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Anästhesie (Fach) / Pharmakologie (Lektion)

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• Inotropie steigernd: Adrenaline Noradrenaline Isoprenaline Dopamine Dobutamine Dopexamine (synthetic dopamine-like drug, more specific for dopamine receptors) Phosphodiesterase inhibitors and Other related agents (calcium, digoxin, glucagon).
• Steroide Äquivalenz: These comparisons take no account of mineralocorticoid effects, nor do they take account of variations in duration of action. Prednisolone 5 mg is equivalent to : Cortisone acetate 25 mg (x5) Dexamethasone 750 mcg (x150) Hydrocortisone 20 mg (x4) Methylprednisolone 4 mg 
• Schleifendiuretika (Lasix)      inhibit sodium chloride reabsorption in the ascending loop of Henle. NW: hyperglycaemia, hypokalaemia, Alkalose      
• Catecholamin metabolismus MAO, COMT > Inaktivierung / Konjugation > Glucuronid acid / Ausscheidung im Urin: 3-methoxy-4-hydroxymandelic acid, metanephrine and normethanephrine Clearance in der Lunge Wideraufnahme von NA (80% des NA zum Widergebrauch)
• Baclofen Baclofen is a gamma-aminobutyric acid (GABA) analogue that is often used for treating spasticity resulting from disease or injury to the spinal cord. It can hyperpolarise cells by increasing potassium ion conductance and inhibit calcium ion channels in others. It is rapidly absorbed from the gastrointestinal tract and approximately 80% is excreted unchanged in the urine, which emphasises the need to reduce the dose in renal dysfunction. NW: myalgia. The dose of baclofen should be increased slowly to avoid muscle hypotonia and sedation. It should also be withdrawn slowly to avoid exacerbating the spasticity and precipitating autonomic dysfunction, psychiatric disturbances, hyperthermia and convulsions.
• Ciprofloxacin and norfloxacin Ciprofloxacin is a fluorinated 4-quinolone  (Gyrasehemmer) that is well absorbed orally with a good bioavailability. It has a wide spectrum of activity against Gram negative organisms but has only moderate activity against Gram positive organisms. Most anaerobic organisms are not susceptible. Bacillus anthracis, Pseudomonas aeruginosa. In moderate renal failure a reduction in dose by 50% is required.  GABA antagonist (NW: convulsions)          
• Atracurium   benzyl isoquinolinium ester  pH in Lösung: 3,5 competitive antagonist at the neuromuscular junction preventing acetylcholine from binding Like all non-depolarising muscular blockers it is a highly charged quaternary compound. It is therefore unable to cross the placenta easily can cause histamine release. This is reduced by using the enantiopure cis-atracurium About 60% of atracurium is metabolised by ester hydrolysis by non-specific esterases. 40 % Hofmann elimination to Laudanosin (is pH and temperature dependent)  Azidose und Hypothermie: weniger Hofmann Elimination. Alkalose: mehr. Hingegen Ester Hydrolyse: mehr bei Azidose It should be stored at 2-8°C, but at room temperature its activity only decreases by a few per cent per month. Laudanosine is a metabolite of the neuromuscular-blocking drugs atracurium and cisatracurium with potentially toxic systemic effects. It crosses the blood-brain barrier and may cause excitement and seizure activity. Except for prolonged administration of atracurium in intensive care units, laudanosine accumulation and related toxicity seem unlikely to be achieved in clinical practice.    
• Antibiotika, Penicillin gegen Zellwand grampositiver Erreger. Nur Breitsprektrum-Penicilline haben gewisse Aktivität gegen gramneg. Penicillinresistenz: Pseudomonas aeruginosa, Haemophilus influenzae < 20% Penicillinase: E. coli, Staphylococcus aureus and Enterobacter Sensitiv: N. meningitidis         
• Allopurinol Hemmt das Enzym Xanthinoxidase ( weniger Harnsäurebildung)
• Prodrugs Examples include: Enalapril (to enalaprilat) Diamorphine (to 6-monoatcylmorphine) Codeine (to morphine) Parecoxib (to valdecoxib)
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• extensive hepatic metabolism Ninety five per cent of nifedipine is metabolised by the liver into three inactive metabolites. Etomidate is metabolised by plasma and hepatic esterases. Ketamine undergoes N-demethylation and hydroxylation in the liver.  Diltiazem undergoes hepatic deacetylation and demethylation followed by conjugation into active metabolites. Enalapril is a prodrug which is hydrolysed in the liver to its active form, enalaprilat.
• Remifentanil   synthetisches Anilidopiperidin Derivat. Reiner μ agonist. Vermischt mit 15 mg glycin und Salzsäure zur Pufferung der Lösung auf pH 3. pKa of 7.07. Wirkmax nach 1-3 Minuten. 70% gebunden an Plasmaproteine (2/3 an alpha-1-acid-glycoprotein). Kleines Verteilungvolumen +  clearance: 40 ml/min/kg ergeben eine kurze Wirkng. Initiales Verteilungsvolumen: 100 ml/kg (Blut + gut perfundierte Gewebe). steady-state Verteilungsvolumen: 350 ml/kg (periphere Gewebe). These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight [IBW]). Metabolisiert durch nicht-spezifische Gewebe -Esterasen, unabhängig von Genetik, Nieren- oder Leberfunktion oder Alter.   context-sensitive HWZ: 3-5 Minuten.   Keine Hitaminausschüttng.  
• Carbamazepin Hemmt Na-Kanäle  structurally related to the antidepressant imipramine  Indications: epilepsy, chronic pain conditions (trigeminal neuralgia) Oral absorption is rapid plasma protein binding is approximately 80%. elimination half life: 13 - 17 hours. It is metabolised in the liver to carbamazepine-10,11-epoxide, which is an active metabolite. The metabolite contributes to its anticonvulsant action and neurotoxic side effects, which include Sedation Vertigo Ataxia Diplopia Nausea Vomiting.
• Calcium-Kanal-Blocker  They can be classified in to: Phenylalkylamines - e.g., verapamil (T) Dihydropyridines - e.g., nifedipine, amlodipine (L) Benzothiazepines - e.g., diltiazem. (T+L) L-Typ-Kalzium-Kanäle (long lasting): Vasodilatation T-Typ-Kalzium-K. (transient): neg. inotrop und chronotrop Nifedipine acts by reducing coronary and peripheral arterial tones, reducing peripheral resistance and may cause a reflex tachycardia. Can be given sublingually. May cause a tremor. Verapamil is well absorbed but has a high first-pass metabolism. Its oral bioavailability is only 20%. Nimodipine is a more lipid-soluble analogue of nifedipine and is used in the treatment after subarachnoid haemorrhage to reduce cerebral vasospasm. All calcium channel antagonists can potentiate the effects of non-depolarising muscle relaxants.  
• Muskelrelaxantien, nicht- depolarisierend Einflüsse auf Wirksamkeit   Resistance to non-depolarising muscle relaxants is associated with: Burns Antiepileptic drugs Intracranial lesions Hemiplegia (when neuromuscular function is monitored on the affected side). Long term phenytoin therapy shortens the duration of action of long acting muscle relaxants by 50%. prolonging their duration of action: Hypothermia reduces the metabolism of muscle relaxants  Succi Tricyclic antidepressants (amitriptyline) by closed channel block. Magnesium is a natural calcium antagonist and reduces the release of acetylcholine Lithium causes sodium channel blockade Calcium channel blockers reduce the release of acetylcholine by reducing calcium influx into the cells. Antibiotics such as aminoglycosides, streptomycin, polymyxin and tetracycline may potentiate the non-depolarising neuromuscular blocking agents. Acetylcholinesterase Hypokalaemia causes the resting membrane potential to be more negative, potentiating the effects of muscle relaxants Hypocalziämie Volatile (ausser N2O) Lidocain u.a. Natriumkanalblocker Trimethaphan (Nikotinrezeptor-Antagonist) Schleifendiuretika Azidose und Alkalose   Patients with myasthenia gravis are extremely sensitive to non-depolarising neuromuscular blockade.  
• Antiarrhythmika Vaughan Williams -Klassifikation   Herold 160    Klasse 1 (Membran Stabilisatoren/ Na-Kanalblocker)  inhibit the rapid influx of sodium ions responsible for phase 0 of the action potential, and reduce the rate of phase 4 depolarisation in pacemaker cells.  1a (Ajmalin, Dysopyramid, Procainamid, Chinidin): Dauer des Aktionspotentials verlängert), 1b (Lidocain: Dauer des AP verkürzt) and 1c (Flecainid: Dauer AP unverändert) Group 1a drugs induce a bi-directional block and interrupt re-entry.   Klasse 2 (beta -Blocker )   antagonise the effects of increased sympathetic tone on the heart by depressing (reducing the slope of) phase 4 depolarisation, decreasing the maximum rate of depolarisation (phase 0), and prolonging the duration of the action potential.   Klasse 3: Amiodaron   prolong the duration of the action potential and the relative refractory period.   Klasse 4 (calcium channel antagonists)   modify the plateau phase in non-pacemaker cells and inhibit the rapid depolarisation (phase 0) of pacemaker cells.      
• Anticholinergika: Hyoscine (Scopolamin), Atropin, Glycopyrolat The anticholinergic agents hyoscine, atropine and glycopyrrolate act on muscarinic receptors with little activity at the nicotinic receptors. Hyoscine and atropine are naturally occurring esters. Glycopyrrolate is a synthetic quaternary amine and therefore does not cross the blood brain barrier. Hyoscine has the greatest antisialogogue properties. It may cause central anticholinergic syndrome characterised by hallucinations, excitement and ataxia.
• folic acid metabolism may be affected by... ...Drugs which inhibit dihydrofolate reductase include: Methotrexate Pyrimethamine (Ind: Toxoplasmose) Trimethoprim (+Sulfamethoxazol = Cotrimoxazol (kurz Cotrim)) ....Drugs which interfere with the absorption and storage of folate include: Phenytoin Primidon (Desoxyphenobarbital) Oral contraceptives
• Galaktorrhö Auslöser: Haloperiodol (Dopaminantagonist) cimetidin (H2-Blocker; Magensaftreduktion) Therapie mit central dopamine receptor agonists: Bromocriptine   quinagolide  
• ACE-Hemmer Angiotensin converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II. This leads to decreased aldosterone secretion, causing a natriuresis. In patients with normal kidneys, renal blood flow is increased, but in renal artery stenosis renal perfusion is reduced. Systemic vascular resistance is reduced in patients taking ACE inhibitors, consequently they are often used in the management of hypertension. The dry cough seen with ACE inhibitors is thought to be due to an accumulation of bradykinins.
• Plazentagängig Plazentagängig: Volatile Pethidin Physostigmin (zentral anticholinerg: tertiäres Amin, nicht ionisiert, gut fettlöslich > Plazenta- und Bluthirnschrankengängig) Naloxon Propranolol (lipophilic) ß-blocker which causes neonatal growth retardation, respiratory depression, bradycardia and hypoglycaemia Atropin (tertiary amine, lipid soluble, at a pH 7.4, 1.4% uncharged)    NICHT Plazentagängig ( und nicht bluthirnschranken-gängig) Rocuronium (quaternary amine) glycopyrrolate (quaternary amine) Heparin suxamethonium Factors influencing the rate of diffusion across the placenta: Materno-fetal concentration gradient Molecular weight of drug <600 Da cross by diffusion Degree of ionisation - unionised molecules diffuse more readily Maternal and fetal blood pH Lipid solubility- lipophilic molecules diffuse readily across the placenta Protein binding Placental blood flow. Drugs that do not readily transfer across the placenta: Neuromuscular blocking agents: All possess at least one quaternary ammonium group and are fully ionised. Poorly lipid soluble, non-lipophilic Cross very slowly through sparse aqueous channels Not clinically significant. Glycopyrrolate. Heparin: Has a high molecular weight 1500 Da and is negatively charged. Drugs transferred across placenta: Opioids (morphine, pethidine and fentanyl if > 1 mcg/kg) , benzodiazepines and ephedrine. Local anaesthetics: MW <600 therefore cross by simple diffusion Accumulation in fetus if the fetus is acidotic due to ion trapping Variable binding to alpha-1 acid glycoprotein. The greater the protein binding the less diffusion Protein binding of bupivacaine >lidocaine>prilocaine Transfer to fetus is affected by other factors such as dose, site of administration and use of adjuncts such as epinephrine, atropine, beta blockers.      
• Eliminationskinetik 0. Ordnung Egal, wie viel Substanz im Blut ist- es wird immer gleichviel pro Zeit abgebaut. Beispiele Phenytoin, Phenylbutazon, Ethanol, Aspirin, Warfarin, Heparin, Theophillin, Tolbutamol, Salicylate 1. Ordnung Verstärkte Elemination bei erhöhten Konzentrationen A first order, single compartment elimination model is described by a negative exponential curve. C = C0e−kt Where C is concentration at time t, C0 is concentration at time 0, e is Euler's number, k is the rate constant and t is time. the time constant (τ) is the inverse of the rate constant (k) and after 1 time constant 37% remains. Bsp k = 0.02 s−1 τ = 1/k = 1/0.02 = 50 s Therefore 1 time constant has elapsed after 50 s and 37% remains.
• Betablocker, Kontraindikationen Cave: Vasokonstriktion! Bronchokonstrktion! Raynaud, COPD (rel), Claudicatio
• Dibucaintest Misst die Hemmung der Pseudocholinesteraseaktivität Normal >= 70% Inhibition betroffene Medikamente: Succi, Mivacron Plasmacholinestetase-Mutationen:   heterozygot: 4% -> leicht verlängerte Wirkung bis zu 10 Minuten homozygot: E1a: 0,03%, E1s: 0,001%, E1f: 0,0003%. Relaxierung für einige Stunden.
• Cimetidin histamine H2-receptor antagonist; blocks the action of histamine on the parietal cells. Parietal cells secrete hydrochloric acid into the stomach lumen, which is stimulated by acetylcholine and gastrin. Although parietal cells possess muscarinic (M1) and gastrin receptors, both acetylcholine and gastrin mainly stimulate acid secretion indirectly, by releasing histamine from paracrine cells located close to the parietal cells. The histamine then acts locally on the parietal cells, where activation of H2-receptors results in an increase in intracellular cyclic-AMP and the secretion of acid. Thus cimetidine reduces both intracellular cyclic-AMP levels and acid secretion. Since acetylcholine and gastrin act indirectly by releasing histamine, the effects on acid secretion of both gastrin and vagal stimulation are reduced by H2-receptor antagonists. It is rapidly absorbed orally and it relieves the pain of the peptic ulcer. It binds to cytochrome P-450 and may reduce the hepatic metabolism of theophylline, phenytoin and warfarin. It also has slight anti-androgenic actions and may rarely cause gynaecomastia.
• Dopexamin Dopamin-Derivat Ind: Herzinsuffizienz Agonist an Beta1-, Beta2-, D1- und D2-Rezeptoren Wirkungen   relaxation of vascular smooth muscle in renal, mesenteric, cerebral and coronary arteries (D1 effect)   stimulation of sympathetic pre-junctional receptors decreasing noradrenaline release (mild D2 effect).   inhibits uptake of noradrenaline (strong beta-2 agonist) positive inotrope Increased cardiac output and decreased renal vascular resistance causes an increase in renal blood flow. NW arrhythmias, mild tachycardia, angina, tremor, flushing nausea and vomiting and headache.    
• Hydralazine relaxation of vascular smooth muscle by the inhibition of Ca2+ release from the sarcoplasmic reticulum by inositol trisphosphate. Since it mainly acts on the arterial circulation and selectively inhibits arteriolar tone, postural hypotension does not usually occur. Reflex tachycardia and fluid retention are relatively frequent, but can be modified by the addition of a beta -adrenoceptor antagonist and a diuretic. Ind: hypertensive emergencies and severe hypertension associated with pregnancy. Chronic therapy, particularly with high doses, may produce an immune response that is similar to systemic lupus erythematosis. The metabolism of hydralazine is subject to genetic polymorphism, and ‘slow acetylators' of the drug are more prone to develop this complication.
• Valproat Wirkung increasing brain concentrations of the inhibitory neurotransmitter GABA. Indikationen: petit-mal   grand-mal epilepsy   chronic pain especially trigeminal neuralgia. UEW hepatic dysfunction
• Benzhexol Benzhexol is a muscarinic antagonist which crosses the blood-brain barrier and is used to treat Parkinsons disease.
• Trimetaphan Trimetaphan is a ganglion-blocking drug that blocks nicotinic acetylcholine receptors at autonomic ganglia. It is used as an infusion to produce hypotensive anaesthesia.
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• Uterus-Tonus herabgesetzt durch   Volatile Beta2-Mimetik Nifedipin erhöht durch: Ketamin unverändert durch: Lachgas Spinal- und Epiduralanästhesie Opiate  
• Halbwertszeit und Eliminationshalbwertszeit   Die Eliminationshalbwertszeit bezieht sich nur auf die Elimination der Substanz aus einem Kompartiment des Körpers. Hingegen spricht man von der biologischen Halbwertszeit, wenn die Elimination aus dem gesamten Körper beschrieben werden soll.
• Beta Lactamase, resistente Antibiotika  Flucloxacillin
• Cardioselective (beta 1 > beta 2) beta adrenoreceptor antagonists include   Atenolol Betaxolol Bisoprolol Metoprolol. Sotalol is not cardioselective, but does have an additional class III anti-arrhythmic activity.
• Antagonisten, nicht-kompetetiv Non-competitive antagonists do not bind to the same receptor as agonists but they reduce its effect in some other way. Increasing the agonist concentration will not overcome the antagonist effect. An irreversible competitive antagonist is a receptor antagonist that dissociates from receptors slowly, or not at all. This term is often used instead of non-competitive antagonist. Phenoxybenzamine is a non-competitive antagonist at alpha receptors by the formation of covalent bonds (it is more active at alpha-1 than alpha-2 receptors). Ketamine is a non-competitive antagonist at NMDA receptors.
• Dosierung fettlöslicher Medikamente Lean body weight (LBW) is particularly useful in calculating the dose of highly lipid soluble drugs such as benzodiazepines and barbiturates. Sometimes the formula LBW = IBW + 20% can be used.
• Salbutamol   stimulates membrane bound adenylate cyclase to cause an increase in cAMP.  Its primary action is on β2 receptors > uterine and bronchial smooth muscle relaxation  tachycardia and arrhythmia (β1-Stimulation) hypokalaemia ( stimulating cell membrane Na+/K+ -ATPase pumps) . immediate management of hyperkalaemia.    
• Midazolam Like other benzodiazepines, midazolam acts on GABAA receptors and has anxiolytic, sedative and anticonvulsant properties. It is unique in that its structure is pH dependent. Midazolam has a water soluble, open-ring structure when stored at pH 3.5. At pH above 4, its ring closes and midazolam becomes lipid soluble. It is a weak base with a pKa of 6.5 and is mostly unionised at physiological pH. Midazolam can be given via the intravenous, intramuscular, nasal and oral routes. Its oral bioavailability is 40%. It is metabolised by the CYP450 isoenzyme 3A3/4. Alfentanil is metabolised by the same enzyme and the effects of midazolam may be prolonged.
• Endocarditisprophylaxe: NICE Guidelines 2008 Patients who are at risk of infective endocarditis, specifically: adults and children with certain problems affecting the structure of the heart (such as a replacement heart valve or hypertrophic cardiomyopathy) adults and children who have previously had infective endocarditis (whether or not they have an underlying cardiac problem) people having any of these procedures: - any dental procedure - any obstetric or gynaecological procedure, or childbirth - any procedure on the bladder or urine system - any procedure on the gullet, stomach or intestines - any procedure on the airways, including ear, nose and throat procedures and bronchoscopy (a test used to diagnose some lung problems).    
• Spironolacton synthetisches Steroid mit Aldosteron ähnlicher Struktur. Antagonisiert dessen Wirkung am distalen Tubulus und Sammelrohr. Auch anti-Antrogene Wirkung. 
• Mannitol Mannitol is an osmotic diuretic and works primarily on the proximal convoluted tubule.
• Fludrocortison synthetisches Aldosteron
• Barbituratstruktur Hypnotic activity is introduced into the barbituric acid molecule by the addition of side chains, especially if at least one of them is branched, in position 5. The length of the side chains in the 5 position influences both the potency and the duration of action of the barbituric acid derivatives. Replacing the oxygen atom with a sulphur atom at position 2 of an active barbiturate produces a barbiturate with a more rapid onset and a shorter duration of action; the thiobarbiturates. Methylation of an active barbiturate in position 1 produces a drug such as methohexitone with not only a rapid onset and short duration of action but also an increased incidence of excitatory side effects. The substitution by an aromatic or heterocyclic group at position 5 is often associated with anticonvulsant effects, that is, phenobarbitone.
• Antiepileptische Therapie NICE guidelines: generalised tonic clonic seizures: valproate and lamotrigine as first line treatment choices.  However in a young woman of child-bearing age and sodium valproate can cause neural tube defects in the fetus, especially if on a dose higher than 800 mg per day. Compared to sodium valproate, lamotrigine would be a safer choice. Also lamotrigine is thought not to induce liver enzymes that have a bearing on contraception. NICE guidelines recommend the prescription of 5 mg of folic acid only in women who are considering the possibility of pregnancy and are on an antiepileptic drug. Anticonvulsant drugs, especially sodium valproate, interfere with the intestinal folic acid absorption. A deficiency of folic acid can lead to neural tube defects in the fetus.
• Stark ionisierte Medikamente The mechanism of drug absorption from the intestines is the same as for other epithelial barriers, namely passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecules. Strong bases of pKa 10 or higher are poorly absorbed, as are strong acids of pKa less than 3 because they are fully ionised. (This is why animals killed with curare [a strong base] are safe to eat, because the drug is not absorbed from the animal's intestines). Highly ionised drugs are metabolised and excreted mainly in the liver following both first and second pass metabolism. Lipid soluble drugs cross the placental barrier easily. Once renal filtered, there is minimal reabsorption of ionised drugs. Lipid soluble drugs are highly protein bound.
• Omeprazol Interaktion mit sulphydryl Gruppen der H/K-ATPase HWZ: Eliminations-HWZ: 40 Minuten
• Gynäkomastie Oestrogens or drugs with oestrogen-like activity - digoxin, diethylstilbestrol, phytoestrogens, oestrogen-contaminated food and oestrogen-containing cosmetics. Drugs that enhance oestrogen synthesis: gonadotropins, clomiphene, phenytoin, and exogenous testosterone. Drugs that inhibit testosterone synthesis or action: ketoconazole, metronidazole, alkylating agents, cisplatin, spironolactone, cimetidine, flutamide, finasteride, and etomidate. Drugs that act by unknown mechanisms: isonicotinic acid hydrazide, methyldopa, busulfan, tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, ACE inhibitors, alcohol, marijuana, and heroin.
• Tramal Tramadol opioid activity derives from low affinity binding of the parent compound to µ-opioid receptors and higher affinity binding of the M1 metabolite:  phase I metabolite (N- and O-demethylation ) Mono-O-desmethyl-tramadol (M1). Eighty two per cent of tramadol is excreted unchanged. Tramadol is a centrally acting opioid analgesic (not peripheral). It is a non-selective pure agonist at mu, delta and kappa receptors with a higher affinity for the mu receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Small quantities of tramadol and its metabolites are found in human breast milk.  
• Edrophonium AChE-I. Tensilon-Test für Myastenia gravis wirkt schneller als Neostigmin
• Acetylcholinesterase-Inhibitor The main anticholinesterases or AChE inhibitors are: Quaternary ammonium structure - edrophonium, neostigmine and pyridostigmine Tertiary ammonium or carbamate structure - physostigmine. All the AChE inhibitors can competitively antagonise non-depolarising blockade and have the potential to prolong the refractory period at the sinoatrial and atrioventricular node. The latter pharmacological effect can result in sinus arrest. For this reason edrophonium with a rapid onset time needs atropine (with a similar onset time) and not glycopyrrolate (longer onset time) given concomitantly.

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