Contractn of Ciliary Body = Accommodation for Near Vision

Name Of Drug / Type / Mechanisms of Action / Uses / Pharmacokinetics / Side-Effects of Drug
Parasympathetic Nervous System – Cholinomimetics(Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – DIRECTLY ACTING
Acetylcholine / Binds to nicotinic & muscurinic receptors (parasymp) / Eye:

Contractn of ciliary body = accommodation for near vision
Contractn of Sphincter Pupillae (circular muscle of the iris) = constricts pupil (miosis) & improves drainage of intra-ocular fliud (glaucoma)
Lacrimatn (tears)

CVS:

Bradycardia↓ CO (↓ed contractn)
Vasodilatn (NO producn on endothelium)

Non-vascular Smooth Muscle:

Lung – Bronchoconstrictn
Gut – ↑ed peristalsis (& motility)
Bladder – ↑ed emptying

Exocrine Glands:

Salivatn
↑ed bronchial & GI secretn
SNS – sweating

/ Does not differentiate b/w muscurinic & nicotinic e.g. skeletal muscle contractn & symp activity
Bethanechol / Choline ester / M3 AChR selective agonist /

Bladder emptying
Enhance GI motility

Resistant to degradation
Orally active (with limited access to brain)
Plasma t1/2≈ 3-4h

Sweating
Impaired vision
Nausea
Bradycardia & Hypotension
Respiratory difficulty

Pilocarpine / Alkaloids /

Selective agonist at muscarinic receptor
Partial agonist for many muscarinic responses – less effective on GI, smooth muscle & heart

/ Glaucoma (↑ed intraocular pressure) – by constritn of pupil / t1/2≈ 3-4h /

Sweating
Blurred vision
GI disturbance & pain
Hypotension
Respiratory distress

Parasympathetic Nervous System – Cholinomimetics (Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – INDIRECTLY ACTING (Anticholinesterase)
Neostigmine/
Physostigmine
Donepezil / Alkaloids (tertiary amine) / Reversible Anticholinesterase:

Donates carbamyl group to the enzyme
Blocks active site
Carbamyl removed by slow hydrolysis

Glaucoma
Atropine Poisoning (iv – particularly in children)

Tertiary amine
Can readily cross bld-brain barrier
Primarily acts at the post-ganglionic parasympathetic synapse
t1/2≈ 30min

/ Effects on CNS (only non-polar organophosphates i.e. these ones)

Low doses = excitation; convulsion
High doses = unconsciousness, resp depression & death
Donepezil – Alzheimer’s disease

& Autonomic side-effects (see next)
Ecothiapate / Organo-phosphorus compunds / Irreversible Anticholinesterase – rapidly react with enzyme active site  leaving a blocking group /

Glaucoma (with prolonged action)
Insecticides

/ Stable & resistant to hydrolysis /

Sweating; Blurred vision; GI pain; Bradycardia; Hypotension; Respiratory difficulty

Autonomic Effects:

Low Dose =↑ muscurinic activity
Moderate Dose – further muscurinic activity & enhanced diffusion at all autonomic ganglia
High Dose – (toxic) depolarising block at ganglia

Pralidoxime / THIS IS NOT AN INDIRECTLY ACTING CHOLINOMIMETIC / Can split the phosphorus-enzyme bond initially & ‘regenerate’ the enzyme / Treatment of Organophosphate Poisoning: Signs/Symptoms – Salivation, Lacrimation, Urination, Diaphoresis, GI motility, Emesis, Bronchorrhea, Bronchconstriction, Bradycardia (SLUDGE BBB) /

Cannot enter CNS – does NOT affect CNS symptoms of organophosphate poisoning
Highly lipid soluble – readily absorbed through the nasal mucosa, skin, lungs

Parasympathetic Nervous System – Cholinoceptor Antagonists– NICOTINIC RECEPTOR ANTAGONISTS
Trimetaphan / 2 blocking ways:
a)Block receptor (ligand cannot bind) – complete block
b)Block ion channel once activated (ligand can bind) – in-complete block / Ganglion Blocking Drugs:

Block transmission at all autonomic ganglia – does NOT block at skeletal muscle due to different nicotinic receptors
Affects more symp than parasymp

/ To cause hypotension during surgery –
short-acting /

CVS effects: Hypotension (dilation of blood vessels); ↓ed renin secretion; ↓ed postural reflex
Smooth Muscle: pupil dilation (impaired light reflex); bronchodilation; impaired bladder dysfunction; ↓ GI tone & motility
Exocrine: sweat, salivary, GI, bronchial & lacrimal glands all have ↓ed secretions

Hexametho-
nium / 1st hypertensive medication
Botulinum Toxin (BOTOX) / Toxin binds to SNARE complex – prevents exocytosis of ACh / Toxic – complete block of nicotinic receptors at autonomic ganglia
Parasympathetic Nervous System – Cholinoceptor Antagonists– MUSCURINIC RECEPTOR ANTAGONISTS
Atropine / Block ACh action at muscarinic receptors (i.e. all parasymp & sweat glands) / CNS Effects:

Atropine  mild restlessness to agitation
Hyoscine sedation (both have similar structure, yet have opposite effects)

Annaesthetic Premeditation (mimic effects of Hyoscine – sedation):

Salivary glands  copious, watery secretions
Heart = ↑ rate & contractility
Trachea & Bronchioles  dilation (remember opposite to parasymp effects)

Neurological:

Motion sickness – Hyoscine patch
Parkinson’s Disease – cholin/dopaminergic balance in basal ganglia

Resp – Asthma/COPD (bronchodilation)
GI – Irritable Bowel Syndrome – ↓ motility & tone /

↓ secretions
↓ sweating
Cycloplegia (paralysis of the ciliary muscle of the eye  loss of accommodation)
CNS disturbances

(N.B. Atropine Poisoning  hyperactivity then CNS depression, ↑ed body temp., dry mouth, blurred vision, urinary retention)

Hyoscine
Tropicamide / Examination of the retina – binds to circular muscle on the eye & ↑es pupil size
Ipratropium / Treatment of chronic obstructive lung diseases (e.g. asthma)
Sympathetic Nervous System – Adrenoceptor Agonists– DIRECTLY ACTING
Adrenaline / Non-selective α/β /

Allergic reactions & anaphylactic shock ( sev hypotension & bronchoconstrictn)
COPD & asthma emergencies
Acute management of heart block
Maintains bp during spinal anaesthesia
Prolongs duration of local anaesthesia by local vasoconstrictn
Glaucoma (↓ aq humour production)

RoA (Route of Admin) – iv
DoA (Duration of Action) – few mins

CVS effects: Tachycardia; Arrhythmias; Cold extremities; sev Hypertension (overdose)  Cerebral haemorhage & Pul oedema
↓ed & thickened Mucous secretions (dry mouth)
Tremor (skeletal muscle)

Phenylephrine / α1 selective (α1>α2>β1/β2) / Related to adrenaline /

Vasoconstrictor – stop superficial bleeding from skin & mucous membranes  hypertension & reflex ↓ in heart rate
Mydriatic (eye drops)
Nasal decongestant (nose drops; oral administration) via vasoconstrictn

RoA – iv, oral or nasal drops
More resistant to COMT but not MAO

Clonidine / α2 selective
(α2>α1>β1/2) /

↓es symp tone via:
α2 adrenoceptor mediated pre-synaptic inhibition of NA release
(in brainstem) baroreceptor pathway to ↓ sympathetic outflow
Treats hypertension & migraine

RoA – iv or oral

Isoprenaline / Non-selectiveβ (i.e.β2/β1)
(β1=β2>α1/2) /

Heart block (cardiogenic shock or MI)
Bronchodilator –asthma but discontinued due to unwanted actions (reflex tachycardia, dysrhthmias)

RoA – oral; iv; inhalation
DoA– t1/2≈ 30min
Less susceptible to Uptake 1 & MAO than adrenaline

Dobutamine / β1 selective
(β1>β2>α1/2) /

Use to treat cardiogenic shock, acute heart failure, MI & heart block
Lacks isoprenaline’s reflex tachycardia

RoA –iv
DoA – t1/2 ≈ 2min (rapid metabolism by COMT)

Salbutamol / Β2 selective
(β2>β1>α1/2) / Synthetic catecholamine derivative with relative resistance to MAO & COMT /

Asthma – relaxatn of bronchial smooth muscle & inhibitn of release of broncho-constrictor substance from mast cells
Treatment of threatened uncomplicated premature labour

RoA – Asthma (oral;inhalation); Premature Labour (i.v.)

Reflex tachycardia
Tremor

Caution with cardiac patients, hyperthyroidism & diabetes – ↑ed sensitivity to adrenoceptors
Sympathetic Nervous System – Adrenoceptor Agonists– INDIRECTLY ACTING(act at adrenergic nerve terminal NOT receptor)
Cocaine / Local anaesthetic in ophthalmology /

Readily crosses bld brain barrier (unlike AD & NA)
Degraded by plasma esterases
Plasma t1/2 ≈ 30mins
Excreted in urine

Euphoria, ↑ed motor activity (CNS effect);may depression
Tachycar, vasoconstrictn, ↑ed bp
Tremors & convulsions ( vomit)
Resp Failure

Tyramine /

Competes with catecholamines for Uptake 1,
Displaces NA from intracellular storage vesicles into cytosol; NA & tyramine compete for sites on MAO; cytoplasmic NA leaks through neuronal memb to act at postsynaptic adrenoceptors

/ Dietary a.a. – cheese, red wine & soya sauce / Hypertensive crisis (when MAO is inhibited)
Sympathetic Nervous System – Adrenoceptor Antagonists
Phentolamine / Non-selective α (i.e.α2/α1) / ↑ NA release from nerve terminals (α2 actions) /

Hypotension (vasodilatn)
Reflex tachycardia [due to fall in arterial pressure (β-receptors)]

/ No longer clinically used /

↑ed GIT motility
Diarrhoea

Doxazosin/Prazosin / α1 selective / Does NOT ↑ NA release from nerve terminals /

Hypotension (vasodilatn), so ↓ CO
↓ tachycardia (as above) – ↓ NA release
↓in LDL & an ↑in HDL cholesterol

Propranolol / Non-selective β (i.e.β2/β1) /

Class II antiarrhythmics
Glaucoma
↓ in peripheral resistance  ↓ in bp
Bradycardia  ↓ CO

/ Very little change in cardiac bp & HR but very effective as antiarrhythmics /

Bronchoconstriction (asthmatics)
Cardiac Failure – pts with heart disease rely on a degree of symp drive to the heart to maintain CO
Hypoglycaemia – symp response to hypoglycaemia  useful symptoms in warning diabetic pts (sweating, palpitations, tremor)
Fatigue –↓ed CO & muscle perfusion
Cold Extremities – loss of β-receptor mediated vasodilatation in cutaneous vessels

Atenolol / β1 selective /

Angina – stabe, unsablte or variable
Hypotension & bradycardia (like propranolol

Labetolol / Non-selective α1/β1 (ratio 4:1 for β1:α1) /

Hypotension by ↓ peripheral resistance
No change in heart rate

Sympathetic Nervous System – False Transmitters
Methyldopa /

Taken up by NA neurones
Decarboxylated & hydroxylated to form false transmitter, α-methyl-NA
Not deaminated by MAO, so accumulates:

Less active than NA on α1-receptors
More active on presynaptic (a2) receptors (auto-inhibitory feedback)
CNS effects, stimulates vasopressor centre in the brain stem to inhibit sympathetic outflow

In hypertensive patients with renal insufficiency or cerebrovascular disease
Hypertensive pregnant women

/ Rarely used due to side-effects /

Dry mouth
Orthostatic hypotension
Sedation
Male sexual dysfunction

Neuromuscular Block Drugs – NON-DEPOLARISING (Competitive Nicotinic Antagonists)
Tubocurarine/ Atracurium / 4° ammonium compound (alkaloid & is powerful positive charge) /

Competitive nAChR antagonist
70 - 80% block necessary (all or nothing action)
Graded block = different proportions of fibres blocked

Flaccid paralysis:
Extrinsic eye muscles (double vision) 
Small muscles of face, limbs, pharynx 
Respiratory muscles
Relaxation of skeletal muscles during surgical operations esp abdominal muscles (therefore require less anaesthetic so safer)
Permit artificial ventilation

RoA – i.v. (highly charged)
Does not cross bbb or placenta (so can be used in caesarean section)
Onset of action: 2-3min (relatively long)
Duration of paralysis: 40-60 min (long)
Not metabolised
Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired)

/ Due to ganglion block & histamine release:

Hypotension:
Ganglion Blockade ( TPR)
Histamine release from mast cells via H1 receptors
Bronchospasm – due to histamine release
Tachycardia: (may  arrhythmias)
Excessive secretions (bronchial & salivary) –histamine release
Apnoea (always assist respiration)

Neuromuscular Block Drugs –DEPOLARISING (Nicotinic Agonists)
Suxamethonium / Structure similar to ACh (2 ACh bonded together via a acetyl group) /

Normally, ACh binds to nicotine receptor  opens Na V-gated channels  degradation of ACh by acetylcholinesterase
Sux cannot be hydrolysed by acetylcholinesterase but by pseudocholinesterase  not degraded  prevents muscle cell to ‘reset’ & keeps the new restign potential below threshold  muscle fasiculations

/ Anaesthesia – allow intubation of the trachea or to maintain relaxation for short surgical procedures /

RoA – i.v.
Onset of action: immediate
Duration of paralysis: 5-10 min (short)
Not metabolised
Excretion: 10% urine; 80% bile

Hyperkalaemia
Bradycardia
Raised intracranial intraocular pressure
Muscle pain due to fasiculations

Drugs & the Heart
Atenolol / Beta-blocker for

NEGATIVE CHRONOTOPE & IONOTROPE
CONTROL or CORRECT DYSRHYTHMIA

Competitive antagonists for mainly1 adrenoceptors
 reductn in CO, renin release & NA release by symp nerves

Angina & improves survival post MI
Cardiac dysrhythmias
Heart failure
Thyrotoxicosis
Glaucoma
Anxiety states
Migraine

No longer 1st line for hypertension in UK
Do NOT↓peripheral resistance (PVR) (except partial agonists or vasodilatory beta blockers)

Due to actions on beta1 (& sometimes beta2 receptors):
Bronchoconstriction
Cardiac failure & Heart block
Bradycardia
Fatigue
Cold extremities
Exacerbation of arterial disease
Hypoglycaemia in diabetics taking insulin

Nicorandil / Organic nitrate for REDUCING PRELOAD /

Drug  release NO from endothemium 
Stimulating guanylate cyclase 
Formation of cyclic GMP 
relaxing smooth muscle in veins
↓ing venous return

Venodilators (if dilatn of coronary arteries have reached max) of veins  ↓ preload
Coronary artery vasodilators – potassium channel openers used in angina (e.g. nicorandil) open KATP channels & also act as nitric oxide (NO) donors
Angina
Antiplatelet agents
Acute & chronic heart failure
BP control during anaesthesia

Nitrates undergo extensive ‘first pass’ metabolism by the liver
Long acting forms of nitrate (e.g. isosorbide mononitrate, or glyceryl trinitrate via a transdermal patch) are available for sustained actions
Glyceryl trinitrate is often given sublingually for rapid relief of angina – has a short t1/2 ≈ 30mins

Hypotension
Headaches
Flushing (due to vasodilation)

Excessive/prolonged use of nitrates is associated with tolerance –avoided by eccentric (asymmetric) dosing
Glyceryl Trinitrate / Organic nitrate for CORONARY VASODILATORS
Isosorbide mononitrate / Organic nitrate
Verapamil / Rate-limiting Calcium channel blockers for CORONARY VASODILATORS (acting on afterload) /

 cardiac & smooth muscle actions
↓ Ca2+ entry in cardiac smooth muscle cells

Negative inotropic effect (verapamil > diltiazem, not dihydropyridines)
Inhibit AV node conduction (verapamil)

Angina
Hypertension (mainly dihydropyridines)
Verapamil is used to treat paroxysmal SVT atrial fibrillation

/ PHENYLALKYLAMINES /

Bradycardia
AV block
Worsening of heart failure
Constipation

Diltiazem / BENZOTHIAZEPINES
Amlodopine /

 only smooth muscle actions
Only inhibit Ca2+ entry in smooth muscle cells

/ DIHYDROPYRIDINES /

Ankle oedema
Headache/Flushing
Palpitations

Adenosine / Antidysrhythmic /

Produced by the metabolism of ATP
Acts on adenosine (A1) receptors to hyperpolarize cardiac tissue & slow conductn through AV node

/ Terminate superventricular tachyarrhythmias (SVT) /

Iv
actions are short-lived (20-30s) & it is consequently safer than verapamil

Chest pain
Shortness of breath
Dizziness
Nausea

Amiodarone / Antidysrhythmic / Momplex action –multiple ion channel block / Useful for a number of superventricular and ventricular tachyarrhythmias / Accumulates in the body (t½ = 10 - 100days) /

Photosensitive skin rashes
Hypo- or hyper-thyroidism
Pulmonary fibrosis
Corneal deposits
Neurological GI disturbances

Digoxin (Cardiac Glycosides) / Antidysrhythmic /

Inhibits Na-K-ATPase (Na/K pump) ↑ed accumulation of intracellular Na+↑es intracellular Ca2+ via Na+/Ca2+ exchange
Central vagal stimulation ↓ed rate of conduction through the AV node

Slows ventricular rate in atrial fibrillation & relieves symptoms in chronic heart failure
Cardiac Effects:
Cardiac slowing ↓ed rate of conductn through the AV node (due to central vagal stimulation)
↑ed force of contraction
Disturbances of rhythm especially: block of AV conduction & ↑ed ectopic pacemaker activity

/ Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
Ivabradine / Antidysrhythmic / Blocks If channel – a Na/K channel imp in the sinoatrial node so slows heart rate / Angina in patients in normal sinus rhythm / Contraindications: Severe bradycardia/sick sinus syndrome/2-3rd degree heart block; Cardiogenic shock; Recent MI /

Bradycardia
First-degree heart block
Ventricular & SVA

Dobutamine / β1 selective for POSITIVE CHRONOTROPHES / ↑es the force of cardiac contraction / Acute heart failure in some situations (e.g. after cardiac surgery or in cardiogenic or septic shock)
Drugs & the Vasculature
Enalapril / ACE Inhibitors for REDUCING PRELOAD & AFTERLOAD / Prevent the conversion of angiotensin I to angiotensin II by ACE /

Hypertension
Heart failure
Post-myocardial infarction
Diabetic nephropathy
Progressive renal insufficiency

Hypotension
Angioedema
Hyperkalaemia
Foetal injury
Renal failure in pts with renal artery stenosis

Captopril
Losartan / Angiotensin Receptor Blockers for REDUCING PRELOAD & AFTERLOAD / At AT1 receptors – preventing the renal & vascular actions of Ang II (agents act as insurmountable) /

Hypertension
Alternative for ACEI for heart failure patients who cannot tolerate ACEI

Hypotension
Foetal injury
Renal failure in patients with renal artery stenosis

Spirono-lactone / Aldosterone Antagonist for REDUCING PRELOAD & AFTERLOAD / Antagonist of aldosterone – inhibits the sodium retaining effects /

Heart failure
Resistant cases of hypotension

Hyperkalemia – aldosterone antagonism
Steroid-like effects such as gynaecomastia, menstrual disorders & testicular atrophy

Bendrofluazide / Thiazide Diuretic for REDUCING PRELOAD & AFTERLOAD / Causes a fall in smooth muscle Na+ 2° reduction in Ca2+ /

Hypertension
Heart Failure

Hypokalaemia
Diabetes
Gout

Doxazosin / α-adrenoceptor antagonist for CORONARY VASODILATOR / Specific for alpha1 / Postural Hypotension
Phenoxybenzamine / Non-selective alpha antagonist / Pheochromocytoma / Tachycardia
Clonidine/
-methydopa / 2-adrenoceptor agonists for VASODILATION / Specific for alpha2 by reducing sympathetic activity / Hypertension
Hydralazine / K+ Channel Openers for CORONARY VASODILATION / Opening ATP-sensitive K+ channels  hyperpolarisation  closing voltage-sensitive Ca2+ channels / Severe Hypertension / Used in combination with a beta-blocker & diuretic /

Reflex tachycardia  angina, headaches & fluid retention
Lupus syndrome  fever, malaise & hepatitis

Minoxidil / Severe fluid retention  oedema
Sumitriptan / 5HT1D receptor Agonist for Vasoconstriction / Vasoconstriction of large arteries & inhibits trigeminal nerve transmission / Migraine attacks / Contraindicated in pts with coronary disease as it also causes coronary vasoconstriction
Anti-coagulants, Fibrinolytics & Anti-platelet drugs
Warfarin / Anticoagulant / Prevents the activation of vitamin K (an important co-factor in the synthesis of a number of clotting factors (II, VII, IX & X) /

Oral, absorbed quickly from GI tract
Binds strongly to plasma proteins (slow turnover of clotting factors)
Metabolised by hepatic mixed function cyt P450

Haemorrhage (especially into the brain or bowel
Teratogenicity (not given to pregnant mothers)
Reversal of effects: vitamin K or prothrombin
Interactions with drugs e.g. drugs which inhibit cyt P450: (will increase plasma conc of warfarin)

Heparin/
LMWH / Anticoagulant / Activates anti-thrombin III which inhibits factor Xa & thrombin by binding to the active serine sites /

Poorly absorbed after oral administration, therefore given either subcut. or intravenously
Short half-life so immediate effect

Bleeding
Thrombocytopenia
Osteoporosis
Hypersensitivity
Chills, fever, urticaria, anaphylaxis
Reversal of effects: stop heparin

Aspirin / Anti-platelets /

Irreversibly inhibits COX-1
Inhibits the production Of TXA2 in platelets

Oral
Highly plasma protein bound

/ GI sensitivity
Clopidogrel / Anti-platelets / Pro-drug which inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors /

Oral
Peak plasma conc 4hrs after a dose but inhibitory effect on platelets not seen until after 4 days of regular dosing

Bleeding (GI haemorrhage)
Diarrhoea
Rash

Abciximab / Anti-platelets / Antagonist of the glycoprotein IIb/IIIa receptor / In acute coronary syndromes – used in combination with heparin & aspirin to prevent ischemia in patients with unstable angina /

IV
Binds rapidly to platelets
Cleared with platelets
Effect persists for 24-48hrs

/ Bleeding (may potentially be immunogenic)
Streptokinase / Thrombolytics (fibrinolytics) / Binds to plasminogen  conformational change exposing the active site  plasmin activity  degrades fibrin /

Acute myocardial infarction
Acute thrombotic stroke – within 3hrs
Deep vein thrombosis; pulmonary embolus; acute arterial thromboembolism; local thromboembolism in the anterior chamber of the eye

IV
30-60 min infusion
Rapidly cleared; t1/212-18 mins

/ Bleeding (may potentially be antigenic)
Alteplase / Thrombolytics (fibrinolytics) /

Recombinant tPA
Activates plasmin  degrades fibrin & dissolving the clot

IV
30min infusion
Rapidly cleared; t1/212-18 mins

/ Bleeding
Statins (& Other LDL Lowering Drugs)
Simvastatin / HMG CoA Reductase Inhibitors /

Inhibition of the enzyme leads to ↓ed hepatic cholesterol synthesis
More enzyme tending to restore cholesterol synthesis to normal
Fall in production of cholesterol also induces a compensatory ↑in hepatic LDL receptors which ↑ clearance of cholesterol from the plasma

/ Non-cholesterol effects of statins include:

Increased NO synthesis
Inhibition of free radical release
Reduced number and activity of inflammatory cells
Inhibition of platelet adhesion and aggregation together with reduced blood viscosity

Main Uses: