Pharm Topics But /3 In 1 Big Topic Flashcards
Pharmacodynamic principles. Receptors and subtypes
General description of parasympathetic nervous system from pharmacological point of view (neurotransmitters and receptors
Antihypertensive mode of action of thiazide diuretics and the side effects, osmotic diuretics
Osmotic diuretics:
Mannitol – the prototypical osmotic diuretic – given intravenously:
10–20% solution
Freely filtered in the glomerulus, poorly reabsorbed in tubules. This results in it remaining in the lumen and “holding” water there by osmotic effects.
Mainly in proximal convoluted tubule (PCT)
Also in descending loop of Henle and collecting tubule.
These are all locations where the nephron is penetrable for water.
Minor Na+ excretion.
Used mainly in situations where it’s important to lose water volume without losing Na+:
Prevention of anuria in ARF due to load of pigments (e.g., hemolysis or rhabdomyolysis).
Infections and hemorrhage.
Used to decrease pathologically elevated intracranial or intraocular pressures (since they increase plasma osmolarity, leading to extraction of water from these compartments and an increase in urine output).
Adverse effects:
Pronounced water extraction from IC compartments and expansion of intravascular and interstitial fluid volume. This can result in:
Acute pulmonary edema.
Heart failure.
Common side effects: headaches, nausea, and vomiting.
Dehydration and hypernatremia in cases of overdose.
Dose-response relationships. Efficacy and potency
Directly acting parasympathomimetics
Toxicity:
• Especially organophosphates that are used as pesticides have toxic behavior. Most toxic is parathion that can be rapidly lethal if antidote is not administered rapidly upon exposure (muscarinic antidote is atropine!– no effects on N receptor toxicity). Nicotinic toxicity is treated with regenerating active ChE (pralidoxime)
• DUMBBLESS symptoms (diarrhea, urination, miosis, broncoconstriction, bradicardia, excitation of sk.muscles and CNS, lacrimation, salivation and sweating)
Effects of direct and indirect cholinomimetics on major organ systems:
• CNS o o o Complex stimulatory effects Nicotine: elevates mood, alerts and is addictive Phyostigmine: convulsions and in excessive CC causes coma
• Eye o o
• Heart o o o o Contraction (miosis) of the sphincter muscle of the iris Contraction/cyclospasms of the ciliary muscle to accommodate near vision and facilitate outflow of aqueous humor into the canal of Schlemm SA node – negative chronotropic effects (decreased firing rate) Note: Baroreceptor reflexes are activated due to the lower ! blood pressure; this causes a compensatory sympathetic discharge to the heart that can cause tachycardia Atria – negative ionotropic effects (decrease in contractile force) This causes a decrease in the refractory period! AV node – negative dromotropic effects Decreased conduction velocity which causes an increase in ! the refractory period Ventricles – small negative ionotropic effects
• Blood vessels Dilation via the release of EDRF (endothel.derived relaxing factor) o ! NO and possibly other relaxing substances o Not a direct action of cholinomimetics on the blood vessels
• Bronchio Bronchoconstriction
• GI tract Increase in SM contraction, peristalsis – increased motility o o Decreased in tone, relaxation of sphincter muscles ! Except the gastroesophageal sphincters that contracts
• Urinary bladder o Increased contraction of the detrusor muscle o Relaxation of the bladder trigone and sphincters that causes voiding
• Skeletal muscles o Activation of NM end plates that results in contraction
• Exocrine glands o Increased secretion Thermoregulatory sweating, lacrimation, salivation, ! bronchial secretion and GI gland secretion
Calcium channel blockers
Graded and quantal dose-response relationships. Therapeutic index, therapeutic window
Parasympatholytics
Centrally acting sympathoplegic drugs
Agonists and antagonists. Antagonism on the receptor level
Sympathomimetics
Pharmacology of renin/angiotensin system
o E.g. when ACE inhibitors cannot be tolerated
Used in treatment of hypertension and HF when ACE inhibitors cant be used (e.g. patients that get severe cough or angioedema)
Require once a day dosing
o Losartan differs from the others by undergoing first-pass hepatic metabolism to be converted into an active metabolite •
o Elimination of the drugs is via kidneys and feces Adverse effects are similar to those of ACE inhibitors
No dry cough
o Not used in pregnancy
Antagonism. Non-receptorial antagonism
Non-selective α-adrenoceptor blockers
General description of antiarrhythmic drugs. Vaughan Williams classification
There are more graphs in the note, check!
Class II (Beta-adrenoceptor blockers):
• ↓ SA and AV nodal activity (by blocking the pacemaker current)
• ↓ slope of phase 4
• Act by blocking the effects of catecholamines at the β1-receptors
Decreasing sympathetic activity on the heart
Making the parasympathetic system the predominant system
• Used in:
Prophylaxis post-MI
The negative inotropic effect decreases the O2 demand
Supraventricular tachyarrhythmias
Decrease conduction through the AV node
• Selective:
Acebutolol, esmolol, metaprolol, nebivolol
• Non-selective:
Propanolol, carvedilol, sotalol
Class III (K+-channel blockers):
• ↓ IK by slowing phase 3
• ↑ APD and ERP
• ↑ QT interval
• Prolongs repolarization markedly
• Used when other anti-arrhythmic fail
• Used in:
A-fib, atrial flutter
Ventricular tachycardias
Sotalol, amiodarone
• Toxicity:
Sotalol – torsades de pointes, excessive β-blockade
Ibutilide – torsades de pointes
Amiodarone – pulmonary fibrosis, hepatotoxicity, hypo/hyperthyroidism, corneal deposits, skin deposits (blue/gray) resulting in photodermatitis, neurologic effects, constipation, CV effects such as bradycardia, AV block and CHF
Class I, II, III, IV drugs
Class IV (Ca2+-channel blockers):
• ↓ conduction velocity, ↑ ERP, ↑ PR interval
• ↓ phase 0 and 4
• ↓ SA and AV nodal activity
• Used in: prevention of nodal arrhythmia, rate control in A-fib
• Toxicity: Constipation, flushing, edema, CV effects (CHF, AV block, sinus node depression)
• Verapamil, diltiazem
Control of receptor expression. Receptor diseases and receptors and disease
β-adrenoceptor blockers
Treatment of myocardial ischemia especially the treatment of angina pectoris
Calcium channel blockers:
Several types are used in angina:
• Nifedipine, dihydropyridine, diltiazem, verapamil
Mechanism:
• Blockage of the voltage-gated L-type calcium channels
• Most important channels in cardiac and smooth muscle
• Reduce intracellular calcium concentration and m. contractility
Actions:
• Relax blood vessels (lesser extent – uterus, bronchi and gut)
• Rate and contractility of the heart reduced by diltiazem and verapamil
• Also used to treat AV-nodal arrhythmias
• Nifedipine and dihydropyridines evoke greater vasodilation
• Possible resulting in reflex tachycardia
• All reduce blood pressure and the double products in angina
• Effective prophylactic agents in effort and vasospastic angina
• Very important agents in combo with nitrates when treating severe/unstable angina
Other uses:
• Hypertension, supraventricular tachycardia, migraine, preterm labor, stroke and Reynaud’s phenomenon
Toxicity:
• Constipation, pretibial edema, nausea, flushing, dizziness
• Heart failure, AV blockade, sinus node depression
• Mainly in verapamil
Beta-blockers in angina:
• Beneficial antiangial effects
• Decreased heart rate, cardiac force, blood pressure
• Beneficial and detrimental effects
• Increased heart size, longer ejection period
• Reduce – cardiac work, double product and oxygen demand
• Only used prophylactically for angina
• No value in acute attacks
• Effective in preventing exercise-induced angina
• Ineffective against vasospastic form
• Useful in preventing the compensatory effects of the nitrates (tachycardia and increased cardiac force)
Newer drugs for angina:
• Ranolazine – reduces the late prolonged sodium current in the myocardial cells
• Reduction in cardiac force
• Might alter cardiac metabolism and switch the preference for FA out for glucose
• Moderately effective in prophylaxis of angina
• Ivabradine – experimental drug that inhibits funny current in SA node
• Decreased HR and cardiac work
Desensitization, tachyphylaxys and tolerance
Indirectly acting parasympathomimetics
Drugs used in the treatment of hyperlipidemias
Niacin (nicotinic acid):
• Reduces LDL, cholesterol, triglycerides, and VLDL in addition to often increasing HDL
• In the liver – reduces VLDL synthesis that reduces LDL levels
• In adipose – activates a signaling pathway that reduces hormone-sensitive lipase (HSL) activity and thus decreases plasma FA and TAG
o Consequently reduces LDL formation
• Increased clearance of VLDL by lipoprotein lipase
• Reduces catabolic rate for HDL
• Decreases circulating fibrinogen and increases tissue-plasminogen activator
• Widely used in treatment of hypercholesterolemia, hypertriglyceridemia, and in low levels of HDL
Adverse effects:
• Cutaneous flushing (prevented with aspirin or NSAIDs)
o Probably due to prostaglandins
o Tolerance develops in few days
• Dose-dependent nausea and abdominal problems
• Pruritus and other skin causes
• Moderate increase in liver enzymes
• Severe hepatotoxicity
• Hyperuricemia – 20%
• Impaired carbohydrate tolerance
Fibric acid derivatives (gemfibrozil, fenofibrate):
• Ligands for peroxisome proliferator-activated receptor-alpha (PPAR-α)
o Receptor that regulates transcription of genes involved in lipid metabolism
• Interaction with PPAR-α results in increased synthesis by adipose tissue of lipoprotein lipase
o Enhanced clearance of TAG-rich lipoproteins – endothelial cells
o Stimulation of fatty acid oxidation in liver
• Limits supply of TAG and decreases VLDL synthesis
• Can increase LDL in patients with familial combined hyperlipoproteinemias (increase in VLDL and LDL)
• Used to treat hypertriglyceridemia and are often combined with other cholesterol-lowering drugs for better results on LDL and VLDL
Adverse effects:
• Nausea – very common
• Skin rashes – gemfibrozil
• Decrease in white blood count and hematocrit
• Increased risk of cholesterol gallstones
• In combo with reductase inhibitors, the fibrate increases risk of myopathy
Combination therapy:
• All patients are treated first and foremost with modification of their diet
• Combinations of drugs are often needed to achieve optimal effects
The movement of drugs through biological membranes
Structure-activity relationships demonstrated among sympathomimetics
Drugs used for the treatment of congestive heart failure
Cardiac glycosides – Digoxin:
• No longer considered first-line drugs in heart failure
• Digoxin inhibits Na+/K+ ATPase of the cell membrane
o Results in small increase in IC Na+
o This changes the transport of Ca2+ out of the cell via Na+/Ca2+
o Increased IC Ca2+ increases the contractile force
• Modifies autonomic outflow – influences electrical properties of the heart
• Effects:
o Increased contractility results in increased ejection
o Decreased end-systolic and end-diastolic size
o Increased cardiac output
o Decrease in the compensatory sympathetic and renal responses
o Decreased sympathetic tone – decreased HR, preload, afterload – this permits the heart to function better
o Early cardiac parasympathomimetic responses
o Increased PR interval and flattening of T waves
o Parasympathetic effects on AV and atria can be blocked with atropine – so we don’t slow the firing rate of AV too much (slow ventricular rate compared to atria)
o Shorter QT, inversion of T and ST depression
o Later arrhythmogenic actions
• Toxic responses:
o Increased automaticity (due to increased IC Ca2+)
o Delayed afterdepolarizations
o Extrasystoles, tachycardia, fibrillation in any parts of the heart
o Premature ventricular beats and bigeminy
o Amplified toxicity occurs in hypokalemia, hypomagnesemia and hypercalcemia
o Interactions with other drugs such as quinidine may increase the serum levels of digoxin even more and cause more toxicity and problems
o Also with amiodarone, verapamil, etc.
• Used in chronic heart failure (positive ionotropic agent)
o Reduces symptoms and improves functional status
o Does not prolong life
o More toxic than the previously discussed drugs
o Long half-life that makes them accumulate in the body
o Dosing is very important and proper monitoring!!!!!
• Used in atrial fibrillation but needs to be monitored closely
Symptoms of toxicity:
• Arrhythmias, nausea, vomiting and diarrhea, confusion and hallucinations (rare) and visual or endocrine abnormalities may occur
• Severe/acute intoxication (suicide/accidental) can result in cardiac arrest
• Detoxification is done with:
o Correcting potassium or magnesium problems
o Antiarrhythmic drugs in not so severe cases
o Digoxin antibodies (digibind) are extremely effective and should always be used if other therapies seem to be failing
Distribution of drugs in the body: the apparent volume of distribution (Vd)