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Standard Drug List 2
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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 emptyingExocrine 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
Glaucoma (with prolonged action) Insecticides
Stable & resistant to hydrolysis Sweating; Blurred vision; GI pain; Bradycardia; Hypotension; Respiratory difficulty
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
active site leaving a blocking group
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
Trimetaphan2 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
AtropineBlock 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 gangliaResp – 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 sizeIpratropium Treatment of chronic obstructive lung diseases (e.g. asthma)
Sympathetic Nervous System – Adrenoceptor Agonists – DIRECTLY ACTINGAdrenaline Non-selective α/β Allergic reactions & anaphylactic shock
( sev hypotension & bronchoconstrictn) RoA (Route of Admin) – iv DoA (Duration of Action) – few
CVS effects: Tachycardia; Arrhythmias; Cold extremities; sev
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
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)
mins 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:o α2 adrenoceptor mediated pre-synaptic inhibition of NA releaseo (in brainstem) baroreceptor pathway to ↓ sympathetic outflow
Treats hypertension & migraine
RoA – iv or oral
Isoprenaline
Non-selective β (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
Dobutamineβ1 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 TremorCaution 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
PhentolamineNon-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
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
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
LabetololNon-selective α1/β1
(ratio 4:1 for β1: α1) Hypotension by ↓ peripheral resistance No change in heart rate
Sympathetic Nervous System – False Transmitters
Methyldopa
1. Taken up by NA neurones2. Decarboxylated & hydroxylated to form
false transmitter, α-methyl-NA3. 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
Competitive nAChR antagonist
70 - 80% block
Flaccid paralysis:o Extrinsic eye muscles (double vision)
RoA – i.v. (highly charged) Does not cross bbb or placenta (so
can be used in caesarean section)
Due to ganglion block & histamine release: Hypotension:
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
powerful positive charge)
necessary (all or nothing action)
Graded block = different proportions of fibres blocked
o Small muscles of face, limbs, pharynx
o Respiratory muscles Relaxation of skeletal muscles during
surgical operations esp abdominal muscles (therefore require less anaesthetic so safer)
Permit artificial ventilation
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)
o Ganglion Blockade (¯ TPR)o 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 HeartAtenolol Beta-blocker for
1. NEGATIVE CHRONOTOPE & IONOTROPE
Competitive antagonists for mainly 1 adrenoceptors
reductn in CO, renin
Angina & improves survival post MI Cardiac dysrhythmias Heart failure Thyrotoxicosis
No longer 1st line for hypertension in UK
Do NOT ↓peripheral resistance (PVR) (except partial agonists or
Due to actions on beta1 (& sometimes beta2 receptors):
Bronchoconstriction Cardiac failure & Heart block
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
2. CONTROL or CORRECT DYSRHYTHMIA
release & NA release by symp nerves
Glaucoma Anxiety states Migraine
vasodilatory beta blockers) 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
VerapamilRate-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 ConstipationDiltiazem 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
Slows ventricular rate in atrial fibrillation & relieves symptoms in chronic heart failure
Cardiac Effects:o Cardiac slowing & ↓ed rate of
conductn through the AV node (due
Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Central vagal stimulation ↓ed rate of conduction through the AV node
to central vagal stimulation)o ↑ed force of contractiono Disturbances of rhythm especially:
block of AV conduction & ↑ed ectopic pacemaker activity
IvabradineAntidysrhythmic 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
Dobutamineβ1 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
EnalaprilACE 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 stenosisCaptopril
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
Doxazosinα-adrenoceptor antagonist for CORONARY VASODILATOR
Specific for alpha1 Postural Hypotension
PhenoxybenzamineNon-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
Severe Hypertension Used in combination with a beta-blocker & diuretic
Reflex tachycardia angina, headaches & fluid retention
Lupus syndrome fever, malaise & hepatitis
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Ca2+ channelsMinoxidil 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
IV 30min infusion
Bleeding
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
degrades fibrin & dissolving the clot
Rapidly cleared; t1/212-18 mins
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: Reduce LDL levels & ↓in CHD
(congestive/coronary heart disease) mortality/morbidity
Support treatment in women, elderly & diabetics
Do not work in patients with familial hyperchloesterolamia (who have no LDL receptors)
Doubling the dose of statins only leads to a 6% reduction in LDL
Reduce plasma LDL by 25-35%
Myopathy can occur Contraindication for pregnancy as
cholesterol is essential for normal foetal development
Benzafibrate
Fibrate Act as ligands for the nuclear transcription receptor PPAR-α (peroxisome proliferators-activated receptor alpha) stimulates lipoprotein lipase activity (↑ed hydrolysis)
Produce a moderate decrease in LDL (10%) and moderate increase in HDL (10%) and a marked fall in plasma triglycerides (30%)
First line treatment for people with very high triglyceride levels
Ezetimibe Inhibitors of Intestinal Cholesterol Absorption
Decreases cholesterol by 18% with little change in HDL Needs combination therapy with statins or fibrates
Nicotinic Acid Reduces release of VLDL and so lowers plasma
triglycerides by 30-50% Lowers cholesterol by 10-20% and increases HDL
Number of adverse effects
Colestipol
Anion Exchange Resins Increase the excretion of bile acids more lipids to be converted into bile acids & so ↑ed lipid excretion
Fall in hepatocyte cholesterol concentration ↑ in HMG CoA Reductase & LDL receptors
Adverse effects are confined to the gut as the resins are not absorbed: Bloating Diarrhoea, constipation
NSAIDs (Non-Steroidal Anti-inflammatory Drugs)
Aspirin
Binds irreversibly to cyclo-oxygenase enzymes
Only be reversed by de novo synthesis of new enzyme
Binds 200-fold more avidly to COX-1 than to COX-2
Analgesic, antipyretic & anti-inflammatory actions
Gastric irritation, ulceration, bleeding &, in extreme cases, perforation
Reduced creatinine clearance & possible nephritis
Prolonged bleeding times, due to
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
reduced platelet aggregation Bronchoconstrction in susceptible
individuals
Ibuprofen
Inhibits COX-1/2 REVERSIBLY
Lowers the pain threshold Pyrogenic – stimulates hypothalamic
neurones initiating a rise in body temperature (therefore, NSAIDS reduce raised temperature)
Enhances production of a number of pro-inflammatory cytokines including Th2 cytokines such as IL4 & IL5
Inhibits the production of others including Th1 cytokines such as IFNγ & IL2
Gastric cytoprotection – downregulates HCl secretion – PGE2 stimulates mucus & bicarbonate secretion (which would otherwise gastric ulceration)
PGE2 enhances renal blood flow and therefore GFR
Celecoxib
Selectively inhibits COX-2 Loss of COX-2 physiological function: Regulation of ovulation Regulation of parturition Renal blood flow Regulation of blood pressure Therefore, increases risk of MI
Paracetamol
It is not a NSAIDs Inhibits peroxidation (conversion of PGG2 PGH2
Good analgesic for mild-to-moderate pain Anti-pyretic action
Paracetamol poisoning – andidote is add a compound with –SH groups (i.v. Acetylcysteine or oral methionine)
Irreversible liver failure (overdose): A reactive metabolite of
paracetamol, (N-acetyl-p-benzoquinoneimine) is normally safely conjugated with glutathione
If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes & causes cell death hepatotoxicity
Inflammatory Bowel Disease
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Prednisolone
GLUCOCORTICOIDS Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription
Anti-inflammatory actions of GCs: Reduce influx and activation of pro-
inflammatory cells o Reduce adhesion molecules on
endothelial cells and leukocytes o Reduce synthesis of some chemokines
Reduce production of mediators causing the signs of inflammation by reducing synthesis of:o Some cytokines and their receptors
(such as IL-1 & TNFα)o Proteolytic enzymes (such as elastase)o Enzymes catalysing mediator
synthesis (e.g. cyclo-oxygenase) o Eicosanoids (such as prostaglandins
and leukotrienes) o Nitric oxide
Immunosuppressive actions of GCs: Reduced antigen presentation Reduced production of mediators (e.g. IL-
2, IL-4, IFNg ) resulting in Reduced cell proliferation & clonal
expansion
Osteoporosis Increased risk of Gastric ulceration Suppression of HPA axis Type II diabetes Hypertension Susceptibility to infection Skin thinning, bruising and slow
wound healing Muscle wasting & buffalo hump
Minimising unwanted effects of GCs Start with high dose & taper down Use drug with high therapeutic
index (e.g. fluticasone) Administer topically – fluid or
foam enemas or suppositories Use an oral or topically
administered drug which is degraded locally e.g. budesonide
Fluticasone
Budesonide
Sulfasalazine
AMINO-SALICYLATES ↓ synthesis of
eicosanoids ↓ free radical ↓ cytokines ↓ leukocyte
infiltration No immune-
suppressive effects
Metabolised by colonic flora/liver
Site of Absorption: colon
Mainly used to maintain remission & prevent relapse
Anti-inflammatory
Pharmacokinetics of 5-ASA: Topical delivery (suppositories,
enemas) pH-dependent release capsules
( small intestine) Slow release microspheres (small
and large bowel):o Leads to gradual release of
mesalazine as it travels through the bowel
o 33% released in upper small intestine, remainder in distal ileum and colon
Mesalazine
5-aminosalicylic acid (5-ASA) Metabolised by…? Site of Absorption:
small bowel & colon
Olsalazine
(2 x 5-ASA molecules linked by an azo bond) Metabolised by colonic
flora Site of Absorption:
colonAzathioprine IMMUNO-
SUPPRESSIVE AGENTS
Azathioprine is a pro-drug which is activated in vivo by gut flora to 6-mercaptopurine –
More effective in Crohn’s disease May enable reduction of glucocorticoid
dose or postponement of colostomy May induce remission in some cases of
Bone marrow suppression If administered with drugs which
inhibit xanthine oxidase e.g. allopurinol, a drug used for the
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
interferes with purine biosynthesis
Interferes with DNA synthesis & cell replication
It impairs: Cell-& antibody-
mediated immune responses
Lymphocyte proliferation
Mononuclear cell infiltration
Synthesis of antibodies It enhances – T-cell apoptosis
active disease treatment of gout, 6 –Mercaptopurine levels rise & blood dyscrasias may result
Infliximab
CURATIVE THERAPY – Anti-TNFα
Crohn’s is a Th1-mediated autoimmune response TNFα plays an important role in disease pathogenesis
Anti-TNFa ↓es activation of TNFα receptors in the gut
Production of other cytokines, infiltration & activation of leukocytes is reduced
Also binds to membrane associated TNFα
Mediates complement activation & induces cytolysis of cells expressing TNFα
Promotes apoptosis of activated T cells
Given intravenously Very long half-life (9.5 days) Benefits can last for 30 weeks after a single
infusion Most patients relapse after 8 – 12 weeks Therefore repeat infusion every 8 weeks
4x - 5x increase in incidence of tuberculosis & other infections
Increased risk of septicaemia, therefore can’t be used if abcess
Worsening of heart failure Increased risk of demyelinating disease Increased risk of malignancy Can be immunogenic – therefore given
with azathioprine
Diuretics – drugs that act on the renal tubule to promote the excretion of Na+, Cl- & H2O
Mannitol
Osmotic Diuretic ¯ H2O reabsorption / H2O excretion (Small ↑ in Na+/Cl- loss)
Prevent acute renal failure – H2O excretion
Intra-cranial pressure plasma osmolarity
Intra-ocular pressure plasma osmolarity
Given iv Onset – 0.5hr DoA: 2-3hr Excretion – glomelular filtrate
Water/electrolyte imbalance – Dehydration/Hypernatraemia
ECF volume – Hyponatraemia; (nausea, vomiting, pulmonary oedema)
Acetazolamide Carbonic anhydrase inhibitors
Prevent the reabsorption of HCO3
- and Na+
o H2O reabsorption is therefore reduced
Intra-ocular pressure (glaucoma) Renal stones – Uric Acid Metabolic Alkalosis – HCO3
- loss
Given oral Onset – 0.5hr DoA: 12hr Excretion – tubular secretion
K+ loss – Balance HCO3- in
collecting duct Metabolic acidosis
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
o delivery of HCO3- to
distal tubule K+ loss tubular fluid
osmolarity ¯ H2O reabsorption in the collecting duct
( Na+/ K+/ HCO3- loss)
Furosemide
Loop diuretics Inhibit Na+ and Cl-
reabsorption in ascending limb
tubular fluid osmolarity/ ¯ osmolarity of medullary interstitium = ¯ H2O reabsorption in the collecting duct
Large in urine volume and Na+, Cl- & K+ loss (& Ca2+ & Mg2+ loss)
Acute pulmonary oedema – Heart failure, pulmonary, renal, hepatic, cerebral
Acute renal failure Hypercalcaemia Hyperkalaemia
Given oral Onset – 1hr DoA: 4-6hr Excretion – tubular secretionN.B. 50% unchanged, 50% metabolised
Hypovolaemia & Hypotension K+ loss (Ca2+/Mg2+), Metabolic
Alkalosis
Bendrofluazide
Thiazides Inhibit Na+ and Cl-
reabsorption in early distil tubule
delivery of Na+ to collecting duct activates N+/K+ exchange mechanism ↓es water reabsorption urine volume is increase [ K+ loss ( Na+/K+ exch)]
Moderate in urine volume & Na+, Cl- , K+ & Mg2+ (but reduced loss of Ca)
Cardiac Heart failure Hypertension – initially ¯ blood
volume/long-term = vasodilation Severe resistant oedema Idiopathic hypercalciuria – stone
formation Nephrogenic diabetes insipidus
(paradoxical)
Given oral Onset – 1-2hr DoA: 8-12hr Excretion – tubular secretionN.B. competes with uric acid
K+ loss, Metabolic Alkalosis Diabetes Mellitus – Inhibits insulin
secretion
Spironolactone
Potassium sparing diuretics
Block aldosterone receptors
Block of Na+/K+ exchange– ↑ed Na+ & ↓ed K+ loss
Small ↑in urine
Primary & secondary hyperaldosteronism Given oral Onset – days DoA: canrenone Excretion – glomeular filtrateN.B. competes with uric acid
Hyperkalaemia, Metabolic Acidosis Spironolactone – Gynaecomastia,
Menstrual Disorders, Testicular Atrophy
AmilorideNa channel blockade
With K+ losing diuretics to prevent K+ loss Given oral Onset – 6hr DoA: 24hr
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
volume Excretion – tubular secretionN.B. unchanged with urine
Anti-emetics – treatment for nausea & vomiting
Promethazine
Phenothiazine derivative
Competitive antagonist at histaminergic (type H1), cholinergic (muscarinic, M) & dopaminergic (type D2) receptors: H1> M > D2
Acts centrally (labyrinth, NTS, vomiting centre) to block vomiting centre
Motion sickness Disorders of the labyrinth e.g Meniere’s
disease Hyperemesis gravidarium Pre- & post-operatively (sedative & anti-
muscarinic action are also useful)Other uses: Relief of allergic symptoms Anaphylactic emergency Night sedation; insomnia
Administer orally Onset of action 1-2 hours Maximum effect circa 4 hours Duration of action 24 hours
Dizziness Tinnitus Fatigue Sedation Excitation in excess Convulsions (children more
susceptible) Antimuscarininc side-effects
Metoclopramide
Dopamine receptor antagonist
Order of antagonistic potency: D2 >> H1 >>> Muscarinic receptors
Acts centrally (CTZ) Acts in the GI tracto ↑es smooth muscle
motilityo ↑ed GI emptying
Uraemia (severe renal failure) Radiation sickness Gastrointestinal disorders Cancer chemotherapy (high doses) e.g.
Cisplatin (intractable vomiting)
May be administered orally; rapidly absorbed; extensive first pass metabolism
May also be given i.v. Crosses BBB Crosses placenta
In CNS: Drowsiness; Dizziness; Anxiety Extrapyramidal reactions;
(parkinsonian-like syndrome: rigidity, tremor)
In the endocrine system: Hyperprolactinaemia Galactorrhoea Disorders of menstruation
Hyoscine
Anti-muscarinic Antagonistic: musc. >>>D2 = H1 receptors
Acts centrally (vestibular nuclei, NTS, vomiting centre) to block activation of vomiting centre
Prevention of motion sickness Has little effects once nausea/emesis is
established In operative pre-medication
Can be administered orally (peak effect in 1-2 hours), i.v., transdermally
Drowsiness Dry mouth Cycloplegia Mydriasis Constipation
Ondansetron
5HT3 receptor antagonist
Block transmission in visceral afferents & CTZ
Main use in preventing anticancer drug-induced vomiting, especially cisplatin
Radiotherapy-induced sickness Post-operative nausea & vomiting
Administer orally; well absorbed, excreted in urine
Headache Sensation of flushing and warmth ↑ed large bowel transit time
(constipation)Treatment of Gastric & Duodenal Ulcers
MetronidazoleAntibiotics for treatment of Helicobacter pylori
Active against anaerobic bacteria & protozoa
Used in combination with “triple therapy” 1st Example:
o Metronidazole or amoxycillino Clarithromycino Proton pump inhibitor, PPI
(omeprazole)
Compliance Development of resistance Adverse response to alcohol,
especially with metronidazole (interferes with alcohol metabolism) Amoxycillin
Broad spectrum antibiotic
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
2nd Example:o H2 receptor antagonistso Clarithromycin o Bismuth
Clarithromycin
Macrolide structure – inhibits translocation of bacterial tRNA
Omeprazole
Inhibitors of Gastric Acid secretion
PPIs: Inhibit gastric acid
secretion from the parietal cell by >90%
Irreversible inhibitors of H+/K+ ATPase
Accumulates in cannaliculi of parietal cells & prolongs its DoA (2-3 days)
Component of triple therapy Peptic ulcers resistant to H2 antagonists Reflux oesophagitis
Orally active Administered as enteric coated
slow-release formulations
(rare)
Ranitidine HISTAMINE TYPE 2 (H2) R ANTAGONISTS – inhibit gastric acid secretion
Healing ulcers (although less effective than PPIs)
Orally administered Well absorbed
Rare (relapses likely after withdrawal of treatment)
Cimetidine
Sucralfate
CYTOPROTECTIVE DRUGS – enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer
Polymer containing aluminium hydroxide & sucrose octa-sulphate Acquires a strong negative charge in an acid environment Binds to positively charged groups in large molecules These coat & protect the ulcer, limit H+ diffusion and pepsin
degradation of mucus Increases PG, mucus & HCO3
- secretion & ↓the number of H. pylori
Most of orally administered drug remains in GI
May cause constipation Reduces absorption of some other
drugs (e.g. antibiotics and digoxin)
Bismuth chelate Like sucralfate Used in triple therapy (resistant cases)
Misoprostol
Stable prostaglandin analogue – mimics the action of locally produced PG to maintain the GI mucosal barrier
May be co-prescribed with oral NSAIDs when used chronically NSAIDs block the COX enzyme for PG synthesis from arachidonic acid Therefore, there is a reduction in the natural factors that inhibit gastric
acid secretion & stimulate mucus & HCO3- production
Diarrhoea, abdominal cramps, uterine contractions
Caution in pregnancy
“Ant-acids” Mainly salts of Al3+
& Mg2+
Neutralises acid, ↑ gastric pH, ↓ pepsin activity
Primarlity used in non-ulcer dyspepsia Reducing duodenal ulcer recurrence rates
Treatment of Gastro-Oesophageal Reflux Disease (GORD) – treat with PPIs (drugs of choice) or H2 antagonists (less effective) &c ombine with drugs that increase gastric motility & emptying of the stomach e.g. DA2 receptor antagonists (metoclopramide)Anxiolytics & Sedatives/Hypnotics
Sodium Valporate
Anti-compulsive; Anti-epileptic (very useful in seizures)
Vigabatrin Selective GABA-T inhibitorGABA GABAA receptor
agonistsMuscimol Selective GABAA receptor
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Bicuculline GABAA receptor antagonists
CompetitivePicrotoxin Non-competetive) – blocks flow of Cl- ions
GABA GABAB receptor agonistsBaclofen Muscle relaxant in sp. cord & spasmolytic drug
Phaclofen GABAB receptor antagonistsSaclofen Competitive
Diazepam
Anxioltyics Benzodiazepines Bind to GABAA receptor Cl- influx
hyperpolarisation ↑ frequency of
openings of channels
Long-acting anxiolytic Anti-convulsants Anti-spastics
Administration: Well absorbed P.O. Peak [plasma] = 1hr I.v. versus status epilepticus Distribution: Bind to plasma proteins strongly Highly lipid soluble wide
distributionMetabolism – extensive in the liver: Diazepam – t1/2 = 32hr Oxazepan – t1/2 = 8hrExcretion – urine – glucoronide conjugatesDuration of Action (vary): short/long
Sedation, confusion, ataxia (impaired manual skills)
Potentiate other CNS depressants (alcohol, barbs)
Tolerance (less than BARBs; ‘tissue’ only)
Dependence: withdrawal syndrome similar to BARBs (lessintense) so imp. to withdraw slowly
free [plasma] by e.g. aspirin, heparin
Oxazepam
Long-acting anxiolytic – if there is hepatic impairment
Short-acting sedative/hypnotics
Buspirone 5HT1A agonist Anxiolytic Slow onset of action (days/weeks) Few side-effects
Propranolol Non-selective β-blocker Improves physical symptoms – tachycardia (β1) or tremor (β2)
Temazepam/Clonazepam
Sedatives/Hypnotics
Benzodiazepines (above) Short-acting sedative/hypnotics Anti-convulsants
(see above for Benzodiazepines) Temazepam – t1/2 = 8hr
(see above for Benzodiazepines)
Amobarbitol/Phenobarbitol
Barbiturates Bind to GABAA receptor Cl- influx
hyperpolarisation ↑ duration of openings
of channels
General Anaethetics Anti-convulsants – Phenobarbitol Sedatives/Hypnotics – Amobarbitol
Amobarbitol – t1/2 = 20-25hr Low safety margins: (↓ respiration or overdosing – alkaline dieresis)
Alter natural sleep (¯ REM) Enzyme inducers Potentiate depressants (alcohol) Dependence: withdrawal
syndrome insomnia, anxietyChloral Hydrate Liver conversion trichloroethanol (a BARB) Wide margin of safety – in children & elderly
Antiparkinsonian/NeurolepticsL-DOPA Ant-Parkinson’s
Disease DOPA – precursor to
dopamine, converted to dopamine in brain
DOPA decarboxylase also present in peripheral tissues
Parkinson’s Disease Rigidity – stiffness, limbs feel heavy/weak Bradykinesia – slowness of movement Postural abnormality Pill-rolling rest tremor Difficulty with fine movements –
Acute: Nausea – prevented by Doperidone (peripheral acting antagonist) Hypotension Psychological effects – schizophrenia like syndrome with delusions,
hallucinations, also confusion, disorientation & nightmares Chronic:
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
cause side effects of nausea & vomiting
macrophagia Monotomy of speech & loss of volume of
voice Disorders of posture – flexion of the neck
& trunk Lack of arm swing Loss of balance – lack of righting reflex,
retropulsion Short steps, shuffling gait
Dyskinesias (54%) – abnormal movements, which affect the face & limbs On-off oscilations (64%) – rapid fluctuations in clinical state, where
hypokinesia & rigidity may suddenly worsen
Bromocriptine D2 Receptors Longer DoA of L-DOPA
Common – confusion, dizziness, nausea/vomiting Rare – constipation, headache, dyskinesias, drowsiness & hallucinations
Carbidopa DOPA decarboxylase
inhibitor Combination of L-DOPA
Prevent DOPA decarboxylase for converting DOPA dopamine side-effects (nausea & vomiting)
Tolocapone/Entacapone
COMT Inhibitors Tolocapone = CNS & peripheral Entacapone =peripheralCNS – prevents breakdown of dopamine Peripheral – COMT inhibitors stop 3-OMD formation, ↑ing bioavailability L-DOPA
Deprenyl MAO Inhibitors – selective for MAO-B,
In early stages of the disease or with L-DOPA, ↓ the dose of L-DOPA
Rare – hypotension, nausea/ vomiting, confusion & agitation
Chlorpromazine Schizophrenia – neuroleptics
All mentioned in the drugs table but NO information givenHaloperidol
Sulpiride
Clozapine
Antagonists to D2 receptors
Clozapine shows non-selectivity with D1 or D2
Block other receptors 5-HT
Schizophrenia Positive symptoms – delusions,
hallucinations, thought disorders Negative symptoms – withdrawal,
flattening of emotional responses Drugs tend to treat the positive
symptoms – neuroleptics are D2 antagonists correcting the over activity of dopamine in the mesolimbic system & striatum
No effect on the forebrain where negative symptoms are produced
Anti-emetic effect: Blocking dopamine receptors in the chemoreceptor trigger zone Phenothiazine , effective at controlling vomiting & nausea induced by drugs Many neuroleptics also have blocking action at histamine receptors –
effective at controlling motion sicknessExtrapyramidal side effects – blockade of dopamine receptors in the nigrostriatal system can induce “Parkinson” like side effects dyskinesisDyskinesias:Endocrine Effects: DA is involved in Tuberoinfundibular system – regulated prolactin secretion Neuroleptics increase serum prolactin concentrations which can lead to
breast swelling (men & women) and sometimes lactation in womenBlockade of cholinergic muscarinic receptors – typical peripheral anti-muscarinic side effects e.g. blurring vision, ↑ed intra-ocular pressure, dry mouth, constipation, urinary retention
General Anaesthetics
Propofol
Intravenous G.A. Potentiate GABAA receptor function
Activation ↑ed inhibitory effect of GABAA receptor ↑ed Cl- into other
Has many different subunits: Β3 – suppression of reflex responses α5 – amnesia
Loss of consciousness at low concn – (e.g. isoflurane - 100μM)o Depress excitability of thalamo-
cortical neuronso Influences reticular active
neurons i.e. Reticular Formatn
INHALATION ANAESTHETIC – given for maintenance of anaesthesia Rapidly eliminated Rapidly control of depth of
anaesthesiaEtomidate
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
neurones hyperpolarisation of nerves around their de-activation
Suppressn of reflexes at high concn – (e.g. isoflurane - 300μM)o Depression of reflex pathways
in the sp cord Relief of pain (analgesia) – opioid
(e.g. i.v. fentanyl)o Synaptic transmission in
hippocampus (new memory formation)/amygdala
Muscle relaxation – Neuro-mus blocking drugs (e.g. suxamethonm)
Amnesia – Benzodiazepines (e.g. i.v. midazolam)
Nitrous OxideInhalation G.A. Poteniate GABAA receptor function (and glycine receptors)
Nitric oxide – Reduced NMDA receptor function (altered synaptic function) – least toxic but least potent (for children)
Inhibits nicotinic acetylcholine receptors (altered synaptic function) – for amnesia & relief of pain
Facilitate TREK (background leak) potassium channel opening (reduced neuronal excitability) – slow hyperpolarisation – for suppression of reflex responses
INTRAVENOUS ANAESTHETIC – given for initiation of anaesthesia Fast Induction Less coughing/excitatory
phenomenaHalothane
Enflurane
Local Anaesthetics
Lidocaine
Amide L.A.
N.B.All L.A. have aromatic region; basic amide side chain; ester or amide bond
Bock of voltage-sensitive Na+ channels in sensory neurones
Use dependant – more L.A used more effect
May also influence:oChannel gating – bind
in the inactivated state ↑ed effect
oLowers surface tensn Block nocioceptor –
small diameter fibres & non-myelinated fibres
Are weak bases Infected Tissue: is
acidic ↑ ionisatn less effect of L.A. (cannot cross memb)
Surface Anaesthesia: Spray or powder via mucosal surface – e.g. mouth, eye, brachial tree High concentrations needed for effect – risks systemic toxicity in high concnInfiltration Anaesthesia: Directly into tissues and sensory nerve fibres (subcutaneous) Used in minor surgery (e.g. removal of cysts) Adrenaline co-injection (not in extremities) causes vasoconstriction ↓ diffusion
away from target site – ↑ DoA & ↓ systemic toxicity & ↓ chances of bleedingIV Regional Anaesthesia: IV given distal to pressure cuff to prevent systemic toxicity (used in limb surgery) Systemic toxicity can occur is the pressure cuff is released prematurelyNerve Block Anaesthesia: Injected close to nerve roots – e.g. in dental surgery (slow onset, low dose) Vasoconstriction co-injection can also be givenSpinal Anaesthesia: (intra-thecal) & can be combined with glucose Used in abdominal, pelvic and lower limb surgery (L3-L4) ↓ BP due to blockade of pre-ganglionic sympathetic fibres prolonged headacheEpidural Anaesthesia: No side-effects of before (i.e. no hypotension & headaches) Injected into the fatty tissue of the epidural space to target the spinal roots For painless childbirth, abd, pelvic & lower leg surgery; slower onset & higher dose
CNS: restlessness, confusion, tremorCVS (Na blockade): v.dilation; ↓ bp
CocaineEster L.A. (symp actions)
CNS: euphoria; excitationCVS: ↑ CO; v.constriction; ↑ bp
Anti-ConvulsantsPhenytoin Interaction with
voltage-dependant sodium channels (inhibit firing) – phenytoin,
Partial epilepsy & acts via blockade of voltage gated Na channels
Pharmacokinetics: Half life 12-40+ hrs with large inter-individual variation (one daily dosage) Hepatic metabolism, hydroxylation and conjugation; excretion in the urine Highly protein bound (70-90%), can be displaced Start with low dose and increase with small increments until desired doseDrug Interactions:
Ataxia Dizziness Sedation Hypersensitivity reactions Fever Folate deficiency
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
PropertyLocal Anaesthetic
Lidocaine (amide)
Cocaine (ester)
Absoprtion (mucus
membranes)
GoodUsed mostly for surface anaesthesia& used for all ROA’s
GoodOnly used as a surface anaesthetic
Protein Binding 70% 90%
Metabolism
Hepatic N-dealkylationAmides are slowly
Liver & plasma via non specific esterases
Plasma t1/2 2hrs 1hr
carbamzepine, sodium valporate
Direct/indirect enhancement of GABA mediated transmission (inhibition) – vigabatrin
Interaction with neuronal calcium channels
Blocking receptors for excitatory neuro-transmitters (glutamate mediated)
Aspirin and valoprate displaces Phenytoin from plasma proteins Causes initial increase in anticoagulation followed by decrease with warfarin Oestrogen containing COCP’s (combined oral contraceptive pill) ↓Phenytoin
efficacy P450 enzyme inducer
Depression
Carbamzepine
Partial and secondary generalised seizures by blockade of Na voltage sensitive channels
Pharmacokinetics: Long half life of 36hrs initially decreasing to 20hrs with chronic treatment 3x daily dosing Hepatic oxidation and conjugation Potent enzyme inducer – complex drug interactionsDrug Interactions: Susceptible to auto-induction with metabolism by hepatic enzymes (P450) Macrolide antibiotics (e.g. erythromycin) inhibit metabolism Ca channel blockers (e.g. verapamil) can double carbamezapine levels Phenytoin induces carbamezapine induction
Ataxia Dizziness Sedation Hypersensitivity reactions Depression
Sodium Valporate
(wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels & enhances GABA mediated inhibition
Pharmacokinetics: T1/2 = 9-18hrs Hepatic oxidation and conjugation – not metabolised by P450 Potent hepatic enzyme inhibitorA potent inhibitor of both oxidation and glucornidation
Sever hepatic toxicity –in children Pancreatitis Drowsiness Encephalopathy Tremor Weight gain
VigabatrinEnhancement of GABA mediated transmission – RARELY used
Relatively short half life (6-8h) but duration of action longer Retinopathy
Lamotrigine
(wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels
Pharmacokinetics: 29hr t1/2, 15hrs with enzyme inducing co-medication, 60hrs with valporate co-
administration Hepatic conjugation (no phase I metabolism) – inhibited by valporate 2% risk of hypersensitivity reaction, otherwise well tolderatedDrug Interactions COCP can lower levels by 1/3 Important drug interactions with valporate and other enzyme inducers (e.g.
Phenytoin)
Mostly dose dependant Dizziness Sedation Diplopia Ataxia
Anti-Microbial Drugs – Antibiotics
Sulpha-methoxazole
ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – SULPHONAMIDES
Sulphanilamide is a structural analogue of P-aminobenzoic acid & competes for dihydropteroate, in the synthesis of folate
Bacteriostatic
Give rise to several other drugs e.g. diuretics – thiazides
Readily absorbed in the GI tract and maximum plasma concn is reached within 4-6 hours
Mild/moderate: (do not warrant withdrawal) nausea & vomiting, headache, mental depression.
Severe: (warrant withdrawal) hepatitis, hypersensitivity reactions, bone marrow suppression
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Trimethoprim
ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – FOLATE ANTAGONISTS
Folate is utilised in tetrahydrofolate by the enzyme dihydrofolate reductase as a co-factor in thymidylate synthesis (purines & pyramidines)
Dihydrofolate reductase is more sensitive to drug trimethoprim in bacteria
Urinary & Resp Infections Oral administration – fully absorbed from the GI tract
Widely distributed throughout the tissues and body fluids – high concentrations in the lungs and kidney
Nausea/vomiting & skin rashes
Co-trimoxazole
ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – SEQUENTIAL BLOCKADE (combination of sulphamethoxazole &trimethoprim)
Infections with pneumocystis carinii, which causes pneumonia in patients with AIDS
Two-thirds of each drug is protein bound & about half of each is excreted within 24 hours
Hypersensitivity Reactions
Penicillin
ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OF PEPTIDOGLYCAN – β-LACTAM ANTIBIOTICS
Penicillin is composed of a 6-aminopenillanic acid, which consists of a thiazolidine ring linked to a β-lactam ring
Interfere with the synthesis of the bacterial wall peptidoglycan Inhibis transpeptidation enzyme that cross-links peptide chains
attached to the backbone of the peptidoglycan
RESISTANCE Production of β-lactamases (bacteria) – solution: β-lactamase inhibitors ↓ in permeability of the outer membrane decreasing ability of the
drug to penetrate to the target site. Occurrence of modified penicillin-binding sites
Orally Drugs are widely distributed in the
body fluids, passing into joints, pleural & pericardial cavities, into bile, saliva, milk & across placenta
Lipid insoluble – do not cross bbb unless meninges are inflamed
Renal excretion (tubular secretion)
Hypersensitivity reactions – breakdown products of penicillin combine with host protein and become antigenic (skin rashes & fever acute anaphylactic shock)
Gut bacterial flora resulting in GI tract disturbances
Cefotaxime
ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OF PEPTIDOGLYCAN – CEPHALOSPORINS
(same as penicillin)
RESISTANCE All Gram -ve bacteria have the gene encoding for β-lactamase ↓ed penetration of drug – alterations to outer membrane proteins or
mutations of the binding site proteins
Given parenterally, i.m. or i.v. Widely distributed in the body as
before but can cross the bbb – useful for bacterial meningitis
Excretion is via the kidney (tubular secretion) but some by bile
Hypersensitivity reactions (very similar to penicillin) may be seen
Nephrotoxicity & diarrhoea can occur with oral cephalosprins
Tetracyclin
ANTIBACTERIAL AGENTS AFFECTING BACTERIAL PROTEIN SYNTHESIS
Active transported into bacteria and interrupt protein synthesis
Competition with tRNA for the A binding site
Bacteriostatic, not bactericidal
Used to prevent gram +ve & -ve bacteria
RESISTANCE Development of energy-dependent efflux
mechanisms which transport the tetracycline’s out of the bacterium
Alterations of the target, the bacterial ribosome, can occur)
Orally or parenterally Tetracycline’s chelate metal ions
(e.g. iron) – non-absorbable complex
Wide distribution, entering most fluid compartments
Excretion via the bile & by glomerular filtration in the kidney
GI disturbances (direct irritation and later to modification of the gut flora)
They chelate calcium, tetracycline’s are deposited in growing bones & teeth staining & bone deformities
Chloramphenicol Inhibition of protein Bacteriostatic – Gram -ve and Gram +ve Given orally or parenterally – Depression of the bone marrow
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
synthesis – binds to 50S subunit of the ribosome & inhibits transpeptidation
bacteria
RESISTANCEProduction of chloramphenicol acetyl-transferase (plasmid mediated)
reaches max cocn in 2 hrs Widely distributed in tissues &
body fluids including the CSF 30-50% plasma protein bound its
half life is approximately 2 hours 10% is excreted in the urine, and
remainder is inactivated by liver
pancytopenia New borns ‘grey-baby
syndrome’(vomiting, diarrhoea, flaccidity)
Hypersensititvity rxns GI disturbances – disruptions in
gut flora
Gentamycin
Inhibition of protein synthesis by binding to the 30S subunit of the ribosome alteration in codon:anticodon recognition misreading of the mRNA production of defective bacterial proteins
Effect is bactericidal; enhanced by agents that interfere with cell wall synthesis
Effective against many aerobic Gram -ve and some Gram +ve bacteria – given with penicillin in infections by Streptococcus, Listeria or Pseudomonas aeruginosa
RESISTANCE Inactivation by microbial enzymes, the
genes for which are carried on plasmids Failure of penetration Lack of binding due to mutations that
alter the binding-site on the 30S subunit
Given i.m. or i.v. – bnding to plasma proteins is minimal
The aminoglycosides are polycations & highly polar – not absorbed in the GI tract
They do not enter cells, nor cross the BBB into the CNS (plasma half life 2-3 hours)
Elimination is virtually entirely by glomerular filtration in the kidney
Ototoxicity – progressive damage to and destruction of sensory cells in the cochlea & vestibular organ of ear
Nephrotoxicity – damage to the kidney tubules (can be reversed if the use of the drug is stopped)
Isoniazid
ANTI-MYCOBACTERIAL AGENTS for tuberculosis & leprosy
Limited to mycobacteria – passes freely into mammalian cells & is thus effective against intracellular organisms (evidence suggests that it inhibits the synthesis of mycolicacids, important constituents of the cell wall and peculiar to mycobacteria)
Bacteriostatic
Absorbed from the GI tract or after parenteral injection (widely distributed throughout the tissues & body fluids, including the CSF)
Penetrates well into the necrotic tuberculous lesion Metabolism, involves largely acetylation, depends on genetic factors –
slow/fast
RifampicinBinds & inhibits DNA-dependent RNA polymerase in prokaryotic but not eukaryotic cells
Orally (widely distributed) Excretion – Urine & bile
(enterohepatic cycling)
Infrequent – skin eruptions, fever, GI disturbances
Pyrazinamide
Effective against the intracellular organism in macrophages, since after phagocytosis the organism will be contained in phagolysosomes in which the pH is low
Oral admin (wel absorbed) Widely distributed (meninges) Renal excretion by glomerular
filtration
Arthralgia GI tract upsets; malaise & fever
Anti-Microbial Drugs – Antifungal
Nystatin
Polyene macrolide – no absorption from the mucous membranes of the body or from skin
Binds to memb & interferes with perme and transport functions
Forms a pore in memb creating trans-membrane ion channel
Fungal infections of the skin and GI tract Drugs greater avidity for ergosterol (fungal membrane sterol) than for cholesterol, the main sterol in the plasma membrane in animal cells
Rare – nausea & vomiting
Miconazole Azole group of synthetic antimycotic agents
Azoles block the synthesis of ergosterol (main sterol in the fungal cell membrane, by interacting with the enzyme necessary for the conversion of lanosterol to ergosterol)
I.v. infusion for systemic infections and orally for infections of the GI tract
GI tract disturbances & blood dyscrasias
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Resulting depletion of ergosterol alters fluidity of the membrane and interferes with action of membrane associated enzymes
The overall effect is an inhibition of replication & inhibition of the transformation of candidal yeast cells into hyphae – the invasive and pathogenic form of the parasite
Short plasma half life and needs to be given every 8 hours
Anti-Microbial Drugs – Antiviral
Acyclovir
Guanosine derivative
Acyclovir is converted to monophosphate by thymidine kinase –virus carries out phosphor-ylation
Converted to the triphosphate by host cellthymadine kinases
Acyclovir triphosphate inhibits viral DNA-polymerase, terminating the chain
High specificity for herpes simplex (which cause glandular fever or shingles)
Acyclovir has reproducible effect against cytomegalovirus (CMV) which can cause glandular fever in adults or severe disease e.g. retinis, resulting in blindness in individuals with AIDS
RESISTANCEdue to changes in the viral genes coding for thymidine kinase or DNA ( pneumonia, encephalitis in immunocompromised pts)
Acyclovir triphosphate is fairly rapidly broken down within the host cells by cellular phosphatases
Given orally, i.v and topically The drug is widely distributed,
reaching concentrations in the CSF which are 50% of those in the plasma
It is excreted in the kidneys partly by glomerular filtration and partly by tubular secretion
Local inflammation can occur during i.v. injection
Renal dysfunction has been reported when acyclovir is given i.v.; slow infusion reduces the risk
Zidovudine (azidothymidine,
AZT)
Thymadine analogue
Phosphorylated to triphosphate form competes with triphosphates (essential for formation of proviral DNA by viral reverse transcriptase, viral RNA-dependant DNA polymerase)
Its incorporation into the growing viral DNA strand results in chain termination
In patients with AIDS: reduces the incidence of opportunistic infection; stabilises weight; reverses HIV-associated thrombocytopenia; stabilises HIV associated dementia; reduces viral load
Can prolong life If given to HIV +ve individuals before the onset of AIDS
In HIV +ve mothers it ↓ risk of transmissn of the virus to the foetus by 66%
In subjects accidentally exposed to HIV e.g. hospital worker, rape victims
RESISTANCE(mutations reverse transriptase)
Given orally or i.v. Bio-availability is 60-80 % due to
1st pass metabolism & peak plasma concn occurs at 30 mins
There is little plasma protein binding no drug interactions
Enters mammalian cells by passive diffusion (passes in to the CSF)
Metabolised to inactive glucuronide in the liver, only 20% being excreted in the urine
Anaemia & Neutropaenia
Cytotoxic DrugsCyclo-
phosphamide(mustard gas)
ALKYLATING AGENT
Highly reactive molecules that bind irreversibly to cell macromolecules, notably DNA, RNA and proteins
Covalently bond with nucleophiles Reactive group is a carbonium ion Most are bifunctional Guanine N7 is main target, also N1 & N3 of adenine and N3 of cytosine intra.interchain crosslinks & interfere with transcriptn & replicatn
N.B. immunopharmacology of these drugs
Myelotoxicity - ¯ leukocyte production ¯ resistance to infection
Impaired wound healing Depression of growth (children) Sterility Teratogenicity
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
Loss of hair Nausea and Vomiting
Fast growing cells Inhibit cell division Cell cycle specific drugs: Bone
marrow, GI tract epithelium, Hair & nails, Spermatogonia
Slow growing cells Introduce DNA mutations Cell cycle independent (alkylating
agents) e.g. secondary tumours
MethotrexateANTIMETABOLITE Folate antagonist. Folate essential to synthesise purine nucleotides
(interfere with thymidylate synthesis)
Doxorubicin CYTOTOXIC ANTBIOTICS
Inhibits DNA and RNA synthesis. Mainly through inhibition of topoisomerase II action
Bleomycin Metal-chelating glycopeptide antibiotics that causes fragmentation of DNA chains. It can act on non-dividing cells
Vinca alkaloids (vincristine)
PLANT ALKALOIDS Inhibits mitosis at metaphase by binding to tubulin and inhibiting polymerisation into microtubules prevent spindle formation
Podophyllotoxins (etoposide)
Inhibits DNA synthesis by an action on topo-isomerase II/inhibits mitochondrial function & cell block at G2
Procarbazine MISCELLANEOUS (monoamine oxidase inhibitor) Inhibits DNA/RNA synthesis and interferes with mitosis at interphase
Cisplatin (similar action to alkylating agents) Interacts with DNA causing guanine intrastrand cross-links
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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG
UC
NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG