxygen cascade from a partial pressure of 159mmHg in atmospheric gas to approximately 105mmHg in the alveoli (dependent on PACO2 as per the alveolar gas equation), then to the mitochondria, where the PO2 may be as low as 2-3mmHg. Note the Pasteur point (1-2mmHg) is the minimum mitochondrial PO2 required for oxidative phosphorylation to proceed.
PD: Route & Doses	Oxygen can be delivered via variable intake devices (nasal prongs, Hudson masks), or in fixed amounts via venturi masks or endotracheal tubes.
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS - If used for hypoxaemia, all cardiovascular parameters are expected to improve - However, administration of 100% for prolonged periods of time will decrease HR (effects on chemoreceptors), decrease diastolic blood pressure, slightly reduce cardiac output and cause coronary vasoconstriction - It causes a decrease in pulmonary vascular resistance Resp - 100% oxygen will lead to a mild respiratory depression - Nitrogen is eliminated from the lungs within 2-3min, leading to atelectasis CNS - 100% O2 leads to cerebrovascular vasoconstriction and a decrease in CNS blood flow
PD: Side Effects / Toxicity	CNS – visual changes and seizures may occur at 3 atmospheres Ocular – retrolental fibroplasia has been seen in premature babies treated with oxygen, possibly due to vasoconstriction of developing retinal vessels CVS – improvement in haemodynamics if oxygen is being used to correct hypoxaemia. Prolonged administration of 100% FiO2 may cause a reduction in heart rate and cardiac output, and coronary artery vasoconstriction. Respiratory – Potential decrease in respiratory drive (significant in patients who are CO2 retainers and rely on their hypoxic drive to breathe). Absorption atelectasis. Tracheobronchitis. ALI/ARDS due to the production of oxygen free radicals (superoxide, hydroxide, hydrogen peroxide), which cause parenchymal damage and diffuse lung injury.


PHARMACOKINETICS (PK)
PK: Absorption	- Freely absorbed across the normal alveolar membrane - Fick’s Law of diffusion

PK: Distribution	Diffuses across the alveolar membrane as per Fick’s Law to enter the blood. Main mode of transportation is bound to haemoglobin, with a small fraction dissolved in blood. Under normal circumstances there is approximately 1.75L of oxygen stored within the body. This may be increased with preoxygenation in anaesthesia or with hyperbaric oxygenation.
Protein binding (PK: Distribution)
Volume of distribution (PK: Distribution)

PK: Metabolism	Oxygen is consumed in oxidative phosphorylation, producing ATP, CO2 and H2O.

PK: Excretion	Exhaled as CO2 and water
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)


SPECIAL POINTS	Measurement: 1. Gas - Mass spectrometer - Paramagnetic analyzer - Fuel cell 2. Blood - Clarke electrode - Pulse oximetry

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AMINOPHYLLINE

Pharmacopeia - Resp

	AMINOPHYLLINE / THEOPHYLLINE
GROUP	BRONCHODILATORS - METHYLXANTHINES
CICM Level of Understanding	Level 2

INTRODUCTION
USES	1. Asthma 2. COPD 3. Used to reduce frequency of central apnoea in premature neonates 4. Heart failure


PHARMACEUTICS (PC)
PC: Chemical	Aminophylline is a Methylxanthine derivative 80% theophylline and 20% ethylenediamine (no therapeutic effects)
PC: Presentation	Oral and IV preparations


PHARMACODYNAMICS (PD)
PD: Main Action	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes
PD: Mode of Action	Non-selective inhibitor of all 5 phosphodiesterase isoenzymes, which hydrolyse cAMP and possible cGMP leading to increases in their levels. This potentiates the effects of Beta-2 receptors. In addition it interferes with translocation of calcium into smooth muscle and stabilizes mast cells by antagonizing the actions of adenosine
PD: Route & Doses	PO/IV Doses: Loading dose 5.7 mg/kg IV Maintenance dose: Continuous infusion - Adults <60yrs: 0.5 mg/kg/hr (max 1,125mg/day) - Adults >60yrs: 0.38 mg/kg/hr (max 500mg/day) - 0.25mg/kg/hr (max 500mg/day): Reduced dose with Cardiac decompensation / cor pulmonale/ Sepsis with MOF Dosing should be adjusted based on serum levels
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	Resp - Bronchodilation - Increased sensitivity of the respiratory center to CO2 - Increased diaphragmatic contraction - In its IV form it impairs hypoxic pulmonary vasoconstriction and therefore requires oxygen therapy CVS - Mild positive inotropic and chronotropic effects and causes coronary and peripheral vasodilation - Lowers threshold for arrhythmias, particularly ventricular Renal - Increases renal blood flow and GFR - Decreased sodium reabsorption leading to a natriuretic and diuretic effect and may precipitate hypokalaemia Metabolic/Other - Hypokalaemia - SIADH
PD: Side Effects / Toxicity	1. Co-administration with drugs that inhibit CYP450 (cimetidine, erythromycin, cipro) will elevate plasma levels 2. In high concentrations it antagonizes NMDR 3. Above concentrations of 35mcg/ml enzymes become saturated and its kinetics change from first order to zero order resulting in toxicity. This manifests as cardiac toxicity (arrhythmias), CNS toxicity (seizures) and rhabdo


PHARMACOKINETICS (PK)
PK: Absorption	Rapidly absorbed orally with bioavailability of 90%

PK: Distribution
Protein binding (PK: Distribution)	50% protein bound
Volume of distribution (PK: Distribution)	Vd 0.5L/Kg

PK: Metabolism	- Low ER and metabolism is independent of blood flow - Hepatic metabolism to active and inactive metabolites including a 3-methylxanthine derivative that is active - Cigarette smoking increases clearance

PK: Excretion	Approximately 10% excreted in urine unchanged
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	First order kinetics T1/2 is 8 hours


SPECIAL POINTS

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INHALED PULMONARY VASODILATORS

Pharmacopeia - Resp

	NITRIC OXIDE	PROSTACYCLIN	EXOGENOUS SURFACTANT
GROUP	PULMONARY VASODILATORS	PULMONARY VASODILATORS	Exogenous Surfactant
CICM Level of Understanding	Level 3	Level 3	Level 3

INTRODUCTION	Endothelium Derived Relaxing Factor Produced by NO synthase from arginine in O2 - and NADPH dependent fashion.	Epoprostenol (Inhaled or continuous infusion) Iloprost (inhaled) PGI2 is a the main arachidonic acid metabolite in vascular endothelium
USES	Selective pulmonary vasodilator in pulmonary hypertension Hypoxic respiratory failure associated with pulmonary hypertension in neonates RV dysfunction after cardiac surgery, ARDS	1. Pulmonary hypertension 2. Refractory hypoxia 3. Anticoagulation including CRRT and limb ischaemia 4. Pre-eclampsia


PHARMACEUTICS (PC)
PC: Chemical	Manufactured as a byproduct in nitric acid synthesis. In vivo it is synthesized from L-arginine in a process catalyzed by nitric oxide synthase	Epoprostenol: PGI2 is reconstituted in a highly viscous and basic glycine diluent (causes tracheitis)
PC: Presentation	In aluminium cylinders containing 100/800 ppm of NO and nitrogen The cylinders may contain either 353 L at standard temperature and pressure (sTP) of NO in nitrogen or 1963 L at sTP. Pure NO is toxic and corrosive. No can also be supplied via stainless steel medical gas piping	Can be delivered as a continuous IV infusion or continuous nebulizer


PHARMACODYNAMICS (PD)
PD: Main Action	pulmonary vasodilation	pulmonary vasodilation
PD: Mode of Action	NO interacts with haem containing compounds - Interacts with haem group in Guanylyl cyclase → increased cGMP - Phosphorylation of proteins leading to reduced cytosolic Ca2+ → reduced Contraction When inhaled, pulmonary vasodilation occurs and an increase in the partial pressure of arterial oxygen results. Dilation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor	Agonist at IP receptor - GsPCR receptor - → Increased cAMP via adenylyl cyclase - → Smooth muscle relaxation and inhibits smooth muscle growth
PD: Route & Doses	Inh Dosing is generally between 10 and 40ppm	Inh
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS: potent vasodilator that mediates the hypotension and significant vascular leak characteristic of septic shock. Inhaled No is a selective pulmonary vasodilator, since it is avidly bound to haemoglobin and thereby inactivated before reaching the systemic circulation. NO released from the vascular endothelium inhibits platelet aggregation and attenuates platelet and white cell adhesion. RS: inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving VQ mismatch CNS: increases the cerebral blood flow and appears to have a physiological role as a neurotransmitter within the autonomic and central nervous systems. GU: may play a role in the regulation of renin production and sodium homeostasis in the kidney. physiological mediator of penile erection. Metabolic/other: NO released from macrophages reacts with superoxide ion to form the free radical peroxynitrite which is toxic to bacteria. Insulin release appears to be modulated by NO.	- Pulmonary vasodilation by agents given via inhalational route → vasodilation of ventilated blood vessels → increased perfusion → improved V/Q matching - Improved V/Q matching → increased paO2 - Pulmonary vasodilation → decreased PVR → Decreased RVSP and improves RV funcion
PD: Side Effects / Toxicity	Exposure to 500–2000 ppm of NO results in methaemoglobinaemia and pulmonary oedema. Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema. Thrombocytopoenia Hypotension	Flushing Headache Nausea Hypotension Diarrhoea


PHARMACOKINETICS (PK)
PK: Absorption	highly lipid-soluble and diffuses freely across cell membranes	Highly lipid soluble and rapidly absorbed through alveoli

PK: Distribution	Little Systemic distribution after inhalation	Little Systemic distribution after inhalation
Protein binding (PK: Distribution)	Highly protein bound
Volume of distribution (PK: Distribution)

PK: Metabolism	- Following inhalation, NO combines with oxyhaemoglobin that is 60–100% saturated, producing methaemoglobin and nitrate. - During the first 8 hours of NO exposure, methaemoglobin concentrations increase. - Nitric oxide also reacts with O2 to produce NO2	Rapidly removed from circulation by hydrolysis to 6-oxo-PGF1 alpha in blood

PK: Excretion	The main metabolite is nitrate (70%) which is excreted by the Kidneys.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half-life of <5 seconds.	Plasma half life is 30sec-3min


SPECIAL POINTS	Benefits of inhalational route - Reduced systemic effects Delivery of drug to ventilated areas → selective vasodilation → improved V/Q	Benefits of inhalational route - Reduced systemic effects Delivery of drug to ventilated areas → selective vasodilation → improved V/Q

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INHALED NITRIC OXIDE

Pharmacopeia - Resp

	NITRIC OXIDE	EXOGENOUS SURFACTANT
GROUP	PULMONARY VASODILATORS	Exogenous Surfactant
CICM Level of Understanding	Level 3	Level 3

INTRODUCTION	Endothelium Derived Relaxing Factor Produced by NO synthase from arginine in O2 - and NADPH dependent fashion.
USES	Selective pulmonary vasodilator in pulmonary hypertension Hypoxic respiratory failure associated with pulmonary hypertension in neonates RV dysfunction after cardiac surgery, ARDS


PHARMACEUTICS (PC)
PC: Chemical	Manufactured as a byproduct in nitric acid synthesis. In vivo it is synthesized from L-arginine in a process catalyzed by nitric oxide synthase
PC: Presentation	In aluminium cylinders containing 100/800 ppm of NO and nitrogen The cylinders may contain either 353 L at standard temperature and pressure (sTP) of NO in nitrogen or 1963 L at sTP. Pure NO is toxic and corrosive. No can also be supplied via stainless steel medical gas piping


PHARMACODYNAMICS (PD)
PD: Main Action	pulmonary vasodilation
PD: Mode of Action	NO interacts with haem containing compounds - Interacts with haem group in Guanylyl cyclase → increased cGMP - Phosphorylation of proteins leading to reduced cytosolic Ca2+ → reduced Contraction When inhaled, pulmonary vasodilation occurs and an increase in the partial pressure of arterial oxygen results. Dilation of pulmonary vessels in well ventilated lung areas redistributes blood flow away from lung areas where ventilation/perfusion ratios are poor
PD: Route & Doses	Inh Dosing is generally between 10 and 40ppm
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS: potent vasodilator that mediates the hypotension and significant vascular leak characteristic of septic shock. Inhaled No is a selective pulmonary vasodilator, since it is avidly bound to haemoglobin and thereby inactivated before reaching the systemic circulation. NO released from the vascular endothelium inhibits platelet aggregation and attenuates platelet and white cell adhesion. RS: inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving VQ mismatch CNS: increases the cerebral blood flow and appears to have a physiological role as a neurotransmitter within the autonomic and central nervous systems. GU: may play a role in the regulation of renin production and sodium homeostasis in the kidney. physiological mediator of penile erection. Metabolic/other: NO released from macrophages reacts with superoxide ion to form the free radical peroxynitrite which is toxic to bacteria. Insulin release appears to be modulated by NO.
PD: Side Effects / Toxicity	Exposure to 500–2000 ppm of NO results in methaemoglobinaemia and pulmonary oedema. Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema. Thrombocytopoenia Hypotension


PHARMACOKINETICS (PK)
PK: Absorption	highly lipid-soluble and diffuses freely across cell membranes

PK: Distribution	Little Systemic distribution after inhalation
Protein binding (PK: Distribution)	Highly protein bound
Volume of distribution (PK: Distribution)

PK: Metabolism	- Following inhalation, NO combines with oxyhaemoglobin that is 60–100% saturated, producing methaemoglobin and nitrate. - During the first 8 hours of NO exposure, methaemoglobin concentrations increase. - Nitric oxide also reacts with O2 to produce NO2

PK: Excretion	The main metabolite is nitrate (70%) which is excreted by the Kidneys.
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Half-life of <5 seconds.


SPECIAL POINTS	Benefits of inhalational route - Reduced systemic effects Delivery of drug to ventilated areas → selective vasodilation → improved V/Q

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CORTICOSTEROIDS

Pharmacopeia - Corticosteroids

	HYDROCORTISONE	METHYLPREDNISOLONE	DEXAMETHASONE	FLUDROCORTISONE
GROUP	Glucocorticoid	Glucocorticoid	Glucocorticoid	Mineralocorticoid
CICM Level of Understanding	Level 2	Level 2	Level 2	Level 3

INTRODUCTION	Natural Dose Equivalence 25	Synthetic Dose Equivalence 4	Synthetic Dose Equivalence 0.75	Synthetic
USES	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. asthma 4. panoply of autoimmune disorders 5. eczema and contact sensitivity syndromes and 6. in leukaemia chemotherapy regimes and 7. for immunosuppression after organ transplantation	1. as replacement therapy in adrenocortical deficiency states and in the treatment of 2. allergy and anaphylaxis 3. hypercalcaemia 4. asthma 5. panoply of autoimmune disorders 6. some forms of red eye and 7. in leukaemia chemotherapy regimes and 8. for immunosuppression after organ transplantation.	1. as replacement therapy in congenital adrenocortical deficiency states and in the treatment of 2. allergic disorders 3. asthma 4. many autoimmune and rheumatologic disorders 5. eczema and contact sensitivity syndromes and 6. leukaemia and lymphoma chemotherapy regimes and 7. immunosuppression after organ transplantation 8. palliative treatment of tumours 9. prevention of post-operative and chemotherapy-induced nausea and vomiting 10. ophthalmic inflammatory diseases 11. acute exacerbations of inflammatory bowel disease 12. acute severe skin diseases 13. cerebral oedema 14. bacterial meningitis—prevents hearing loss 15. tests for Cushing’s syndrome 16. hypercalcaemia of malignancy, sarcoidosis, and vitamin D toxicity 17. antenatal use in preterm labour 18. myasthenia gravis 19. autoimmune renal disease and 20. has been used for epidural injection.	used to treat adrenocortical insufficiency and salt-losing adrenogenital syndrome.


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	10/20mg tablets White lyophilized power to be mixed in water Other topical preparations	White powder – mixed with water	0.5/2mg tablets Oral solution Vials – white powder	100mcg tablets


PHARMACODYNAMICS (PD)
PD: Main Action	Anti-inflammatory	Anti-inflammatory	Anti-inflammatory	To replace endogenous aldosterone
PD: Mode of Action	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins	Bind to mineralocorticoid receptors → Renal: ↑ Na resorption, K excretion lipid solubile → crosses cell membranes → bind to steroid receptors via “zinc finger” binding site → signal trascribed via second messenger → alters gene transcription and the production of proteins
PD: Route & Doses	PO,TOP, IV, IM, IA	PO,TOP, IV, IM, IA, epi	PO,TOP, IV, IM, IA	PO
PD: Metrics (Onset/ Peak/ Duration)	Dur: 8-36h	Dur: 12-36h	Dur: 36-54h	Dur: 3-5 days
PD: Effects	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	1. Metabolic effects ▪ ↑’s gluconeogensis ▪ ↑ protein catabolism and lipolysis → muscle wasting and thin skin and fat redistribution (cushingoid) ▪ ↑ bone catabolism → osteoporosis ▪ ↑ glucose release but ↓ absorption from the GIT 2. Anti inflammatory effects ▪ ↓’d phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins 3. Immunosupression ▪ ↓’d inflammatory mediators ▪ ↓ IL 1-2 → ↓’d lymphocyte prod ▪ altered neutrophil and macrophage function	- sodium and water retention (aldosterone like) - inc Na reabsorption on distal tubles, K+ and H+ excretion Glucocorticoid action: Metabolic, Anti-inflammatory effects, Immunosuppresion
PD: Side Effects / Toxicity	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels Inhaled: oral candidiasis (poor technique), dysphonia, minor adrenal suppresion	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels	▪ Adrenal supression via negative feedback on the HPA ▪ Fluid retention - via weak mineralcorticoid activity ▪ Vascular reactivity - plays a permissive role in the actions of catecholamines on vessels	GI disturbances Weight gain Allergy


PHARMACOKINETICS (PK)
PK: Absorption	IV Rapidly given PO or PR PO BA: 50%	IV	IV PO BA 80-90%	Rapid and complete

PK: Distribution
Protein binding (PK: Distribution)	CBG 70%, Alb 20%	80%	70%	70-80% (Albumin, Corticosteroid binding Globulin)
Volume of distribution (PK: Distribution)	0.5 L/kg	Low	Low	80-85 L

PK: Metabolism	Liver – Tetrahydrocortisone	Liver	Liver – CYP3A4	Liver – CYP3A - 2 main metabolites

PK: Excretion	Urine	Urine	Urine	80% urine 20% feces
- Clearance (PK: Excretion)	167-283 ml/min			40 L/h
- Half Life (PK: Excretion)	0.5-1.5h	2-4h	3.5-5h	18-36hrs


SPECIAL POINTS Glucocorticoid Action Mineralocorticoid Action Duration	100 1 Short	20 Min Intermediate	4 Min Long	15 150 Long

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Y01. Pharmacopeia: Respiratory Pharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLE (excluding Corticosteroids)

Pharmacopeia - Resp

INDIVIDUAL TABLES

ASTHMA DRUGS

Pharmacopeia - Resp

SALBUTAMOL

Pharmacopeia - Resp

SALBUTAMOL vs IPRATROPIUM

Pharmacopeia - Resp

OXYGEN

Pharmacopeia - Resp

AMINOPHYLLINE

Pharmacopeia - Resp

INHALED PULMONARY VASODILATORS

Pharmacopeia - Resp

INHALED NITRIC OXIDE

Pharmacopeia - Resp

CORTICOSTEROIDS

Pharmacopeia - Corticosteroids

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