Y02. Pharmacopeia: Cardiovascular Pharmacology

SYLLABUS (Fourth Edition, 2023)

LEVEL 1	LEVEL 2	LEVEL 3
Adrenergic Drugs
Adrenaline (Epinephrine)	Ephedrine	Dopamine
Noradrenaline	Metaraminol	Dobutamine
		Isoprenaline / Isoproterenol
		Phenylephrine
Non-Adrenergic Drugs
Phosphodiesterase II inhibitors – Milrinone		Calcium Sensitisers – Levosimendan
Vasopressin
Antiarrhythmics
Amiodarone	Adenosine	Beta Blockers – Not listed before
Atropine		Calcium channel antagonists – Verapamil
Magnesium		Digoxin
Sodium channel antagonists – Lignocaine		Sodium channel antagonists – Flecainide
		Sotalol
	Antihypertensive Drugs
	Glyceryl Trinitrate	ACE inhibitors
	Sodium Nitroprusside	Alpha blockers – Prazosin
	Mixed antagonist – Labetalol	Angiotensin receptor blockers
	Beta-blockers – Esmolol	Beta blockers – not listed before
		Calcium channel antagonists – Non-dihydropyridines and Dihydropyridines
		Centrally acting drugs – Clonidine
		Hydralazine
		Mixed antagonists – Carvedilol

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 TABLES	Adrenergic and Non-Adrenergic Drugs
	Central Antihypertensives
	Adrenoreceptor Antagonists
	Direct Vasodilators (including Calcium Channel Blockers)
	ACE Inhibitors and Angiotensin Receptor Blockers
	Diuretics
	Antiarrhythmics
	Antidotes
INDIVIDUAL TABLES (New Pages)	Page 1
	Page 2

MASTER TABLES

ADRENERGIC AND NON-ADRENERGIC DRUGS

Pharmacopeia - Adrenergic and Non-Adrenergic Drugs

	ADRENALINE EPINEPHRINE	NORADRENALINE NOREPINEPHRINE	DOBUTAMINE	DOPAMINE	ISOPRENALINE ISOPROTERENOL	METARAMINOL	EPHEDRINE	PHENYLEPHRINE	ARGIPRESSIN VASOPRESSIN	MILRINONE	LEVOSIMENDAN
GROUP	ADRENERGIC	ADRENERGIC	ADRENERGIC	ADRENERGIC	ADRENERGIC	ADRENERGIC	ADRENERGIC	ADRENERGIC	NON-ADRENERGIC	NON-ADRENERGIC	NON-ADRENERGIC
CICM Level of Understanding	Level 1	Level 1	Level 3	Level 3	Level 3	Level 2	Level 2	Level 3	Level 1	Level 1	Level 3

INTRODUCTION	Is a naturally occurring catecholamine released in the adrenal medulla	Is a naturally occurring catecholamine released in post ganglionic SNS, medulla (20:80 Adr)	synthetic catechol derivative of isoprenaline	natural catecholamine released in certain cells in the brain and interneurons of the autonomic ganglia, dopamine is not converted to noradrenaline and is released as a neurotransmitter	synthetic catecholamine which used primarily for its beta agonist properties.	synthetic noncatecholamine with both direct and indirect sympathomimetic actions.	Synthetic direct and indirect sympathomimetic with alpha and beta activity	synthetic sympathomimetic amine with alpha1 agonist effects and no beta effects.	Is a naturally occurring nonapeptide-9AA. Produced hypothal. released by the posterior pituitary. similar to oxytocin complex molecule wt	selective phosphodiesterase inhibitor	Ca sensitizer and PDE-III inhibitor selectively
USES	1. Anaphylaxis 2. Cardiac arrest 3. Low cardiac output states (including complete heart block) 4. Severe asthma 5. Glaucoma 6. Local vasoconstriction 7. Adjunct to local anaesthetic to prolong duration of action	Used to treat hypotension due to decreased SVR	1. Inotropic support in low cardiac output secondary to MI, cardiac surgery, cardiomyopathy 2. Cardiac stress testing	primarily for improving haemodynamic parameters and increasing urine output	In Australia-indicated in heart block, unstable bradycardia and as an adjunct in cardiogenic, septic or hypovolaemic shock.	short term correction of BP in the setting of regional anaesthesia and off label for short term BP correction	1. Hypotension during surgery 2.Nocturnal enureisis 3. Diabetic autonomic neuropathy 4.Hiccups 5. Nasal decongestant	1. hypotension occurring during general or spinal anaesthesia 2. as a nasal decongestant and 3. as a mydriatic agent	Catecholamine sparing drug in shock Diabetes insipidus Bleeding in vWF def / mild haemophilia	used in severe refractory heart failure and for short periods post cardiac surgery	short term management of severe acute heart failure


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	IV,Neb. in clear sol, Vials 1mg/mL in 5 and 50 mL, Minijets with 1mg in 10mL(1:10000). With Lignocaine (1:80000-200000). In acidic sol as turns pink in alk(oxid to Adrenochrome)	injectable solution only, 1mg/mL in 2 mL vials diluted in 5D or NS. CVC only due to risk of extravasation associated necrosis	Is a racemic mixture. White powder for reconstitution(250mg) or Clear fluid 12.5mg/ml in 20ml vials. Should not be mixed with alkaline solutions (HCO3)	Inj-clear liquid 40mg/mL in 5 mL vials. CVC only(necrosis). Not with alk solns such as NaHCO3	injectable form only, in concentrations of 200mcg/mL, in 1 and 5ml vials Available as MDI though no longer used for reversible airway constriction due to increased mortality	clear solution 10mg/mL in one mL vials and usually diluted to 10mg in 10ml or 20ml	- Clear colourless solution for injection (3-9mg slow injection, dose repeated ever 3-4 min) - Oral tablets - Nasal spray	clear solution containing 10 mg/ml of phenylephrine hydrochloride.	measured in international units 20 IU/ml vial requiring dilution for eff¬ective delivery. It cannot be given orally as it is inactivated by trypsin	is a yellow solution, stored at room temperature, should not be given with HCO3 or frusemide pKA of 9.67 and pH of 6.35	in IV form only - clear yellow solution 2.5mg/mL in 5 and 10ml vials


PHARMACODYNAMICS (PD)
PD: Main Action	It is a non selective adrenergic agonist. Mast cell stabilizer (anaphylaxis)	Alpha and beta adrenergic receptor activity	the + enantiomer is a potent α1 antagonist and β1 agonist, the -ve enantiomer has opposite effects on α1 causing agonism and is less potent (10%) β1 agonist.	acts centrally as a neurotransmitter and peripherally it has natriuretic and diuretic properties.	β1,2 agonist.	both direct and indirect sympathomimetic actions. It acts mainly via alpha1/2 adrenoceptors to cause vasoconstriction but also has some minor beta activity.	alpha and beta activity	Peripheral vasoconstriction	Acts at the GPCR Vasopressin receptors	PDEIII Inhibition: Improves myocardial contractility, vasodilation	Increases Myofilament Ca sensitivity, vasodilation
PD: Mode of Action	- Adrenaline is a natural catecholamine with alpha and beta effects. At low doses, beta 1 and beta 2 effects predominate. At high doses alpha 1 effect predominate. - Alpha1- GqPCR → stimulates phospholipase C → increased IP3/DAG → increased intracellular calcium and smooth muscle constriction - Beta1 and 2 → GsPCR → increased adenylate cyclase → increased cAMP → increased phosphorylation	- Acts primarily directly at alpha-1-adrenoreceptors (phospholipase C → IP3 → increased calcium) - To a lesser extent acts on beta 1>beta 2 effects	Predominant mechanism is via direct acting B1 stimulation (increased cAMP) and retains a small amount of B2 effects	α, β + dopamine (D1 and D2) receptors via Gs and Gi coupled adenylyl cyclase leading to increased or decreased levels of cAMP. 1. Low doses (1-5mcg/kg/min) dopamine acts on dopamine receptors. D1 increases cAMP. 2. At moderate doses (5-10mcg/kg/min) acts via direct and indirect stimulation of alpha and beta receptors- beta predominates 3. High doses (>15mcg/kg/min) alpha effects predominate	β1,2 agonist. ↑HR, inotropy (beta1), and tends to maintain SBP but ↓DBP due to ↓TPR (beta2). Potent bronchodilator but worsen V/Q matching (withdrawn due to ↑mortality). CNS stimulant. ↑Splanchnic and renal perfusion due to vasodilation (beta2)	through ↑TPR May be transient bradycardia due to baroreceptor feedback upon infusion initiation. ↑Pulmonary vascular resistance. ↑coronary artery flow by an indirect mechanism (stimulates NA release)	direct and indirect sympathomimetic with alpha and beta activity	direct-acting sympathomimetic agent that has agonist effects at alpha-1 adrenoceptors. The drug does not affect beta-adrenoceptors.	Acts at the GPCR Vasopressin receptors V1 on vascular smooth muscle Inc intracellular Ca conc, vasoconstrictive V1 on platelets increase platelet aggregation V2 on the nephron Aquaporin-2 trafficking from intracellular vesicle membrane – allowing water reabsorption V2 on endothelial cells – allow vWF release that prevents breakdown of factor VIII V3 (prev V1b) on pituitary Contribute to ACTH release	Via selective PDE3 inhibition which causes decreased cAMP breakdown intracellularly and hence increased Ca This improves myocardial contractility and improves cAMP-dependent protein phosphorylation leading to vascular smooth muscle relaxation.	i) ↑myofilament Ca sensitivity by binding to Cardiac trop C in Ca-dependent manner. ii) Vasodilation through opening of ATP-sensitive K channels iii) selective PDE-III inhibition at higher conc - inotropy
PD: Route & Doses	1. 1mg in PEA arrest IV 2. Infusion of 0.01-0.1micrograms/kg/min 3. 10mcg/kg (up to 500mcg) IM 4. Nebulizer or MDI	IV infusion- 0.05-0.5mcg/kg. Through a central line diluted with glucose or saline.	IV Infusion Dose range 0.5-40mcg/kg/min. Response within 2 minutes	IV Infusion As above	IV infusion. Dose 0.5-8mcg/min	IV boluses or infusion	IV 3-6mg bolus	SC/IM: 2-5mg IV: 50-100mcg boluses	IV infusion 0.01–0.04 units/min	IV 50mcg/kg loading dose over 10min (optional) 0.375mcg/kg/min-0.75mcg/kg/min	IV, loading dose of 6 to 24 mcg/kg over 10 minutes then continuous infusion of 0.05-0.2 mcg/kg/min
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	lower doses: β2 - vasodilatory, bronchodilation Higher doses β1 agonism: ↑ino+chronotropy Highest doses: primarily a vasoconstrictor. Detail: CVS: - At low dose infusions (beta predominates), beta 2 effects lead to skeletal muscle vasculature vasodilation, leading to a decrease in DBP and SVR. It also causes coronary artery vasodilation. - Beta-1 leads to increased inotropy, increased chronotropy (increases phase 4 gradient), and increased dromotropy. It increases myocardial oxygen consumption and lowers arrhythmia threshold - At higher doses, alpha 1 effects predominate. This causes arteriolar vasoconstriction, which may increase aortic diastolic BP and therefore increase coronary perfusion pressure (e.g. arrest). At these doses it also increases coronary artery vasoconstriction. Venous return may be enhanced as capacitance vessels constrict - Extravasation may cause tissue necrosis and injection into end arteries may lead to digital ischaemia CNS: - May cause anxiety, tremor and raises pain threshold. Causes mydriasis Resp: - Small increase in MV. Potent bronchodilator - PVR increased Renal: - Decreased renal blood flow. Renin stimulation → increased aldosterone and potassium secretion - Decreases plasma volume - Increased bladder sphincter tone, may lead to difficulty of micturition GIT: - Decreased hepatosplanchnic flow. May lead to decreased lactate clearance - Relaxation of gastrointestinal smooth muscle, leading to increased transit times Haem: Coagulation is accelerated by adrenaline. Induces platelet aggregation and increases factor V activity Metabolic - Increases BMR - Increases glycolysis (liver and skeletal muscle) and gluconeogenesis. Alpha1 effects suppress insulin secretion. Causes hyperglycaemia and lactic acidosis. - Lipase activity is augmented, leading to increased lipolysis and keto-acidosis - B2 stimulates Na/K/ATPase, lowering K+. B1 activates RAAS, which leads to aldosterone increasing K+ secretion	Low doses: β - ↑ino+chronotropy increased MVO2 Higher doses: 1 - peripheral vasocontriction. ↑systolic/diastolic pressures may cause reflex bradycardia Detail: CVS - Increased SVR leading to increased SBP/DBP/MAP - Increased afterload - leading to increased myocardial oxygen consumption, slight decrease in cardiac output and may lead to reflex bradycardia (through beta-1 effects limit this) - Coronary artery vasodilation increased coronary O2 delivery - Pulmonary vascular resistance is increased - Excessive doses may lead to limb or organ ischaemia - Extravasation may lead to tissue necrosis CNS - Generally improves cerebral blood flow by way of improved CPP more than it decreases CBF by cerebral vasoconstriction Renal/GU - Decreases renal blood flow - Causes uterine constriction (may lead to fetal asphyxia) GIT: - Decreased splanchnic blood flow Metabolic - Less hyperglycaemia/acidosis, although it may decrease insulin secretion	composite of α and β actions. Mostly β1 effect: ↑ ino+ chrono tropy and MVO2. Mild β2 eff¬ects. Detail: CVS - Beta1 effects lead to increased SA node activation (increased chronotropy), increased dromotropy and increased inotropy, thereby increasing cardiac output (inotropy greatest) - Coronary artery vasodilator - Beta-2 activity tends to decrease LVEDP and SVR, contributing to increased CO and cardiac index - Increased MVO2 - Increased risk of arrhythmias (especially at doses >10mcg/kg/min) - Should be avoided in patients with cardiac outflow obstruction (AS, tamponade) Resp - Modest pulmonary vasodilation - Inhibits HPV Renal- Increased RBF due to increased CO may occur	1. CVS - At lower doses it primarily acts on beta1 receptors to increase HR and contractility. Acts indirectly to increase endogenous noradrenaline release. - At higher doses alpha effects predominate which increases SVR - Less arrhythmogenic than adrenaline 2. Resp - Attenuates carotid bulb chemo-R to hypoxia - Increased PVR 3. GIT - Vasodilates mesenteric vessels via D1-R - Increased GIT transit time 4. Renal - Increased RBF - Inhibits proximal sodium reabsorption leading to increased UO 5. CNS - Modulates EPS and inhibits prolactin secretion from pituitary. Cannot cross BBB 6. Miscellaneous - CTZ stimulation leads to N/V	CVS - Power inotrope, chronotrope and dromotrope leading to increased cardiac output - Beta-2 effects decrease SVR leading to a decrease in DBP - Increased myocardial O2 consumption, and a decrease in diastolic time and aortic DBP may significantly decrease delivery. Increased coronary arterial vasodilation may offset this effect - Increased automaticity CNS - CNS stimulant Resp - Potent bronchodilator - Worsens dead space and may cause hypoxia Renal - Reduces renal blood flow in non-shocked states - Uterine relaxation GIT - Decreased GIT tone and motility Metabolic - Lipolysis and hyperglycaemia - Inhibits histamine release	CVS: - Increased SVR leading to an increase in diastolic and systolic BP - Reflex bradycardia may occur despite B1 effects - It has positive inotropic effects but cardiac output is more likely to decrease as a result of increased afterload - Coronary artery blood flow increases as an indirect mechanism - Increased PVR CNS: - Doesn’t cross BBB - Causes cerebral vasoconstriction but increases CPP Renal/GU - Renal vasoconstriction but re-established renal perfusion pressure in hypotension - Uterine contraction and reduces uterine blood flow Metabolic - Inhibits insulin release and increases lipolysis - May increase VO2	1. CVS - Effects similar to adrenaline but longer duration as drug is not metabolized by MAO or COMT - Positive inotrope, chronotrope. Increases CO MVO2 - Increases coronary blood flow - Increased SVR and PVR 2. Resp - Respiratory stimulant - Bronchodilation 3. CNS - Stimulatory effect similar to amphetamine - Cerebral blood flow increases - Mydriasis occurs - Has local anesthetic effects 4. GIT - Relaxes GI smooth muscle - Splanchnic vasoconstriciton 5. GU - Decreased RBF - Contracts bladder sphincter and relaxes detrusor muscle- acute urinary retention - Does not cause uterine constriction 6. Metabolic - Increased hepatic glycogenolysis - Increased BMR	CVS Phenylephrine causes a rapid increase in the systolic and diastolic blood pressures due to an increase in the systemic vascular resistance. A reflex bradycardia occurs, which may cause a decrease in cardiac output. RS The drug is not known to cause bronchodilatation or act as a respiratory stimulant. CNS Phenylephrine has no stimulatory effects on the CNs. Phenylephrine causes mydriasis. GU The drug reduces uterine artery blood flow via its effect at alphaadrenoceptors. Renal blood flow is decreased. Metabolic/other The drug may cause alterations in glucose metabolism.	CVS: - in the presence of shock, vasopressin causes an increase in MAP and SVR via its vasoconstrictor effect. - In low doses it causes vasodilation in certain vascular beds in animal models. - It causes pulmonary vasodilation in hypoxic and physiological conditions. GU: a reduction in urine output and polydipsia is seen following administration in DI GIT: Gastric smooth muscle contraction Other: Increase in vWF and Factor 8 can be detected	CVS - Positive inotrope, leading to increased cardiac output. CI increases 30% - PCWP decreases 20%, with improved lusotropy - SVR and MAP decrease - May increase AV nodal conductance, accelerating arrhythmias in atrial fibrillation or flutter Resp: Decreased PVR GU: UO and GFR may increase in response to increased CO	CVS: - Increased cardiac output without increasing MVO2 - Causes coronary and peripheral vasodilation → anti-ischaemia and anti-stunning effects GU: Increased GFR and UO secondary to increased CO
PD: Side Effects / Toxicity	High doses: HTN+++, tachyarrhythmias, deranged metabolic States: ↑ glucogenolysis, lipolysis, gluconogenesi Insulin Prodxn: initial ↑ (β2) → ↓ (α) limiting use in DM. Can worsen PHTN. Avoid in glaucoma. Peripheral necrosis.	Excessive doses cause severe hypertension Reduced flow to organs splanchnic renal Issues with increased MVO2 and IHD	1. Arrhythmias (especially at doses >10mcg/kg/min) 2. Arrest in fixed output patients (AS, tamponade) 3. Increased MVO2 4. Eosinophilic myocarditis in prolonged infusion	Needs adequate fi-lling prior to initiation of therapy. At very high doses it may cause peripheral tissue necrosis due to vasoconstriction. May cause vomiting CTZ activation. Caution with MAO inhibitors	contraindicated in tachycardia, and may worsen ischaemia due to increased MVO2. May cause hypoxia due to a worsening of V/Q matching. Tachyphlaxis may occur in prolonged use.	Caution should be exercised in patients with pulmonary hypertension. May cause severe hypertension in some patients	Insomnia, anxiety, tremor, headache, dysrhythmias, nausea and vomiting, and chest pain irritant to mucous membranes Acute hypertensive crisis with: MAOIs, doxapram, beta-blockers, oxytocin, and ergot alkaloids	Headaches, sweating, hypersalivation, tremor, and urinary retention. Extravascular injection of the drug may lead to tissue necrosis. Hypertension with MAOIs. Dysrhythmias with cardiac glycosides, TCAs, Quinidine.	Hyponatraemia with H2O retention May cause severe vasoconstriction -CVC only Arrhythmias at higher doses GIT smooth muscle constriction cramping, nausea, diarrhoea	may be proarrhythmogenic causing SVT and VT. Have been shown to worsen outcomes in acute on chronic heart failure	Interference with potassium channels causes an increase in the QTc- theoretical ↑risk of arrhythmias. May cause hypotension. Caution should be exercised in patients with renal or hepatic impairment.


PHARMACOKINETICS (PK)
PK: Absorption	IV, IM, SC, Inhaled, ETT 1mg arrest, 0.1mg anaph. Inf: β effects: 0.1-0.3mcg/kg/min α: >0.3 (vasocon). on/dur imm/1-2min	IV only Clear Solution 1:1000 8-12 mcg/min uptitrated to effect onset / duration immediate / 1-2 minutes	IV, dose starts at 5mcg/kg/min uptitrate to e¬ffect, max 40mcg/kg/min	IV. BA 100%. commence @ 2.5 mcg/kg/min-max 60mcg/kg/min onset / dur 5 min/10min	IV. BA 100% 20mcg bolus or 0.5-10mcg/min onset / dur IV imm / 10-15 mins	IV. BA 100% 0.1-0.2mg boluses titrated to BP onset / dur imm / up to 20 mins	- Rapidly absorbed orally	no quantitative data available	IV only	IV only	IV only

PK: Distribution	doesn’t cross the BBB	doesn’t cross the BBB	Small vd	does not cross the BBB	65% protein bound	limited data on pharmacokinetics	- Widely distributed and crosses BBB, placenta and breast milk	no quantitative data available	limited data	small vd	small vd
Protein binding (PK: Distribution)					65% protein bound				No PB		98% protein binding. Peak concentration after 48 hrs
Volume of distribution (PK: Distribution)			0.2L/kg						0.14 L/kg	0.4 L/kg	0.2 L/kg

PK: Metabolism	Taken up into adrenergic neuron – Metabolized by MAO and COMT Circulating drug hepatically metabolized	Rapidly metabolised into adrenaline by MAO (Uptake 1, Nv terminal) COMT (Uptake 2 circulation) 25% removed in the lungs	via COMT then gluruonidation hepatically	Renal, hepatic, plasma by COMT and MAO; 75% to inactive metab and 25% to norad	Via conjugation in many tissues including hepatic and pulmonary	Hepatic	- Resistant to MAO and COMT. Hepatic metabolism with a major metabolite being active and may have central effects	in the gastrointestinal tract and liver by monoamine oxidase	Metabolised by peptidases (Vasopressinases) to amino acids	minimally hepatic	Intestinal bacteria OR1896 active metabolite Hepatic conjugation

PK: Excretion	Urine as inactive metabolites	urine as inactive metabolites (84-96%)	urine as inactive metabolites	Urine (as metabolites)	Urine (1° as sulfate conjugates)	Unknown	- 50-90% excreted unchanged in urine. Urinary elimination is pH dependent (enhanced by acidic urine) - Tachyphylaxis rapidly occurs	no quantitative data available	65% unchanged in urine	excretion is in the urine, mostly as unchanged drug, dose adjustment in renal failure	excretion renal and fecal. Cardiac Effects 2-7 days
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	2 minutes	2 minutes	2 minutes	2 minutes	2.5-5 minutes	short	Elimination T1/2 is 6 hours		10-35 mins	2 hours	1 hour (70hr for active metabolite)


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CENTRAL ANTIHYPERTENSIVES

Pharmacopeia - Central Antihypertensives

	DEXMEDETOMIDINE	CLONIDINE	METHYLDOPA
GROUP	Central Antihypertensive	Central Antihypertensive	Central Antihypertensive
CICM Level of Understanding	-	Level 3	-

INTRODUCTION	Central alpha2 agonist Greater selectivity for A2 than clonidine	partial alpha agonist with an affinity for alpha2 receptors 200 times that for alpha1 receptors	Central alpha2 agonist exerts its antihypertensive action via an active metabolite.
USES	1. Sedation 2. Analgesia 3. Delirium prevention and management 4. Withdrawal syndromes 5. Perioperative sympatholytic	- refractory hypertension - adjunct in pain management and during anaesthesia - in patients withdrawing from opiods - diagnosis of phaechromocytoma	significant adverse effects currently limit its use - used in treatment of hypertension in pregnancy, where it has a record for safety


PHARMACEUTICS (PC)
PC: Chemical	D-stereoisomer
PC: Presentation	Clear, colourless solution IV only in Aus (PO overseas) Comparitively expensive	both in oral form as a white tablet in dosages of 100-150mcg and IV/IM forms as a colourless solution with 150mcg/ml	oral formulation in Australia in 250mg tablets


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Specific alpha-2 agonist acting primarily in the locus coeruleus to increase conductance through K+ channels. 8 times more selective than clonidine. Acts on all 3 subtypes of alpha-2R (A, B, C)	useful effects of clonidine rest on its ability to stimulate alpha2 receptors in the lateral reticular nucleus resulting in decreased central sympathetic outflow by a positive feedback mechanism, and in the spinal cord where it augments endogenous opiate release and modulates descending noradrenergic pathways.	Its metabolite produces a clonidine like alpha2 agonist effect in cardiovascular control centres that results in reduced sympathetic outflow. The metabolite also acts as a false neurotransmitter reducing peripheral SNS effects by reducing noradrenaline synthesis.
PD: Route & Doses	IV Infusion Dose: 0.3-1mcg/kg/min	PO/IV/IM doses usually 150-300mcg twice daily	PO doses 125-250mg BD titrated
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CNS - Decreased sympathetic activity - Decreased agitation - Induces state resembling non-REM sleep without impairment of cognitive function. Easily roused but sedated. - Analgesia produced in the posterior horns of the spinal cord, reduces need for opioid analgesia - Decreases circulating cerebral catecholamines - Decreases CBF/CMRO2/Mild decrease in ICP - Decreases shivering CVS: Decreased MAP and HR Resp: Clinically insignificant increase in PaCO2 and decrease in RR	CVS - transient increase in BP due to alpha2 agonism peripherally but this is followed by a more prolonged fall in BP. - CO is usually maintained despite bradycardia. CNS - sedation and anxiolysis at low doses but anxigenic at higher doses. - Provides analgesia without respiratory centre depression and is synergistic with opiods. Renal - inhibition of ADH may be the cause of diuresis. Endocrine - stress response to surgery inhibited. Insulin release in reduced, usually BSL ok	It is primarily used to depress overall SNS activity (HR, BP and TPR) but can also cause sedation, psychosis and depression
PD: Side Effects / Toxicity	- Transient hypertension (due to peripheral smooth muscle α2B agonism) -> reflex bradycardia Later, hypotension and bradycardia. Rebound HTN on ceasing dose - Dry mouth - nausea	- multiple effects of this drug make it intolerable to many patients, with somnolence and dry mouth being a frequent concern. - It may cause profound bradycardia if used with beta blockers. - If withdrawn suddenly it may cause a rebound hypertension	- Sedation, decreased mental acuity and depression may occur. - Dry mouth is also a problem. - A small percentage of patients develop hepatotoxicity or a haemolytic anaemia.


PHARMACOKINETICS (PK)
PK: Absorption	Without loading dose (commonly not used because of bradycardia), 30 minutes to reach effective concentration	bioavailabilty Immediate release: 75% to 85% routes of administration Oral, IV and IM	bioavailabilty absorded by an amino acid transporter (% ?) routes of administration oral onset of action 3-6 hours, duration 24 hours (this is becuase of the prolonged process in substituting for noradrenaline in peripheral sites)

PK: Distribution	Lipid soluble (rapid distribution)	lipid solubility highly lipid soluble in order to cross the BBB
Protein binding (PK: Distribution)	95%	20% to 40%	<15%
Volume of distribution (PK: Distribution)	2l/kg (steady state)	2.1 L/kg

PK: Metabolism	Hepatic via CYP and glucuronidation inactive metabolites	Extensively hepatic to inactive metabolites	mechanism Intestinal and hepatic

PK: Excretion	Inactive metabolites Excreted in urine	Urine (40% to 60% as unchanged drug)	Urine (85% as metabolites) within 24 hours
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Large variation in CSHT with infusion length (T1/2 5 minutes after 10 minutes IV, T1/2 240 minutes after 8 hour IV)	12-16 hours (increased in pts with renal disease)	75-80 minutes (extended in renal failure)


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ADRENORECEPTOR ANTAGONISTS

Pharmacopeia - Adrenoreceptor Antagonists

	PRAZOSIN	PROPRANALOL	ESMOLOL	ATENOLOL	METOPROLOL	LABETALOL	CARVEDILOL
GROUP	Alpha Blocker	Beta Blocker	Beta Blocker	Beta Blocker	Beta Blocker	Mixed alpha and beta blocker	Mixed alpha and beta blocker
CICM Level of Understanding	Level 3	Level 3	Level 2	Level 3	Level 3	Level 2	Level 3

INTRODUCTION	highly selective alpha1 blocker	non-selective Beta Blocker with no intrinsic sympathomimetic activity.	Cardio-selective beta blocker with rapid onset and offset.	Cardio-selective beta blocker	relatively selective beta blocker with no intrinsic sympathomimetic activity.	an alpha 1 blocker and a non selective beta blocker.	third generation non selective beta blocker with alpha 1 antagonist properties.
USES	- essential hypertension - congestive heart failure - raynaud’s - benign prostatic hypertrophy	- Hypertension - Angina - essential tremor - haemodynamically stable oesophaegeal varices - migraine prophylaxis - Treatment of choice in thyrotoxicosis as it treats the effects and prevents conversion of T4 to T3.	- Short term management tachycardia and hypertension in a monitored patient - For SVT termination - No intrinsic sympathomimetic activity or membrane stabilising properties	1. hypertension 2. angina 3. tachydysrhythmias, and 4. in the acute phase of myocardial infarction and prevention of reinfarction.	- Early use of metoprolol in haemodynamically stable myocardial infarction reduces infarct size and incidence of VF. - rate control in atrial fibrillation - hypertension	- Used in the setting of an acute hypertensive crisis - Pregnancy related hypertension	- used to reduce the excessive adrenergic activity that occurs in response to heart failure. - hypertension


PHARMACEUTICS (PC)
PC: Chemical		Racemic mixture with S-isomer confers most effects, R-isomer stops T4 to T3 conversion.				It is a racemic solution with four stereoisomers present in equal proportions. The SR isomer is likely responsible for the alpha blocking effects and the RR isomer for the betablockade
PC: Presentation	presented as 0.5 - 2mg tablets	PO, IV PO: May be enterically coated. sustained release 60-160mg. Immediate release 10-80mg. IV: significantly smaller due to extensive first pass metab - 20mg/5ml.	only available as an IV formulation. presented as a clear liquid usually at a concentration of 10mg/ml	As 25/50/100 mg tablets (and in fixed-dose combinations), a 0.5% syrup, and as a clear, colourless solution for injection containing 0.5 mg/ml of atenolol.	available in oral form as an immediate release or sustained release in increments of 25mg. It is also available as an IV formulation usually 1mg/ml	available as a 50-400mg tablets and as a colourless solution containing 5mg/ml.	oral form in both immediate and sustained release formulations


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Alpha blockage leads to ↓ Gq activation and subsequent ↓in IP3 and intracellular Ca2+	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓in adenylyl cyclase and intracellular Ca2+.	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓in adenylyl cyclase and intracellular Ca2+.	Atenolol acts by reversible, competitive blockade of cardiac beta-1 receptors and also has some action at beta-2 receptors.	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓in adenylyl cyclase and intracellular Ca2+.	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓in adenylyl cyclase and intracellular Ca2+. Alpha blockage leads to ↓ Gq activation and subsequent ↓in IP3 and intracellular Ca2+	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓in adenylyl cyclase and intracellular Ca2+. Alpha blockage leads to ↓ Gq activation and subsequent ↓in IP3 and intracellular Ca2+
PD: Route & Doses	oral doses commenced at 0.5mg TDS then uptitrated	oral or IV doses PO up to 320mg, IV 0.5mg - 10mg titrated to effect	IV dose In 10mg increments titrate to effect	PO Dose 50-100mg daily IV 2.5-10mg, may be administered at a rate of 1mg/min	PO or IV dose Orally in 12.5mg increments, IV in 1-2mg boluses	IV and oral doses IV in 20mg pushes, oral for HTN 100-400mg BD	oral doses start at 6.25 BD and doubled 1/52 until not tolerated
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	CVS: peripheral arterial and venous vasodilation and subsequent decrease in TPR but little or no reflex tachycardia (diastole decreases the most). GU: bladder trigone and sphincter muscle relaxation which is useful in BPH (Tamulosin is also an alpha1 blocker). CNS: - syncope and headaches may occur due to rapid BP decrease.	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption	CVS: - decreased sinus node automaticity and AV node conduction - Negative inotropic and chronotropic effects – decreased MVO2 - prolonged antihypertensive effect Metabolic: inc TG, and dec HDL-cholesterol	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. Whilst it does have some β 2 action it has little or no effect on these receptors at doses less than 100mg	β: It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. α: Peripheral vasodilation	β: It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. α: Peripheral vasodilation
PD: Side Effects / Toxicity	- May ppt orthostatic hypotension, syncope or vertigo. - It blunts the compensatory vasoconstriction in spinal and epidural anaesthesia and may cause profound hypotension. - Dryness of mouth is also a side-effect	- Rapid withdrawal should be avoided as it may precipitate tachycardia, HTN and/or ischaemia. - Care should be taken when used in conjunction with opioids and halothane and in patients with obstructive airway disease	- Care with: Opioids, Halo, OAD, CCB - It is an irritant to veins and may lead to tissue necrosis with extravasation	- exacerbation of peripheral vascular Disease - bronchospasm - masking of the signs of hypoglycaemia - depression - impotence - altered bowel habits	- Withdrawal - Care with: Opioids, Halo, OAD, CCB - Use with Ca Channel blockers may result in complete heart block	- Withdrawal. - Care with: Opioids, Halo, OAD, CCB - Due to its metabolism, it should be used in caution in liver failure patients and elderly	- Withdrawal. - Care with: Opioids, Halo, OAD, CCB - Due to its metabolism, it should be used in caution in liver failure patients and elderly


PHARMACOKINETICS (PK)
PK: Absorption	bioavailabilty 43% to 82% due to first pass metabolism	bioavailabilty - lipid soluble and well absorbed but has a high 1st pass metabolism leading to a bioavailability of 30%	bioavailabilty Only available as IV therefore 100%	Oral BA 50%	bioavailabilty Absoption is rapid and complete, however there is extensive first pass metabolism bioavailability = 50%	bioavailabilty complete absorption but high first pass metabolism results in bioavailability 25%	bioavailabilty rapid and extenisve absorption but high fi-rst pass metabolism leading to bioavailability of 25-35%

PK: Distribution		lipid solubility high lipid solubility	lipid solubility is high so it crosses the BBB		lipid solubility is high so it crosses the BBB	lipid solubility moderately lipid soluble, can enter CNS	lipid solubility moderate
Protein binding (PK: Distribution)	92% to 97%	90%	60% to albumin	3%	10-20% to albumin	50%	98% to albumin
Volume of distribution (PK: Distribution)	0.5 L/kg	4 L/kg	3.5 L/Kg	0.7 L/kg	5.5 L/Kg	3-16 L/kg	105 L/kg

PK: Metabolism	Extensively hepatic by demethylation and conjugation with some active metabolites	Hepatic via CYP2D6, and CYP1A2 to 4-hydroxypropranolol (active) and inactive comp	neither hepatic or renal! by red blood cell esterases to a mostly inactive metabolite	<10% metabolized in liver	hepatic or renal Extensively hepatic via CYP2D6	Hepatic, primarily via glucuronide conjugation	Extensively hepatic, via CYP2C9, 2D6, 3A4, three active metabolites

PK: Excretion	Mostly faeces, (6% to 10% as unchanged drug)	most metabolites are excreted in urine	urine	Urine - unchanged	urine 5-10% unchanged	Urine (60% as glucuronide conjugates, <5% as unchanged drug)	faeces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	2-3 hours	3-6 hours	10 minutes	6-9hrs	3-8hours	6-8 hours	7-8 hours


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DIRECT VASODILATORS
(including Calcium Channed Blockers)

Pharmacopeia - Direct Vasodilators incl. Calcium Channel Blockers

	VERAPAMIL	NIMODIPINE	NIFEDIPINE	DILTIAZEM	SODIUM NITROPRUSSIDE (SNiP)	GLYCERYL TRINITRATE (GTN)	HYDRALAZINE	MINOXIDIL
GROUP	(CCB) Ca channel blocker – Class I Antiarrhythmic – Vaughan Williams Class IV	(CCB) Ca channel blocker – Class II	(CCB) Ca channel blocker – Class II	(CCB) Ca channel blocker – Class III Antiarrhythmic – Vaughan Williams Class IV	Nitro	Nitro	Direct Vasodilator	Direct Vasodilator
CICM Level of Understanding	Level 3	Level 2	Level 3	Level 3	Level 2	Level 2	Level 3	-

INTRODUCTION	Phenylalkylamine (Non-dihydropyridine calcium channel blocker) Synthetic papaverine derivative	Dihydropyridine calcium channel blocker	prototypical dihydropyridine calcium channel blocker	Benzothiazepine (Non-dihydropyridine calcium channel blocker)	inorganic complex that acts as a prodrug. 5CN groups and 1NO group attached to Fe molecule covalently bonded to Na.	organic nitrate similar to isosorbide mononitrate and isosorbide dinitrate.	direct vasodilator whose mechanism of action is poorly understood.	direct vasodilator whose mechanism of action is poorly understood.
USES	HTN Angina Paroxysmal SVT and AFib/Aflutter	Treatment and prevention of cerebral vasospasm after SAH Also used in migraine, CVA and drug resistant epilepsy can pass the blood-brain barrier	primarily arterial vasodilatory e¬ffects with little effect on electrical conduction in the heart. Used primarily for HTN, angina and in preterm labour	It is used for angina and hypertension	used primarily to treat hypertensive emergencies but can also be used in many situations when short-term reduction of cardiac preload and/or afterload is desired	It is used for the treatment of Stable (and unstable) angina and acute pulmonary oedema.	sometimes used intravenously in the treatment of hypertensive emergencies, and in the management of severe hypertension associated with pregnancy	It is used primarily in severe refractory hypertension in combination with other antihypertensives Topical to treat baldness


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	Racemic mixture. PO: 40-240mg. Also in combo w Trandolapril. IV Clear solution at 2.5mg/ml	IV 200mcg/ml with ethanol and macrogol PO 30mg tablets	available in sustained and immediate release oral formulations, 10-60mg	sustained and immediate release oral formulations, 60-360mg	only available in injectable form. It is unstable and must be stored out of light and not in alkaline conditions or it rapidly degrades.	PO/SL/TD Patches Clear liquid with a conc 5mg/ml. IV: glass vial due to GTN being absorbed into some plastics.	PO 25-50mg IV 20mg powder for reconstitution and inj. Should not be reconstituted with 5% dex as this degrades the drug quickly.	10mg tablets Topical


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Binds to V binding site of L-type channel. Levoisomer: main effects (arterial vasodilation). Slows conduction through the AV and SA node to a greater extent than other CCBs. Dextro: Only acts on fast sodium channels, accounting for local anesthetic effects (1.6x potent as procaine)	Binds to N binding site of L-type Ca channel on vascular smooth muscle to reduce intracellular Ca.	Selectively dilates arterial resistance vessels. The ↓in arterial BP elicits sympathetic reflexes, with resulting tachycardia and positive inotropy.	Similar to the other Ca Channel blockers in terms of blood pressure.	The nitroso group (−N = O−) in sodium nitroprusside reacts with sulphydryl groups (–SH) in vascular smooth muscle, forming nitric oxide and nitrosothiol derivatives. Both metab stimulate guanylate cyclase, ↑cGMP levels and produce generalized relaxation of vascular smooth muscle (both arterial and venular dilatation)	MoA is same for inorganic nitrates although GTN must first combine with Thio containing compound to produce NO. NO activates guanylyl cyclase in smooth muscles which ↑cGMP leading to a ↓intracellular Ca and vasodilation. Venous > arterial dilation and the benefits in angina are believed to be related to decreased MVO2.	Poorly understood. It is possible that hydralazine activates guanylyl cyclase, increasing cAMP and decreasing Ca, causing vasodilation. NO may play a role. IP3 may be a second messenger involved.	Poorly understood. May be potassium channel activator) ↑hair production
PD: Route & Doses	40mgPO or 5-10mg IV.	60mg Q4h PO or 20mcg/kg/hr IV	PO 10-20mg BD.	PO/IV 30-80mg TDS	IV. 10-200mcg/min uptitrated to effect	400-800mcg SL, 5mg Top, 5-80mcg min uptitrated IV	PO 25-100mg BD PO, IV 5-10mg over 20mins, titrated	PO. doses 10-40mg PO daily
PD: Metrics (Onset/ Peak/ Duration)					on/dur onset <30 secs; peak effect 2 mins, effect disappears within 3 mins after the infusion is stopped	on/dur SL 1-3 mins / 25 mins. IV immediate/ 5mins	PO 25-100mg BD PO, IV 5-10mg over 20mins, titrated	PO. doses 10-40mg PO daily
PD: Effects	CVS: slow conduction of AP at SA and AV node, negatively inotropic, peripheral vasodilation (↓SVR), arrhythmia (heart block, VF in WPW). CNS: ↑CBF, may potentiate effects of depol/NDMBs. GIT - Constipn/Nausea	CVS: systolic and diastolic hypotension, 1mcg/kg/h → ↑CO+30% CNS: increases CBF+18% without steal, blunts cardiovascular responses to surgical stimulus/intubation	Thus, arteriolar resistance and blood pressure are lowered, contractility and segmental ventricular function are improved, and heart rate and cardiac output are modestly increased.	Produces more peripheral vasodilation than verapamil and more conduction delay than the dihydropyridines such as nifedipine	Equal Arterial and venous dilation Attenuates HPV in lungs Increases ICP due to increase in CBF Renal blood flow maintained	Venous > arterial dilation Can cause bronchodilation ↑ICP due to ↑in CBF Disrupt renal autoregulation in CCF pts. relaxation of sphincter of Oddi	Arteriole vasodilation with preserved venous tone, and minimal eff¬ect on epicardial vasculature. Reflex increase in HR, CO and activation of the RAAS → peripheral oedema.	Arteriole vasodilation with preserved venous tone, and minimal effect on epicardial vasculature. Reflex ↑ in HR, CO and activation of the RAAS → peripheral oedema.
PD: Side Effects / Toxicity	Dizziness, nausea, flushing, postural hypotension. in patients without CCF: ↑LV fn by improving ischemia. In pts with CCF: ↓contractility and LV fn. Should be avoided in pts with WPW- cause VT/VF. Inhibits CYP3A4.	Decreases SVR and can increase CO (overall, May drop BP)	should not be used for acute blood pressure reduction in hypertensive emergencies. Peripheral oedema is a common side e¬ffect, 2-3 weeks post initiation of therapy. Other side e¬ffects are related to its vasodilating properties: flushing, vertigo, headaches, hypotension and parathesias. Risk of coronary vasospasm with acute withdrawal.	Peripheral oedema is a common side effect, 2-3 weeks post initiation of therapy. Other side effects include ushing, vertigo, headaches, hypotension and parathesias.	Main side effects are from excessive hypotension and include nausea, vomitting, abdominal pain, and postural hypotension. Abrupt withdrawal may lead to a rebound hypertension. Longer term there is significant risk of cyanide accumulation and associated toxicity and impaired oxidative phosphorylation. (See Special points below for further details)	Tolerance develops rapidly due to depletion of sulphydryl (thiol) groups reqrd for metabolism of GTN to NO2. Breaks for patches CNS – headache (intracerebral vasodilatation) and ↑in ICP CVS – at high doses ↓SVR → ↓afterload, however a compensatory tachycardia (baroreceptor induced) may reduce myocardial blood supply. GIT – relaxes sphincter of oddi HAEM – may precipitate methaemoglobinaemia (See Special points below for further details)	activation of the RAAS and the increase in HR and Co make this drug less efficacious. Because of this reason it is often given in combination with a thiazide or betablocker. Long term use is associated with lupus like syndrome	activation of the RAAS and the increase in HR and CO make this drug less efficacious. Because of this reason it is almost always given in combination with a thiazide or betablocker. It is contraindicated in phaechromocytoma and may precipitate pericardial eff¬usion and worsen angina.


PHARMACOKINETICS (PK)
PK: Absorption	PO/IV. BA 20-25% Well absorbed with high fi¬rst pass metabolism on/ dur 1-2 hrs / 6-8 hrs (PO)	PO/IV. BA 30% Well absorbed high first pass metabolism	PO. BA 60% Well absorbed moderate first pass metabolism on/dur ~20 minutes / not stated	PO/IV. BA 40% Well absorbed high -first pass metabolism on/dur PO: 30-60 min; IV: 3 mins	IV. BA 100%.	Top, SL, IV BA PO 5%. Rapidly absorbed from the sublingual mucosa and enters the circulation via the SVC. Also absorbed in the gut but high first pass metabolism.	PO,IV BA 30% well absorbed but high first pass metabolism	PO. BA up to 90%

PK: Distribution		Highly lipid sol – use cerebral vasospasm	lipid solubility moderately low, minimal BBB
Protein binding (PK: Distribution)	~90%	98%	~90%	70% to 80%		60%	87%	None
Volume of distribution (PK: Distribution)	3.89 L/kg	1-2 L/kg	0.62-1.12 L/kg	3-13 L/kg	15L (ECF)	~3 L/kg	4.2 L/kg

PK: Metabolism	Hepatic via multiple CYP isoenzymes, one active metabolite with 20% activity	Demethylation and dehydrogenation to inactive pyridine analogue.	Hepatic via CYP3A4 to inactive metabolites	Hepatic active metabolites desacetyl-diltiazem	As per MOA via reaction with OxyHb, then products as: • Fe recycled by liver • CN + MetHb → Cyanomethaemoglobin • CN + Hepatic rhodenase enzymes → Thiocyanate • CN + B12 → Cyanocobalamin (non-toxic)	Hepatic via thiols into NO products	N-acetylated in the bowel and/or the liver	Hepatic primarily via glucuronidation

PK: Excretion	Urine (70% metab, 3% to 4% unchanged); feces (16%)	Inactive metabolites urine and faeces.	Urine (60% to 80% as inactive metabolites); faeces	Urine ( 4% as unchanged, 7% as metab); faeces	Urine (as thiocyanate - inactive)	Urine (as inactive metabolites)	Mostly excreted in urine, primarily as metabolites	Urine (12% as unchanged drug)
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	3-7 hours	2-4 hrs	2-5 hours (↑ in liver failure)	3-4.5 hours (↑ in renal failure)	Parent drug: <10 minutes; Thiocyanate: 2.7-7 days	1-4 minutes	greatly dependent on genetically acetylation rates, ranging from 1-8 hours	4 hours


SPECIAL POINTS					TOXICITY: • Cyanide poisoning (↑ lactate, “decoupling” of mitochondrial OxPhos via action on cytochrome oxidase, ↑ mixed venous saturation) • ↓VR → ↓ CO → Tachycardia + ↑ myocradial contractility → ↑ myocardial oxygen demand • Coronary steal → worsening myocardial ischaemia • Rebound hypertension on withdrawal ANTIDOTE: 1. Disodium edetate – acts via chelation of CN molecules 2. NaNitrate - ↑ methaemoglobin → ↑ cyanmethaemoglobin 3. NaThiosulphate – acts as thiodonor increasing hepatic rhodenase enzyme activity 4. Hydroxycobalamin – Increases conversion of CN to cyanocobalamin 5. Methylene blue – Increases formation of methaemoglobin	TOXICITY: Methemoglobinemia can rarely occur at conventional doses. MetHb is dose-related and it can be even more pronounced in patients with genetic abnormalities of hemoglobin that favor methemoglobin formation. Methemoglobinemia can be managed with the administration of methylene blue unless the patient has a known G-6-PD deficiency

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ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

Pharmacopeia - ACE inhibitors & Angiotensin Receptor Blockers (ARBs)

	CAPTOPRIL	LISINOPRIL	RAMIPRIL	LOSARTAN
GROUP	ACE inhibitor	ACE inhibitor	ACE inhibitor	Angiotensin Receptor Blocker
CICM Level of Understanding	Level 3	Level 3	Level 3	Level 3

INTRODUCTION	active drug converted to active metabolites. It is a competitive ACE inhibitor	Active drug that is not metabolised and is excreted directly into urine. It is a competitive ACE inhibitor	prodrug requiring hepatic activation to ramiprilat. Ramiprilat is a competitive ACE inhibitor	substituted imidazole compound which selectively blocks AT2 receptors throughout the body.
USES	used for management of hypertension, LV dysfunction post-myocardial infarction and in the setting of heart failure. Its use has been shown to decrease progression of heart failure (disease modifying)	used for management of hypertension, LV dysfunction post myocardial infarction and in the setting of heart failure. Its use has been shown to decrease progression of heart failure (disease modifying).	used for management of hypertension, LV dysfunction post myocardial infarction and in the setting of heart failure. Its use has been shown to ↓progression of heart failure (disease modifying).	1. essential and renovascular hypertension 2. diabetic nephropathy 3. congestive cardiac failure, and 4. in patients intolerant of angiotensin-converting enzyme inhibitors (ACEIs).


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	oral formulation presented as white tablets in dosage ranging from 12.5mg to 50mg	oral formulation presented as white tablets in dosage ranging from 5mg to 20mg tablets.	oral formulation presented as tablets or capsules in dosage ranging from 1.25mg to 10mg	presented in 50mg tablets. Combo not available (available overseas with thiazide)


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Competitive inhibition of angiotensin converting enzyme leads to decreased angiotensin II production and its effects.	Competitive inhibition of angiotensin converting enzyme leads to decreased angiotensin II production and its effects.	Competitive inhibition of angiotensin converting enzyme leads to decreased angiotensin II production and its effects.	Eff¬ects are broadly similar to ACE inhibitors. The blocking of AT2 receptors reduces the action of angiotensin II.
PD: Route & Doses	PO: doses commenced at 6.25mg TDS and uptitrated	PO: doses commenced at 6.25mg TDS and uptitrated	PO: doses commenced at 2.5 mg Daily and uptitrated	PO: doses 50-100mg daily
PD: Metrics (Onset/ Peak/ Duration)	moderately potent	highly potent	potent	on/dur 6 hours, prolonged action due to metabolite
PD: Effects	CVS - TPR and Afterload is decreased to a greater extent than preload, and this may result in improved CO in heart failure patients. - HR is usually unchanged and baroreceptor reflexes also unchanged. Renal - the impairment of Ang-II means that the body is less able to respond to a drop in renal perfusion and this may precipitate failure. Metabolic – Accumulation of K+ may occur due to decreased aldosterone.	CVS - TPR and Afterload is decreased to a greater extent than preload, and this may result in improved CO in heart failure patients. - HR is usually unchanged and baroreceptor reflexes also unchanged. Renal - the impairment of Ang-II means that the body is less able to respond to a drop in renal perfusion and this may precipitate failure. Metabolic – Accumulation of K+ may occur due to decreased aldosterone.	CVS - TPR and Afterload is decreased to a greater extent than preload, and this may result in improved CO in heart failure patients. - HR is usually unchanged and baroreceptor reflexes also unchanged. Renal - the impairment of Ang-II means that the body is less able to respond to a drop in renal perfusion and this may precipitate failure. Metabolic – Accumulation of K+ may occur due to decreased aldosterone.	Notably as ACE is not inhibited, there is not increased levels of bradykinin, hence there is less cough associated with ARBs and possibly less vasodilation and peripheral oedema attributed to bradykinin levels
PD: Side Effects / Toxicity	A dry cough may occur especially in patients with pre-existing lung disease. Caution should be exercised in patients on potassium sparing medications. NSAIDs may precipitate renal failure.	A dry cough may occur especially in patients with pre-existing lung disease. Caution should be exercised in patients on potassium sparing medications. NSAIDs may precipitate renal failure.	A dry cough may occur especially in patients with pre-existing lung disease. Caution should be exercised in patients on potassium sparing medications. NSAIDs may precipitate renal failure.	Contraindicated like ACE inhibitors in bilateral renal artery stenosis, and pregnancy. Caution in sodium depleted patients similar to ACE inhibitors


PHARMACOKINETICS (PK)
PK: Absorption	PO. rapidly absorbed, BA: 60-70%	PO. absorbed variably. BA: 30%	PO. 50–60% is absorbed. BA: 30%	PO. Well absorbed from the gut but extensive first pass metabolism leads to BA of 25% to 33%,

PK: Distribution
Protein binding (PK: Distribution)	25%	25%	75%	98%
Volume of distribution (PK: Distribution)	2 L/kg	1.7 L/kg	0.1 L/kg	0.48 L/kg

PK: Metabolism	oxidised in the liver and converted to sulphides	not metabolised	Hepatic to the active form, ramiprilat	Hepatic (14%) via CYP2C9 and 3A4 to active metabolite, E-3174 (40 times more potent than losartan)

PK: Excretion	urine both as active metabolites and unchanged	urine unchanged	Urine (60%) and feces (40%) as parent drug & metab	Urine (4% as unchanged drug, 6% as active
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	2-4 hours	12 hours	triphasic elimination profile of the active metabolite ramiprilat with T1/2 1-2 hrs, 13-17hrs and >50hrs.	1.5-2 hours E-3174 6-9 hours


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DIURETICS

Pharmacopeia - Diuretics

	MANNITOL	ACETAZOLAMIDE	FRUSEMIDE	HYDROCHLOROTHIAZIDE	SPIRONOLACTONE
GROUP	Diuretic - Osmotic	Diuretic – Carbonic Anhydrase Inhibitor	Diuretic - Loop	Diuretic - Thiazide	Diuretic – Aldosterone antagonist
CICM Level of Understanding	Level 3	Level 3	Level 1	Level 3	Level 3

INTRODUCTION	polyhydric alcohol MW 200, synthesized by redn of mannose	Sulfonamide	Sulfonamide derivative	related to the sulphonamides	A synthetic steroid
USES	osmotic diuretic (to ↓intracranial pressure or introccular pressure). Used to test for airway hyperresponsiveness	Glaucoma Miniere’s disease Altitude sickness Adjunct in epilepsy	Oedema of cardiac, renal or hepatic origin, Renal insufficency Hypertension Raised ICP Hypercalcaemia	heart failure and hypertension. Used in combination. mostly bound to plasma prot, and gain access to the tubule via secretion in the PCT.	Oedema – CHF, cirrhosis with ascites, refractory. HTN, Nephrotic syndrome. With loop/thiazide to conserve K+, diagn of Conn's syndr


PHARMACEUTICS (PC)
PC: Chemical
PC: Presentation	1-% or 20% (100gm in 1000ml or 500ml) Crystallizes at ↓temp	250mg white tablets 500mg vials for reconstitution	Photosensitive solution 10mg/ml 20/40/500mg tabs, Syrup	orange scored tablets of 25mg and combos	25/100mg tablets


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	osmotic agent. inc plasma osmolality and draws water out of the CSF and vitreous body. Freely fi¬ltered at the glomerulus but poorly reabsorbed. Because the PCT is involved in the reabsorption of 60-70% of the -filtered load this is the most important site of action	Diuresis Reversible, non-competitive inhibitor of carbonic anhydrase PCT: ↓H+ and HCO3- prodn ↓ cytosol H+ → ↓Na+ reabs in PCT→ ↑H2O loss ↓cytosol HCO3→↑luminal HCO3→ H2O diffusion with HCO3 ,Na, K to urine Eye: ↓Na pump, ↓AH formation	Diuresis Inhibition of active chloride ion reabsorption in PCT and ascending limb of LoH ↓ reabsorption of NaCl → ↓ tonicity in the renal medulla → ↓water reabsorption and diuresis. Other effects are mediated by the induction of the COX-2 enzyme which assists in synthesis of prostaglandins.	inhibit Na+ reabsorption in the early portion of the distal tubule by blocking the Na+.Cl- symporter in the apical membrane of these cells. Naturesis occurs with thiazide diuretics is 5-10% of the filtered load	Acts in the DCT. It is a competitive antagonist of aldosterone at the receptors in the DCT. Decreased Na reabsorption and increased K reabsorption = Increased Na loss and Diuresis.
PD: Route & Doses	1-2gm/kg IV	250-1000mg q6hrly IV/PO	20-2000mg daily PO/IV/SL/IM.	PO. 12.5-200mg/day	PO. 25-200mg/day
PD: Metrics (Onset/ Peak/ Duration)
PD: Effects	↓ICP/IOP	Metabolic: Acidosis via ↑ excretion of bicarb (and reabsorption of Cl) Resp: ↑MV → comp resp alk CNS: anticonvulsant properties, ↓ CSF and IOP by ↓d formation GIT: ↓ Pancreatic and gastric GU: mild diuresis, Na retention	Pulmonary and systemic vasodilation Diuresis ↑ RBF and ↑ corticomedullary blood flow ↓O₂ demand in the LoH (ischaemic protection)	Anti-HTN: (↓TPR, ↓plasma volume) ↓RBF → ↓GFR ↓K+,Na+,Mg. Hyperchloremic MA ↑Ca++ (↓excretion) ↑Glu: (↓glycogenolysis, ↓insulin)	Sedation and muscle weakness (due to electrolyte abnm) Antihypertensive, Diuresis (in 3-4 days) Potassium retention Anti-androgenic effect- inhbn of ovarian androgen secretion ↑renal Ca excr, ↑plasma urea Reversible hyperchloraemic MA
PD: Side Effects / Toxicity	Usually rare and idosyncratic. It may cause symptoms of pulmonary hypertension.	metabolic acidosis, urinary alkalinisation, parathesias, fatigue, hypokalaemia, N+V, abdo pain Tox: Rashes, renal stones	↓ K+/Na+/Cl-/Ca++, Hyper- urea/glu/chol, Metabolic alkalosis Tox: Deafness, Pancreatitis BM depression Interstitial nephritis (worse with aminoglycoside)	↓K+/Na+/Mg++, ↑Ca++/urea/glu/chol. indiosyncratic blood dyscrasias. Rash, photsensitivity. Interactions may prolong action of NDMBs. NSAIDs antagonise the action	↑K+(esp in renal failure). N/V and GI disturbances Menstr irreg, Gynaecomastia ↑digoxin conc. ↓pressor response ↑effects of CVS depressants


PHARMACOKINETICS (PK)
PK: Absorption	IV only.	IV/PO PO BA = 100%	PO/IV/SL/IM. PO BA 50% Onset PO/SL 30-60mins, IV 5 mins . Dur PO/SL 6-8hrs, IV 2hrs	PO- BA ~50-80%. Onset 2hrs Dur 6-12hrs.	PO - BA 70%, extensive 1st pass metb. Onset 3-4hrs, dur upto 3 days

PK: Distribution	Biphasic – plasma and ECF. Does not cross BBB	Lip sol: crosses BBB
Protein binding (PK: Distribution)		70-90%	91-99% (Albumin)	68%	90%
Volume of distribution (PK: Distribution)	0.47 L/kg		0.1L/kg	3.6-7.8L/kg

PK: Metabolism	Minimally hepatic to glycogen	Not metabolised	Renal to glucuronide Minimal hepatic	Not metabolized	Hepatic: Rapidly and extensively metabolised by deacetylation and dethiolation. Active metab: canrenone and 7-alpha-spirolactone

PK: Excretion	Urine (~55% to 87% as unchanged drug)	Unchanged in urine	80% unchanged in urine	Urine (unchanged)	Urine and faeces
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Term half life: 4.7 hrs	6-9hrs	0.5-2hrs. ESRF: 9hrs	5.6-14.8hrs	1-2hours, metab upto 24hrs


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ANTIARRHYTHMICS

Pharmacopeia - Antiarrhythmics

	PROCAINAMIDE	LIGNOCAINE	FLECAINIDE	PROPRANALOL	ESMOLOL	ATENOLOL	METOPROLOL	AMIODARONE	SOTALOL	VERAPAMIL	DILTIAZEM	ADENOSINE	DIGOXIN	MAGNESIUM	ATROPINE
GROUP	Antiarrhythmic – Vaughan Williams Class Ia Na channel blocker	Antiarrhythmic – Vaughan Williams Class Ib Na channel blocker	Antiarrhythmic – Vaughan Williams Class Ic Na channel blocker	Antiarrhythmic – Vaughan Williams Class II Beta blocker	Antiarrhythmic – Vaughan Williams Class II Beta blocker	Antiarrhythmic – Vaughan Williams Class II Beta blocker	Antiarrhythmic – Vaughan Williams Class II Beta blocker	Antiarrhythmic – Vaughan Williams Class III K channel blocker	Antiarrhythmic – Vaughan Williams Class III K channel blocker	Antiarrhythmic – Vaughan Williams Class IV (CCB) Ca channel blocker – Class I	Antiarrhythmic – Vaughan Williams Class IV (CCB) Ca channel blocker – Class III	Antiarrhythmic – Vaughan Williams Class V Other	Antiarrhythmic – Vaughan Williams Class V Other	Antiarrhythmic – Vaughan Williams Class V Other	Muscarinic antagonist
CICM Level of Understanding	-	Level 1	Level 3	Level 3	Level 2	Level 3	Level 3	Level 1	Level 3	Level 3	Level 3	Level 2	Level 3	Level 1	Level 1

INTRODUCTION	Aminobenzamides local anaesthetic Class Ia antiarrhythmic Na channel blocker	amide local anaesthetic class IB antiarrhythmic Na channel blocker	Amide local anaesthetic Class IC antiarrhythmic Na channel blocker	non-selective Beta Blocker with no intrinsic sympathomimetic activity.	Cardio-selective beta blocker with rapid onset and off-set.	Cardio-selective beta blocker	relatively selective beta blocker with no intrinsic sympathomimetic activity.	benzofuran derivative - 37% iodine by weight class III antiarrhythmic displays actions of all four classes.	beta blocker but it also has class III effects and is often categorised in this class	Phenylalkylamine (Non-dihydropyridine calcium channel blocker) Synthetic papaverine derivative	Benzothiazepine (Non-dihydropyridine calcium channel blocker)	natural purine nucleoside slows conduction through the AV node	glycoside derived from the dried leaves of the foxglove Block Na-K-ATPase pump	fourth most common cation in the body (after Na+, K+ and Ca2+), and ~35-40% in cardiac and skeletal muscle	anticholinergic activity
USES	Local or regional anesthesia Treatment of VT during cardiac manipulation (surgery, cath), AMI, digitalis toxicity	reduces nerve propagation in the PNS (and CNS) and in cardiac tissue- to treat ventricular arrhythmias. Also used to treat cerebral gas embolism (controversial)	1. for the suppression of irritable foci, e.g. ventricular tachycardia and ventricular ectopics 2. in the treatment of re-entry dysrhythmias, e.g. the Wolff–Parkinson–White syndrome and 3. in the treatment of symptomatic paroxysmal atrial fibrillation intolerant of other medication.	- Hypertension - Angina - essential tremor - haemodynamically stable oesophaegeal varices - migraine prophylaxis - Treatment of choice in thyrotoxicosis as it treats the eff¬ects and prevents conversion of T4 to T3.	- Short term management tachycardia and hypertension in a monitored patient - For SVT termination - No intrinsic sympathomimetic activity or membrane stabilising properties	1. hypertension 2. angina 3. tachydysrhythmias, and 4. in the acute phase of myocardial infarction and prevention of reinfarction.	- Early use of metoprolol in haemodynamically stable myocardial infarction reduces infarct size and incidence of VF. - rate control in atrial -fibrillation - hypertension	critical care for treating many arrythmias	used for the prevention of SVT and in the treatment of ventricular tachyarrhythmias	HTN Angina Paroxysmal SVT and AFib/Aflutter	It is used for angina and hypertension	e¬ffective treatment for the termination of paroxysmal SVT. Used for slowing rapid atrial arrhythmias to aid diagnosis.	used in AF and atrial flutter, SVT and in heart failure	Used in arrhythmias, for termination of VF/torsades as per ALS and in the treatment of digitalis toxicity. Other uses: pre-eclampsia, eclampsia and Mg replacement. O¬ff label use in acute severe asthma.	used to antagonize muscarinic e¬ffects produced by AChE drugs, Mx of intraop bradycardia during GA, or Rx and Dx of Organophosphate poisoning. Ophthal: to induce mydriasis and cycloplegia to aid examination


PHARMACEUTICS (PC)
PC: Chemical				Racemic mixture with S-isomer confers most effects, R-isomer stops T4 to T3 conversion.				structurally resembles thyroxine.	Racemic mixture of d- and l- sotalol both isomers: similar Class III effects l-isomer: all of the Class II effect	Racemic mixture.					anticholinergic activity is primarily due to the L enantiomer although it is presented as a racemic mixture.
PC: Presentation	PO IV: 100mg/mL (10 mL); 500mg/mL (2 mL)	PO: Viscous IM/IV: 1% or 2% sol (10-20mg/ml). Also with Adr. Inf: SS in 7hrs	As 50/100 mg tablets and as a 10 mg/ml solution of flecainide acetate for intravenous administration	PO, IV PO: May be enterically coated. sustained release 60-160mg. Immediate release 10-80mg. IV: significantly smaller due to extensive first pass metab - 20mg/5ml.	only available as an IV formulation. presented as a clear liquid usually at a concentration of 10mg/ml	As 25/50/100 mg tablets (and in fixed-dose combinations), a 0.5% syrup, and as a clear, colourless solution for injection containing 0.5 mg/ml of atenolol.	available in oral form as an immediate release or sustained release in increments of 25mg. It is also available as an IV formulation usually 1mg/ml	tablets – 100/ 200mg. clear colourless solution 50mg/ml for inf. Therapeutic range (1-2.5mg/L) but monitoring rarely necessary	PO: 80 or 160mg tablets. IV: clear liquid 10mg/ml	PO: 40-240mg. Also in combo w Trandolapril. IV Clear solution at 2.5mg/ml	sustained and immediate release oral formulations, 60-360mg	IV: clear liquid with 6mg in 2mL	PO: tablets 62.5mcg or 250mcg. IV:25-250mcg/ml. Narrow therapeutic window. Monitoring necessary - 0.5-2mcg/L(~1)	PO/IV 3 forms: oxide,Cl,SO4 All 3 for replacement Only MgSO4 for eclampsia, arrhythmias 10ml vial 0.5mg/ml	IV. Although previously available in oral formulations, it is only available for topical application to the eye.


PHARMACODYNAMICS (PD)
PD: Main Action
PD: Mode of Action	Blocks Na channels. stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action.	Blocks Na+ channels in cardiac muscles, motor&sensory nerve fibres mild↓ Phase 0 slope ↓APD ↓ERP In pacemaker cells: phase 4 prolonged → ↑ threshold potential → ↓automaticity	Flecainide reduces the maximum rate of depolarization in heart muscle and thereby slows conduction, particularly in the His–Purkinje system. It has a profound effect on conduction in accessory pathways, especially on retrograde conduction, and markedly suppresses ventricular ectopic foci. It is a local anaesthetic agent which depresses membrane responsiveness and conduction velocity, with no effect on the duration of the action potential.	Beta blockage leads to ↓ Gs activity in receptor associated organs and associated ↓ in adenylyl cyclase and intracellular Ca2+.	Beta blockage leads to ↓ Gs activity in receptor associated organs and associated ↓ in adenylyl cyclase and intracellular Ca2+.	Atenolol acts by reversible, competitive blockade of cardiac beta-1 receptors and also has some action at beta-2 receptors.	Beta blockage leads to ↓Gs activity in receptor associated organs and associated ↓ in adenylyl cyclase and intracellular Ca2+.	blocks potassium channels, calcium channels, sodium channels and adrenoceptors	Non-selective beta adrenergic antagonist Cause anti-arrhythmic effect by: --- Decreased pacemaker potential current --- Decreased slow-inward Ca2+ current --- Decreased repolarising K+ and Cl- currents --- Decreased Ca2+ stored in the sarcoplasmic reticulum --- Increased serum [K+]*	Binds to V binding site of L-type channel. Levoisomer: main effects (arterial vasodilation). Slows conduction through the AV and SA node to a greater extent than other CCBs. Dextro: Only acts on fast sodium channels, accounting for local anesthetic effects (1.6x potent as procaine)	Similar to the other Ca Channel blockers in terms of blood pressure.	acts on the A1 adenosine receptors found in the SA and AV markedly slows or completely blocks conduction in the AV node, probably by hyperpolarizing this tissue (through increased IK1) and by reducing calcium current	i) Na/K ATPase inhibition → ↑ intracell Na → ↓ Na-Ca pump → ↑ intracell Ca → inotropy ii) direct: ↑ AV node ERP, ↓ V ERP iii) Indirect: Via Vagus – bradycardia, ↓ A refr. Augmentn of direct ↑ AV node ERP	MoA is unknown but may reflect an eff¬ect on the inward current, possibly a Ca2+ current, responsible for the triggered upstroke arising from EADs. Magnesium ions are bound to cellular ATP, and act as a cofactor for Na+/K+ ATPase, so that intracellular concentrations of Mg2+ may aff-ect Na+ and K+ transfer. It has benefit even in magnesium replete patients	Low doses (2mcg/kg) act centrally and may augment vagal outflow, ↓ HR Normal 15-70mcg/kg also acts on periph muscarinic receptors blocking the action of the vagal nerve and ↑ HR & pupil size whilst ↓ secretory gland activity. cholinergic poisoning to ↓ bronchorrhoea& bronchoconstriction. Other eff¬ects: ↓ tone in the gut, bile ducts, and contractions in the ureter and bladder
PD: Route & Doses	PO / IV. IV loading: 15-18mg/kg over 30min Maintenance: 1-4mg/min	SC, IV/IM, ETT IV 75-100mg -> infusion 2mg/min Max dose: 3mg/kg or 7mg/kg with Adr	PO 100-200mg Q12hrly IV: Bolus 2mg/kg over 10min → Infusion 1.5mg/kg/hr for 1hr → 0.25 mg/kg/hr	oral or IV doses PO up to 320mg, IV 0.5mg - 10mg titrated to eff¬ect	IV dose In 10mg increments titrate to eff¬ect	PO Dose 50-100mg daily IV 2.5-10mg, may be administered at a rate of 1mg/min	PO or IV dose Orally in 12.5mg increments, IV in 1-2mg boluses	doses PO 200mg TDS 1/52, BD 1/52, then OD IV 5mg/kg over 1hr → 15mg/kg over 24 hrs IV	Doses 80-160mg PO or 50-100mg IV over 20mins	40mgPO or 5-10mg IV.	PO/IV 30-80mg TDS	IV. doses 3-6mg bolus	IV/PO. loading 250-500mcg QID then 62.5-125mcg daily	IV/PO. doses 1-2g IV over 15 mins for torsades de pointes	IV. doses 15-70 mcg/kg
PD: Metrics (Onset/ Peak/ Duration)								onset / duration 2 days to 3 wks / 1 wk to 5 mon	Onset IV: 5-10mins, PO 1-2hrs Duration 8-16hrs	on/ dur 1-2 hrs / 6-8 hrs (PO)	on/dur PO: 30-60 min; IV: 3 mins	onset / duration seconds / seconds	onset / duration Oral: 1-2 hours; I.V.: 5-60 mins / 3-4 days	onset / duration immediate / 30 mins	onset / duration rapid / 1-2 hours
PD: Effects	Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole. The sinoatrial node is, however, unaffected.	CVS: ↓ electrical excitability, conduction rate, force of contraction CNS Stimulation	CVS Flecainide is generally well tolerated; the blood pressure and heart rate usually remain unchanged. The drug has negative inotropic potential. CNS Visual disturbances may occur and are probably a central effect of the drug	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption	CVS: - decreased sinus node automaticity and AV node conduction - Negative inotropic and chronotropic effects – decreased MVO2 - prolonged antihypertensive effect Metabolic: inc TG, and dec HDL-cholesterol	It produces decreases in heart rate and cardiac output and myocardial oxygen consumption. Whilst it does have some β 2 action it has little or no effect on these receptors at doses less than 100mg	- Sinus rhythm slowed by 15% secondary to slowed diastolic depolarization of nodal cells - AV nodal automaticity is decreased and AV nodal conduction speed is slowed 25% - After IV administration decreased SVR and LV contractility - Coronary artery vasodilation with increased coronary blood flow - QT prolongation	Effect: Prolonged Action potential. Reduced Inotropy Ventricular rate is slowed QT interval is prolonged	CVS: slow conduction of AP at SA and AV node, negatively inotropic, peripheral vasodilation (↓ SVR), arrhythmia (heart block, VF in WPW). CNS: ↑ CBF, may potentiate effects of depol/NDMBs. GIT - Constipn/Nausea	Produces more peripheral vasodilation than verapamil and more conduction delay than the dihydropyridines such as nifedipine	Effects: causes a temporary heart block and/or asystolic pause which acts to terminate SVT	CVS - The main action of digoxin is to increase the force of cardiac contraction; automaticity and contractility also increase. - The heart rate is slowed due to a combination of improved haemodynamics, depression of sinus node discharge, slowing of AV nodal conduction, an increase in the AV nodal refractory period, and an indirect vagotonic effect. - Rapid intravenous administration of digoxin may cause vasoconstriction, leading to hypertension and decreased coronary blood flow. - The characteristic ECG changes produced by the drug include prolongation of the PR interval, ST-segment depression, T-wave flattening, and shortening of the QT interval GIT - Anorexia/N/V/Diarrhoea (especially if therapeutic range exceeded) CNS - Headache, confusion, coma (toxicity) - Visual disturbances (deranged red-green colour perception) Renal- Mild diuretic effect Miscellaneous- Rashes, eosinophilia; Gynaecomastia
PD: Side Effects / Toxicity	Myocardial depression Watch for QRS/QT segment prolongation, ventricular tachycardia, ventricular fibrillation, complete atrioventricular block, torsades de pointes. Abnormal LFTs GI intolerance	narrow therapeutic window, with ideal concentrations <5mcg/ml for antiarrhythmic effects. >5 mcg/ml: CNS effects including confusion, sedation, agitation and paraesthesia. >20 mcg/ml: AV block, unresponsive hypotension and eventually death.	Reversible liver damage, dizziness, paraesthesiae, headaches, and nausea may complicate the use of the drug.	- Rapid withdrawal should be avoided as it may precipitate tachycardia, HTN and/or ischaemia. - Care should be taken when used in conjunction with opioids and halothane and in patients with obstructive airway disease	- Care with: Opioids, Halo, OAD, CCB - It is an irritant to veins and may lead to tissue necrosis with extravasation	- exacerbation of peripheral vascular Disease - bronchospasm - masking of the signs of hypoglycaemia - depression - impotence - altered bowel habits	- Withdrawal - Care with: Opioids, Halo, OAD, CCB - Use with Ca Channel blockers may result in complete heart block	CVS - not arrhythmogenic despite QT prolongation (likely because of its multiple actions), bradycardia and hypotension Resp- pneumonitis, fibrosis or pleuritis. Endo - it may cause hypothyroidism (6%) or hyperth (1%). Hepa - cirrhosis, hepatitis, jaundice. LFT monitoring. Corneal microdeposits common- resolve on cessation.	class III: QT prolongation predisposes torsades de pointes (with a risk of 2% in pts with sustained VF/VT). This risk is increased in electrolyte imbalance. May precipitate heart failure. Other:bronchospasm, visual disturbances and sexual dysfunction.	Dizziness, nausea, flushing, postural hypotension. in patients without CCF: ↑ LV fn by improving ischemia. In pts with CCF: ↓ contractility and LV fn. Should be avoided in pts with WPW- cause VT/VF. Inhibits CYP3A4.	Peripheral oedema is a common side effect, 2-3 weeks post initiation of therapy. Other side effects include ushing, vertigo, headaches, hypotension and parathesias.	side effects are transient but can be distressing for patients (sense of impending doom). May induce AF/AFL due to ↓ refractory period. Contraindicated in sick sinus syndrome. Avoid in asthma/ COPD - may cause bronchospasm.	Thyroid-Vd Narrow therapeutic window -monitoring - 0.5-2mcg/L(~1) Toxic > 2.5- arrhythmias, AV block. anorexia,N/V/D, lethargy. Altered Red green colour perception. ECG: ↑ PR, ST dep, T fl-attening, ↓QT. (may not indicate toxicity)	Care should be taken when delivering IV: ECG monitoring, vital signs, deep tendon re exes; magnesium concentrations if frequent or prolonged dosing required particularly in patients with renal dysfunction, calcium, and potassium concentrations. Contraindicated in myasthenia gravis and care to be taken in renal failure.	Although less pronounced than scopolamine (hyoscine) high doses and overdosage of atropine may cause a central anticholinergic syndrome characterised by excitement, hallucinations and hyperpyrexia. In overdosage this leads to coma, respiratory depression and death


PHARMACOKINETICS (PK)
PK: Absorption	PO/IV. BA 75-95%	SC, IV/IM, ETT On/dur: 45-90sec / 10-20min	PO. Rapidly absorbed. BA 85-90%	bioavailabilty - lipid soluble and well absorbed but has a high 1st pass metabolism leading to a bioavailability of 30%	bioavailabilty Only available as IV therefore 100%	Oral BA 50%	bioavailabilty Absoption is rapid and complete, however there is extensive fi¬rst pass metabolism bioavailability = 50%	poorly absorbed, BA 40-70%	IV, PO BA 95%	PO/IV. BA 20-25% Well absorbed with high fi¬rst pass metabolism	PO/IV. BA 40% Well absorbed high -first pass metabolism	IV only	IV, PO BA 60-80%	IV/PO	IV

PK: Distribution		Lip sol high – crosses BBB. pKa 7.9		lipid solubility high lipid solubility	lipid solubility is high so it crosses the BBB		lipid solubility is high so it crosses the BBB
Protein binding (PK: Distribution)	15-20%	60-80%	37-58%	90%	60% to albumin	3%	10-20% to albumin	96%	Nil	~90%	70% to 80%	NA	prot bind ~25%; uremia- displaced fm pl prot bind sites	30% (Alb)	50%
Volume of distribution (PK: Distribution)	2 L/kg	1.1-2.1 L/kg (alt in CHF/CLF)	5.8-10 L/kg	4 L/kg	3.5 L/Kg	0.7 L/kg	5.5 L/Kg	66L/kg	1.2—2.4 L/kg	3.89 L/kg	3-13 L/kg	NA	6-7 L/kg thyroid (↑ in hyper, ↓ hypo).		1-2 L/kg rapidly distributed from central compartment

PK: Metabolism	Hepatic. 1 main metabolite: N-Acetyl-3-hydroxyprocainamide	90% hepatic; active metabolites monoethylg lycinexylidide (MEGX) and glycinexylidide (GX) can accumulate and cause CNS toxicity	Liver 2 metabolites: metao-dealkylated flecainide and its lactam	Hepatic via CYP2D6, and CYP1A2 to 4-hydroxypropranolol (active) and inactive comp	neither hepatic or renal! by red blood cell esterases to a mostly inactive metabolite	<10% metabolized in liver	hepatic or renal Extensively hepatic via CYP2D6	complex metabolism, hepatic via de-ethylation catalysed by CYP 2C8 and 3A4. active metabolite N-desethylamiodarone	None	Hepatic via multiple CYP isoenzymes, one active metabolite with 20% activity	Hepatic active metabolites desacetyl-diltiazem	Rapidly deaminated in plasma and taken up by RBCs	Stomach:Sequential sugar hydrolysis+ redn of lactone ring by intestinal bacteria min hepatic, most excr unchanged	bound to bone or excreted unprocessed in urine	extensively metabolised by liver esterases

PK: Excretion	Urine (30-60% unchanged)	Urine (<10% unchanged , ~90% metabolites)	Urine (10-50% unchanged)	most metabolites are excreted in urine	urine	Urine - unchanged	urine 5-10% unchanged	via skin, faeces, urine, lachrymal glands	urine unchanged	Urine (70% metab, 3% to 4% unchanged); feces (16%)	Urine ( 4% as unchanged, 7% as metab); faeces		Urine (50% to 70% unchanged)	Urine (as magnesium)	urine (fraction unchanged)
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	2.5-4.5 hrs	half life Biphasic: Prolonged with CHF, Liver, shock, ARF/CRF Initial: 7-30 minutes; Terminal: 2 hours	IV: 7-15hrs PO: 12-27hrs	3-6 hours	10 minutes	6-9hrs	3-8hours	~40-55 days	12 hrs	3-7 hours	3-4.5 hours (↑ in renal failure)	<10 seconds	36-48 hours	not known	h 2-3 hours


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ANTIDOTES

Pharmacopeia - Antidotes

	DIGOXIN ANTIBODIES	INTRALIPID
GROUP	Antidote	Antidotes
CICM Level of Understanding	Level 3	Level 3

INTRODUCTION
USES	- For treatment of acute and chronic digoxin overdose - Treatment of toxicities of other cardiac glycosides: oleander, bufotoxin (cane toad), Chinese medicines


PHARMACEUTICS (PC)
PC: Chemical	Monoclonal antibody (mAB) FAB (Fragment antigen-binding) fragment from sheep immunized with digoxin derivative
PC: Presentation	powder contains 38-40mg of digoxin-specific Fab fragments (which binds approx. 0.5mg Digoxin) reconstitute with sterile water


PHARMACODYNAMICS (PD)
PD: Main Action	Binds Digoxin Molecules
PD: Mode of Action	Binds excess digoxin or digitoxin molecules circulating in the blood - Fab fragment-digoxin complex excreted by kidney - Net shifts the equilibrium away from binding of digoxin to receptors
PD: Route & Doses	IV Empiric: 10vials of Fab fragments Known dose, no level: Total body load = Dose (in mg) x 0.8 (BA of digoxin) Number of vials = TBL x 2 Known concentration: No of vials = [(serum digoxin concentration in ng/mL) x (patient's weight in kg)]/ 100
PD: Metrics (Onset/ Peak/ Duration)	Onset: 0-60min Peak: 30-360min
PD: Effects
PD: Side Effects / Toxicity	Anaphylaxis – rare Digoxin Withdrawal: AF, heart failure, hypokalemia


PHARMACOKINETICS (PK)
PK: Absorption	-

PK: Distribution
Protein binding (PK: Distribution)	-
Volume of distribution (PK: Distribution)	0.3 L/kg [DigiFab] 0.4 L/kg [Digibind]

PK: Metabolism	Nil

PK: Excretion	Urine
- Clearance (PK: Excretion)
- Half Life (PK: Excretion)	Unbound: 11 hrs Bound: 15-20 hrs


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Y02. Pharmacopeia: Cardiovascular Pharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

ADRENERGIC AND NON-ADRENERGIC DRUGS

Pharmacopeia - Adrenergic and Non-Adrenergic Drugs

CENTRAL ANTIHYPERTENSIVES

Pharmacopeia - Central Antihypertensives

ADRENORECEPTOR ANTAGONISTS

Pharmacopeia - Adrenoreceptor Antagonists

DIRECT VASODILATORS
(including Calcium Channed Blockers)

Pharmacopeia - Direct Vasodilators incl. Calcium Channel Blockers

ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

Pharmacopeia - ACE inhibitors & Angiotensin Receptor Blockers (ARBs)

DIURETICS

Pharmacopeia - Diuretics

ANTIARRHYTHMICS

Pharmacopeia - Antiarrhythmics

ANTIDOTES

Pharmacopeia - Antidotes

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Y02. Pharmacopeia: Cardiovascular Pharmacology

CICMWrecks Tables (Click to Open)

MASTER TABLES

ADRENERGIC AND NON-ADRENERGIC DRUGS

Pharmacopeia - Adrenergic and Non-Adrenergic Drugs

CENTRAL ANTIHYPERTENSIVES

Pharmacopeia - Central Antihypertensives

ADRENORECEPTOR ANTAGONISTS

Pharmacopeia - Adrenoreceptor Antagonists

DIRECT VASODILATORS (including Calcium Channed Blockers)

Pharmacopeia - Direct Vasodilators incl. Calcium Channel Blockers

ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS

Pharmacopeia - ACE inhibitors & Angiotensin Receptor Blockers (ARBs)

DIURETICS

Pharmacopeia - Diuretics

ANTIARRHYTHMICS

Pharmacopeia - Antiarrhythmics

ANTIDOTES

Pharmacopeia - Antidotes

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DIRECT VASODILATORS
(including Calcium Channed Blockers)