Cholinomimetic drugs week 1 Flashcards

Question

Name 3 nootropic drugs. (generic and brand name) Which is most commonly used for the treatment of AD? What are the side effects of these drugs?

Answer 1

Donazepil (aricept) most commonly used Rivastigmine (Excelon) Galantamine (Reminyl) Nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps

Answer 2

Donepezil (Aricept; Most widely used) 1) **Non-competitive, reversible inhibitor** 2) **t1/2 = 60 hours**, producing once a day dosing 3) Typical peripheral side effects with somewhat greater selectivity for CNS AChE (sleep disturbances) 4) **High oral bioavailability** with some first pass metabolism 5) Most of administered dose is **eliminated renally** thus reducing the potential for drug interactions. Renal impairment can lead to significant accumulation. Drugs that are cleared predominantly via the renal route are always preferred and generally considered safer drugs. In the absence of biotransformation in the liver and the need for CYP or non-CYP enzymes, there is a significantly reduced risk for drug interaction or drug-disease interaction (liver disease).

Answer 3

Rivastigmine (Excelon) 1) **Pseudo-irreversible competitive inhibitor** of AChE at active site similar to physostigmine although with a significantly longer duration of action.

Answer 4

Galantamine (Reminyl) 1) **Reversible, low potency** agent with a t1/2 of 5-6 hours requiring multiple dosing (now available as a patch). 2) **Extensively metabolized** 3) **Also acts as a non-competitive nicotinic (Nn) agonist**. a) As a nicotinic agonist, it can activate post- synaptic receptors in brain, which has been shown to have some efficacy against AD. (Nicotine patches have been used, but no significant effects seen).

Answer 5

Memantine (Namenda) is now used in AD management after the Nootropics are no longer effective (generally moderate to severe AD (Stages II and III)). It is a **mild NMDA indirect-acting Glu antagonist**. A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. By binding to the NMDA receptor with a higher affinity than Mg++ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the presynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. Memantine is, in general, well-tolerated. Common adverse drug reactions (≥1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.

Answer 6

SLUDGEM: Salivation, lacrimation, urination, defecation, GI upset, emesis and miosis

Answer 7

Salivation: M3 \> M1 which causes contraction of smooth muscle of the glands and secretion of watery saliva. 1. Vasoactive intestinal peptide (VIP) is co-localized in PANS terminals and released at higher frequencies of stimulation. When released, this co-localized large molecule neurotransmitter **reduces vascular resistance increasing blood flow to the gland and thereby increases saliva production**. Acting through its receptors it also **enhances the post-synaptic signaling of ACh on Acinar cells---\>GI secretions**.

Answer 8

Sjogrens syndrome: **lymphocytic infiltration of exocrine glands, especially lacrimal and salivary** classic triad: Xerophthalmia (abnormal dryness of the conjunctiva and cornea of the eye, with inflammation and ridge formation), xerostomia (dry mouth), arthritis parotid enlargement, increased risk of B-cell lymphoma, dental carries

Answer 9

Physiologically, micturition involves reflexive coordination between the central, autonomic and somatic nervous systems. Brain centers that regulate urination include the pontine micturition center, periaqueductal gray, and the cerebral cortex. The urge to urinate occurs generally when the bladder is filled with 300-400 ccs. Pelvic sensory nerves mediate the reflex, which involves voluntary control of the external sphincter, which also signals PANS reflexive activation to cause contraction of the detrussor, primarily by a M3 mediated action. M2 receptors are most prevalent in the detrusor, but likely function presynaptically to inhibit release of NE from SANS terminals, which through beta receptors, induces relaxation. The trigone is normally contracted and spontaneously active. This activity helps maintain the patency of the ureteral openings while causing closure of the internal urethral sphincter (which is not really a sphincter but behaves as one with parallel smooth muscle fibers). During micturition, this activity is relaxed closing the ureteral openings and opening the internal urethral sphincter. There is a complex interplay between PANS and SANS in regulating bladder function that will be covered later. Thus, cholinomimetics will cause urinary urgency and produce adequate contraction of the detrusor to overcome voluntary control of the external sphincter via a M3 mediation contraction. (Drugs used to manage urinary incontinence will be discussed later).

Answer 10

Defecation: The defecation cycle is very similar to the urination cycle with ANS and voluntary control. Peristaltic contraction waves in the rectum are under PANS control by sacral efferents working through muscarinic M3 receptors and enhance rectal filling creating the sense of fullness and the need to defecate. If intense enough, external sphincter control can be overcome. Often the consequence of muscarinic agonism is watery diarrhea (dysmotility diarrhea). This results from a markedly reduced transit time due to increased peristalsis associated with inadequate absorption and a watery diarrhea. The muscarinic agonists will also increase secretions, which contributes as well.

Answer 11

Emesis: The emesis induced by cholinergic stimulation is a consequence of central pathways. Specific brainstem areas which mediate motion-induced emesis include the **area postrema (AP)** which is also referred to as the **chemoreceptor trigger zone (CTZ), vagal nuclear complex (VNC), reticular formation (RF) at the site of the vomiting center, and the vestibular complex (VC)**. 1. The CTZ itself has muscarinic receptors, but is predominated by DA and 5HT receptors. Stimulation of these cholinergic receptors by direct-acting agonists can induce vomiting, but high dose, extended exposure is needed. 2. The CTZ and vestibular complex project to the medullary vomiting center, which is rich in cholinergic fibers. Both direct and indirect acting cholinergic agonists that enter brain (i.e., are lipid soluble) increase this afferent activity which stimulates the CTZ which then projects to the vomiting center. Stimulation leads to a feeling of motion sickness that is experienced as nausea and eventually vomiting. Cholinergic drugs would induce vomiting if there was differential stimulation of the vestibular apparatus as this structure activates the vomiting center when there is a left-right mismatch, which frequently occurs in motion sickness. Based on this mechanism, motion sickness is effectively treated with an antimuscarinic drug (i.e., scopolamine patches (see next chapter)).

Answer 12

Miosis MIOSIS ACCOMODATION and GLAUCOMA (MAG) 1. Application of ACh acting on M3 receptors in the eye causes muscarinic-induced contraction of the sphincter and ciliary muscle producing miosis and accommodation (cycloplegia or paralysis of accommodation), respectively. These contractions also pull on the trabecular meshwork draining the anterior chamber and thereby reduce intraocular pressure. Again, these responses involve M3 and M2 receptors with M3 mediating the smooth muscle contraction and M2 inhibiting the counteracting SANS effects by reducing NE release. a. pilocarpine (direct M1-M3 agonist) is widely used in the management of glaucoma

Answer 13

Cardiac: Although not part of the SLUDGEM acronym, the effects of PANS activity on the cardiovascular system involve vasodilatation mediated by ACh- induced release of NO (M3 effect) producing transient reductions in blood pressure together with negative chronotropic, inotropic, and dromotropic effects. Many of these effects will be masked by reflexive responses from the baroreceptor, which will be covered in detail in the adrenergic chapters. ## Footnote 1. The vascular bed effects are normally mediated by M3 receptors working indirectly through NO. Although there is no direct PANS innervation, circulating ACh, not affected by butyrylcholinesterase, or by direct-acting agents will produce dilatation leading to transient reductions in BP, which will be compensated for by increased baroreceptor reflex vasoconstriction. a. In vascular disease (e.g., atherosclerosis), M3 mediated NO production is markedly reduced and the overall effect is to produce vasoconstriction. b. In coronary vessels, the same principle is at work, although the effect on vascular tone is less pronounced. 2. ACh, acting through M2 receptors, increases potassium currents in the sinoatrial (SA) and atrioventricular (AV) nodes as well as in atrial (primarily) and, to a lesser extent, ventricular cardiac muscle. ACh reduces the slow inward Calcium current and also reduces the hyperpolarization-activated current. These effects result in: a. a negative chronotropic effect due to reduced SA node activation b. decreased conduction velocity (negative dromotropy) through the AV node. c. negative inotropic effect in the atria d. negative inotropic, albeit mild, in the ventricles.

Answer 14

Respiratory system: M3-mediated effects produce smooth muscle contraction in the bronchial tree. M3-mediated effects also induce secretion of mucosal cells. Combined, these effects can have devastating effects in asthmatic patients. Sweat glands: Eccrine (Merocrine) glands are stimulated by M3 receptors to secrete sweat reducing body temperature by evaporative cooling. These are separate from apocrine glands that secrete a more viscous sweat around hair cells.

Answer 15

Indirect agonists are used instead of direct acting drugs so as to potentiate the effects of normally released ACh creating more normal muscle control.

Answer 16

Pyridostigmine or neostigmine and ambenonium are used. Indirect agonists are used instead of direct acting drugs so as to potentiate the effects of normally released ACh creating more normal muscle control. a. Patients managed with pyridostigmine, (a quaternary compound that does not cross the BBB) can exhibit MG signs due to too little or too much drug. Too little drug symptoms are obvious. However, too much drug produces muscle weakness caused by excessive Nm stimulation producing depolarization blockade. b. Edrophonium (Tensilon and referred to commonly as the Tensilon Test) is a very short acting quaternary AChEI and is diagnostic. If administration improves weakness, the pyridostigmine dose is too low. If weakness increases, the pyridostigmine dose is too high.

Answer 17

AChEIs can be used to produce muscle paralysis secondary to depolarization blockade in surgery although direct-acting Nm agonists like succinylcholine are widely used as well. The AChEIs are also used to reverse curare-like drug NMJ blockade in surgery. (curare: reversible Nm inhibitor). The curare-like drugs are used in surgery to produce complete muscle relaxation, but they often reverse slowly. To facilitate patient recovery, AChEIs are used to re-instate normal muscle tone.

Answer 18

1. False. SLUDGEM-like effects are generally observed in response to AChEIs due to the muscarinic effects, and although AChEIs will also increase nicotinic tone because of their actions at preganglionic sites, the SLUDEGEM effects predominate. 2. CV effects are similar to muscarinic effects with a notable exception. Generally, AChEIs produce increased BP due to vasoconstriction. This is a consequence of the fact that SANS is the predominant tone in vascular beds and there is no direct innervation of vascular beds by PANS fibers. The preganglionic sympathetic effects of AChEIs, will increase ACh in the ganglia which will activate Nn receptors to increase SANS tone and produce vasoconstriction. This preganglionic effect will also cause the release of Epi producing central CNS agitation associated with EPIs anxiogenic effects (mediated by action on peripheral receptors that then transmit signal into the brain).

Answer 19

**Management of Post-operative Urinary retention**: A single dose of bethanechol is commonly used in cases where there is NO OBSTRUCTION. Other drugs including alpha blockers are also used as are sedative hypnotics such as midazolam. **Management of Post-operative (neurogenic) ileus**: Common problem associated with anesthesia and abdominal surgery. Causes are multi-factorial involving effects on the ANS, inflammation, and especially the use of opioid drugs, the constipating effects of which are legend. Neostigmine has been used successfully although other treatments are also used.

Cholinomimetic drugs week 1 Flashcards

(43 cards)